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Index to Consolidated Financial Statements

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As filed with the Securities and Exchange Commission on January 24, 2014

Registration no. 333-193158

UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549



Amendment No. 2
Form F-1
REGISTRATION STATEMENT
UNDER
THE SECURITIES ACT OF 1933



UNIQURE B.V.*
(Exact Name of Registrant as Specified in Its Charter)

N/A
(Translation of Registrant's Name into English)



The Netherlands
(State or Other Jurisdiction of
Incorporation or Organization)
  2834
(Primary Standard Industrial
Classification Code Number)
  Not applicable
(I.R.S. Employer
Identification Number)

Jörn Aldag, Chief Executive Officer
Meibergdreef 61
Amsterdam 1105 BA, the Netherlands; Tel: +31 20 566 7394
(Address, Including ZIP Code, and Telephone Number,
Including Area Code, of Registrant's Principal Executive Offices)



Philip Astley-Sparke, President U.S. Operations
uniQure, Inc.
113 Hartwell Avenue
Lexington, MA 02421
Tel: +31 20 566 7394
(Name, Address, Including ZIP Code, and Telephone Number,
Including Area Code, of Agent for Service)



Copies to:
David E. Redlick, Esq.
Timothy J. Corbett, Esq.
WilmerHale LLP
10 Noble Street
London EC2V 7QJ
United Kingdom
+44 20 7645 2400
  Eric W. Blanchard, Esq.
Brian K. Rosenzweig, Esq.
Covington & Burling LLP
The New York Times Building
620 Eighth Avenue
New York, New York 10018
+1 212 841 1000



Approximate date of commencement of proposed sale to the public: As soon as practicable after this Registration Statement becomes effective.

If any of the securities being registered on this Form are to be offered on a delayed or continuous basis pursuant to Rule 415 under the Securities Act of 1933, check the following box.     o

If this Form is filed to register additional securities for an offering pursuant to Rule 462(b) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.     o

If this Form is a post-effective amendment filed pursuant to Rule 462(c) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.     o

If this Form is a post-effective amendment filed pursuant to Rule 462(d) under the Securities Act, check the following box and list the Securities Act registration statement number of the earlier effective registration statement for the same offering.     o

CALCULATION OF REGISTRATION FEE

 

TITLE OF EACH CLASS OF SECURITIES TO BE REGISTERED
  PROPOSED
MAXIMUM
AGGREGATE OFFERING
PRICE(1)(2)

  AMOUNT OF
REGISTRATION FEE(3)

 

Ordinary shares, par value €0.05 per share

  $79,350,000   $10,221

 

(1)
Estimated solely for the purpose of determining the amount of registration fee in accordance with Rule 457(o) under the Securities Act of 1933.
(2)
Calculated pursuant to Rule 457(o) based on an estimate of the proposed maximum aggregate offering price.
(3)
$9,660 of the registration fee was previously paid.

The Registrant hereby amends this Registration Statement on such date or dates as may be necessary to delay its effective date until the Registrant shall file a further amendment which specifically states that this Registration Statement shall thereafter become effective in accordance with Section 8(a) of the Securities Act of 1933 or until the Registration Statement shall become effective on such date as the Securities and Exchange Commission, acting pursuant to said Section 8(a), may determine.

   

*
We intend to convert the legal form of our company under Dutch law from a private company with limited liability (besloten vennootschap met beperkte aansprakelijkheid) to a public company with limited liability (naamloze vennootschap) and to change our name from uniQure B.V. to uniQure N.V. prior to the consummation of this offering.

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The information contained in this preliminary prospectus is not complete and may be changed. We may not sell these securities until the registration statement filed with the Securities and Exchange Commission is effective. This preliminary prospectus is not an offer to sell these securities and is not soliciting an offer to buy these securities in any jurisdiction where the offer or sale is not permitted.

SUBJECT TO COMPLETION, DATED JANUARY 24, 2014

PRELIMINARY PROSPECTUS

4,600,000 Shares

GRAPHIC

Ordinary Shares

We are offering 4,600,000 ordinary shares. This is our initial public offering, and no public market currently exists for our ordinary shares. We expect the initial public offering price to be between $13.00 and $15.00 per ordinary share. uniQure B.V. is a private company with limited liability (besloten vennootschap met beperkte aansprakelijkheid) incorporated under the laws of the Netherlands. On or prior to completion of this offering, we intend to convert into a public company with limited liability (naamloze vennootschap), and our legal name will be uniQure N.V.

We have applied for listing of our ordinary shares on The NASDAQ Global Market under the symbol "QURE." We are an "emerging growth company" as defined by the Jumpstart Our Business Startups Act of 2012 and, as such, we have elected to comply with certain reduced public company reporting requirements for this prospectus and future filings.

Investing in our ordinary shares involves a high degree of risk. Please read "Risk Factors" beginning on page 15 of this prospectus.

Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or determined if this prospectus is truthful or complete. Any representation to the contrary is a criminal offense.


 
  PER ORDINARY
SHARE
  TOTAL  

Public Offering Price

  $     $    

Underwriting Discounts and Commissions(1)

             

Proceeds to uniQure before Expenses

             

(1)
The underwriters will also be reimbursed for certain expenses incurred in this offering. See "Underwriting" for details.

Certain of our existing investors and their affiliated entities have indicated an interest in purchasing an aggregate of up to approximately $20 million of our ordinary shares in this offering at the initial public offering price. However, because indications of interest are not binding agreements or commitments to purchase, these entities may determine to purchase fewer shares than they indicate an interest in purchasing or not to purchase any shares in this offering. It is also possible that these entities could indicate an interest in purchasing more of our ordinary shares. In addition, the underwriters could determine to sell fewer shares to any of these entities than the entities indicate an interest in purchasing or not to sell any shares to these entities. The underwriters will receive the same underwriting discount on any shares purchased by these entities as they will on any other shares sold to the public in this offering.

Delivery of the ordinary shares is expected to be made on or about                             , 2014. We have granted the underwriters an option for a period of 30 days to purchase an additional 690,000 ordinary shares. If the underwriters exercise their option in full, the total underwriting discounts and commissions payable by us will be $               , and the total proceeds to us, before expenses, will be $               .

Jefferies   Leerink Partners

Piper Jaffray & Co.

   

Prospectus dated                                        , 2014.


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Prospectus Summary

  1

Risk Factors

  15

Special Note Regarding Forward-Looking Statements and Industry Data

  56

Use of Proceeds

  57

Dividend Policy

  58

Capitalization

  59

Dilution

  60

Selected Consolidated Financial Data

  62

Exchange Rate Information

  64

Management's Discussion and Analysis of Financial Condition and Results of Operations

  65

Business

  95

Management

  149

Related Party Transactions

  161

Principal Shareholders

  164

Description of Share Capital

  167

Shares Eligible for Future Sale

  181

Taxation

  182

Underwriting

  191

Notice to Investors

  195

Expenses of the Offering

  198

Legal Matters

  198

Experts

  198

Enforceability of Civil Liabilities

  199

Where You Can Find Additional Information

  200

Index to Consolidated Financial Statements

  F-1



Neither we nor the underwriters have authorized anyone to provide you with any information other than that contained in this prospectus or in any free writing prospectus we may authorize to be delivered or made available to you. We take no responsibility for, and can provide no assurance as to the reliability of, any other information that others may give you. This prospectus may only be used where it is legal to offer and sell our ordinary shares. The information in this prospectus is accurate only as of the date of this prospectus, regardless of the time of delivery of this prospectus or any sale of our ordinary shares. Our business, financial condition, results of operations and prospects may have changed since that date. Neither we nor the underwriters are making an offer of these securities in any jurisdiction where the offer is not permitted.

Through and including                             , 2014 (25 days after the commencement of this offering), all dealers that buy, sell or trade our ordinary shares, whether or not participating in this offering, may be required to deliver a prospectus. This delivery requirement is in addition to the dealers' obligation to deliver a prospectus when acting as underwriters and with respect to their unsold allotments or subscriptions.

For investors outside the United States: Neither we nor the underwriters have done anything that would permit this offering or possession or distribution of this prospectus in any jurisdiction, other than the United States, where action for that purpose is required. Persons outside the United States who come into possession of this prospectus must inform themselves about, and observe any restrictions relating to, the offering of our ordinary shares and the distribution of this prospectus outside the United States.



Unless the context specifically indicates otherwise, references in this prospectus to "uniQure B.V.," "uniQure N.V.," "we," "our," "ours," "us," "our company" or similar terms refer to (1) uniQure B.V., together with its subsidiaries prior to our conversion into a public company with limited liability (naamloze vennootschap), and (2) uniQure N.V., together with its subsidiaries, after giving effect to our conversion into a public company with limited liability (naamloze vennootschap), which is expected to occur immediately prior to the consummation of this offering. The trademarks, trade names and service marks appearing in this prospectus are the property of their respective owners.

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PROSPECTUS SUMMARY

This summary does not contain all of the information you should consider before buying our ordinary shares. You should read the entire prospectus carefully, especially the "Risk Factors" section beginning on page 15, the "Management's Discussion and Analysis of Financial Condition and Results of Operations" section beginning on page 64 and our financial statements and the related notes appearing at the end of this prospectus, before deciding to invest in our ordinary shares.

Overview

We are a leader in the field of gene therapy and have developed the first and currently the only gene therapy product to receive regulatory approval in the European Union. Gene therapy offers the prospect of long-term and potentially curative benefit to patients with genetic or acquired diseases by directing the expression of a therapeutic protein or restoring the expression of a missing protein through a single administration. Our first product, Glybera, was approved by the European Commission in October 2012 under exceptional circumstances for the treatment of a subset of patients with lipoprotein lipase deficiency, or LPLD, a potentially life-threatening, orphan metabolic disease. We expect to launch Glybera commercially in selected European countries in the first half of 2014 through our collaboration with Chiesi Farmaceutici S.p.A., or Chiesi, which we entered into in April 2013. We retain full commercial rights to Glybera in the United States. In August and December 2013, we met with the Food and Drug Administration, or FDA, to discuss the regulatory pathway for Glybera in the United States, and we plan to file an Investigational New Drug application, or IND, with the FDA for Glybera in the first half of 2014.

We are developing a pipeline of additional gene therapies through multiple collaborations that are designed to accelerate the development and commercialization of these programs. We deliver our gene therapies through a delivery system, or vector, based on an engineered, non-replicating version of the adeno-associated virus, or AAV, one of several viruses commonly used as a vector in gene therapy. We develop our gene therapies using our innovative, modular technology platform, which consists of a suite of components that may be applied to multiple gene therapies and includes our proprietary, cost-effective manufacturing process. Our pipeline includes product candidates targeting diseases for which either the efficacy of existing treatments is limited or the administration regimen is burdensome, such as hemophilia B, as well as diseases for which there are currently no treatments, such as Sanfilippo B syndrome. We initially intend to focus on orphan diseases but believe that we will also be able to leverage our technology to develop gene therapies targeting chronic and degenerative diseases that affect larger populations. Through our gene delivery know-how, our proprietary manufacturing process, the state-of-the-art facility we are building out in the United States, and our experience in developing and obtaining regulatory approval for Glybera in the European Union, we believe we will be able to develop and commercialize additional gene therapies more efficiently than our competitors.

Our Gene Therapy Platform

Our gene therapy approach seeks to treat the causes of genetic diseases by enabling patients to effectively express a missing or deficient protein. To accomplish this, Glybera and our product candidates are designed to deliver a functional gene, or transgene, through a delivery system called a vector. Our approach is designed to be modular, in that it may allow us to efficiently develop, manufacture and seek regulatory approval for multiple gene therapies generally using the same principal components. The key components of our gene therapy approach are:

    Therapeutic genes.  We design our gene therapies to deliver into the body's cells a transgene that encodes, or provides the blueprint for the expression of, a therapeutic protein. The transgene is carried in a gene cassette, or DNA sequence that encodes the specific gene, that includes DNA promoters that direct expression in specific tissues. We either develop our own gene cassettes or in-license them, often as part of our collaborations with academic research institutions and biotechnology and pharmaceutical companies. In-licensing gene cassettes provides us access to key

 

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      intellectual property and allows us to build upon our collaborators' scientific expertise and financial investment, as well as their preclinical and, in some cases, clinical development efforts.

    AAV-based vector delivery system.  We deliver the gene cassette to the target tissue using an engineered, non-replicating viral vector delivery system based on AAV, a common virus that affects humans but does not cause disease. We believe that AAV is the vector of choice for most in vivo gene therapy applications, such as ours, in which the functional gene is introduced directly into the patient's body. We use different variants, or serotypes, of AAV, including AAV1, AAV2 and AAV5, each of which selectively targets particular tissues. In the case of diseases for which relatively modest levels of gene expression may result in therapeutic benefit, we expect that we will be able to achieve adequate levels of expression using existing, naturally derived AAV serotypes. In the case of diseases for which higher levels of gene expression may be required for therapeutic benefit, however, we believe we may need access to more potent vectors than are currently available. To complement our internal development efforts in this regard, in January 2014 we entered into a collaboration and license agreement with 4D Molecular Therapeutics, or 4D, a recently formed, private biotechnology company with a team that we believe is a leader in AAV vector discovery and optimization. 4D uses directed evolution techniques, which involve an iterative selection process in which researchers screen libraries of mutant AAV variants to identify those that are expected to have optimal properties for achieving higher levels of gene expression.

    In more than 80 gene therapy clinical studies conducted by us or third parties, AAV-based vectors raised no material safety concerns. AAV-based vectors have also demonstrated sustained expression in target tissue in non-human primates for more than five years. In the hemophilia B Phase I/II clinical trial described below, St. Jude Children's Research Hospital in Memphis, Tennessee, or St. Jude, has reported expression in target tissue in humans for more than three years after a single treatment.

    Administration technologies.  We and our collaborators are developing expertise in utilizing a variety of administration technologies to optimize the introduction of our gene therapy vectors to effectively deliver the transgene into the tissues and organs relevant to the indications we are targeting.

    Scalable, proprietary manufacturing process.  We produce our AAV-based vectors in our own facilities with our proprietary manufacturing process, which uses insect cells and baculoviruses, a common family of viruses found in invertebrates. We believe that our manufacturing facility in Amsterdam, which the European Medicines Agency, or EMA, has approved for clinical and commercial grade production, and our facility near Boston, Massachusetts, which we are currently building out and equipping, will enable us to produce Glybera and other gene therapies cost-effectively at commercial scale.

Our Competitive Strengths

Gene therapy has historically confronted a number of significant challenges, including safety concerns, limited efficacy, lack of commercially viable manufacturing technology and difficulties with effective administration. We believe we have overcome many of these challenges and have established integrated capabilities to support the clinical development and potential commercialization of our gene therapies. We believe that our key competitive strengths are the following:

    A modular approach designed to enable us to develop gene therapies targeting multiple orphan diseases cost-effectively and on relatively short development timelines.  We expect that our modular approach will allow us to use the same building blocks to efficiently develop, manufacture and seek regulatory approval for multiple new gene therapies. In some cases, we believe that the disease-specific gene cassette will be the only component we need to change to target a new disease. As a result, we may be able to reduce the overall preclinical and potentially clinical development activities required to obtain regulatory approval, which may allow us to significantly reduce overall development risk, time and cost.

 

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    Experienced gene therapy research, clinical development and regulatory team.  We are applying the specialized research, clinical development and regulatory expertise we have acquired in developing and obtaining marketing authorization in the European Union for Glybera to develop additional gene therapies and navigate the complex regulatory process for gene therapies in other countries and for other product candidates. We have a team of more than 60 scientists and other experts, including 27 with Ph.D. or M.D. degrees or the foreign equivalent, with extensive experience in AAV-based gene therapy research and development.

    Scalable, proprietary manufacturing process and facilities.  Our manufacturing process, which uses insect cells, is designed to produce higher yields of vectors more cost-effectively and efficiently than the mammalian cell-based approaches that many of our competitors utilize. We hold a non-exclusive license from the NIH for the use of baculoviruses and insect cells in the production of AAV-based vectors and have augmented this licensed technology with patented improvements to the replication process designed to allow us to produce gene therapies at commercial scale. We have begun the build out of our 53,000 square foot manufacturing facility near Boston, Massachusetts, which we believe will be the world's largest dedicated, advanced production facility for AAV-based vectors. We believe that our manufacturing capabilities position us as a partner of choice for academic research institutions and biotechnology and pharmaceutical companies looking to bring AAV-based therapies into larger, late-stage clinical trials that require commercial scale processes.

    Pioneering experience in gene therapy commercialization.  Gene therapy represents a potential shift in the paradigm of medical care, with the commercialization challenges that often accompany a new approach. With our collaborator Chiesi, we are the first to initiate the market roll-out of an approved gene therapy in the European Union, including designing new models for product pricing and reimbursement based on a one-time intervention, expanding key opinion leader relationships, identifying centers of excellence, and developing physician and patient education and patient access programs. We believe our experience with Glybera in the European Union will facilitate our future efforts, subject to obtaining marketing approval, to commercialize Glybera and additional gene therapies in the United States and elsewhere.

Glybera

Glybera is indicated for the treatment of adult patients diagnosed with familial LPLD confirmed by genetic testing and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. We and our collaborator Chiesi are working to launch Glybera commercially in the European Union in the first half of 2014. We and Chiesi are developing a gene therapy pricing and business model for Glybera that is designed to capture the significant value we believe Glybera delivers to patients.

LPLD is a serious, debilitating disease caused by mutations in the lipoprotein lipase, or LPL, gene, resulting in significantly diminished or absent activity of the LPL protein and, as a consequence, severe hypertriglyceridemia. Severe hypertriglyceridemia results in hyper-chylomicronemia, or dramatic and potentially life-threatening increases in the level of fat-carrying particles, called chylomicrons, in the blood after eating. In many cases, LPLD and the associated elevated levels of chylomicrons can cause acute and potentially life-threatening inflammation of the pancreas, known as pancreatitis, thus leading to frequent hospitalizations. Recurrent pancreatitis can lead to chronic abdominal pain, pancreatic insufficiency, which is an inability to properly digest food due to a lack of digestive enzymes made by the pancreas, and diabetes. Prior to Glybera, there was no approved therapy for LPLD. Patients are required to adhere to a strict low-fat diet and to abstain from alcohol. These restrictions, as well as the need for frequent hospitalizations and the constant fear of pancreatitis attacks, have a significant negative impact on the daily activity level of LPLD patients and on their quality of life.

Glybera is designed to restore the LPL enzyme activity required by tissues of the body to clear, or process, the fat-carrying chylomicron particles that are formed in the intestine and transported via the blood to the muscle after a fat-containing meal. The product consists of an engineered copy of the human LPL gene

 

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packaged in a non-replicating AAV1 vector together with promoters that allow tissue-specific gene expression. AAV1 has a particular affinity, or tropism, for muscle cells.

As a basis for approval by the EMA, we conducted three open-label clinical trials in which we administered Glybera to a total of 27 LPLD patients. We also carried out a retrospective review of the clinical case notes for 17 of the 27 patients to determine the impact of Glybera treatment on the frequency and severity of pancreatitis events. In this clinical program, the EMA concluded that Glybera had an acceptable overall safety profile based on a risk-benefit analysis.

In the three clinical studies, we did not observe a statistically significant reduction in triglyceride levels beyond 12 weeks, which was the primary efficacy endpoint; however, in our third clinical trial of Glybera, involving five adult LPLD patients, we observed a consistent and significant improvement in the clearance of newly formed chylomicrons after a meal, which was a secondary endpoint. The graph below depicts the appearance and removal of newly formed chylomicrons in the blood over a 24-hour period after a standardized meal. Patients were observed prior to treatment with Glybera, and at 14 weeks and 52 weeks following treatment. The top line in the graph represents the pretreatment condition and depicts mean levels of newly formed chylomicrons in the five patients prior to treatment with Glybera. We observed a consistent and significant improvement in the appearance and removal of newly formed chylomicrons in the blood in all five patients measured at week 14 after treatment, indicated by the bottom line in the graph, and all three patients measured at week 52 after treatment, indicated by the middle line in the graph.

Appearance and Removal of Newly Formed Chylomicrons Post-Meal

CHART


(1)
Depiction of mean levels of newly formed chylomicrons using a radiolabeled tracer measured by tritium activity (in centimorgans). Participants consumed a standardized meal containing tritium-marked particles, which were measured in newly formed chylomicrons in the 24-hour period after the meal.

The case note review also provided evidence of clinical benefit in the form of a reduction of pancreatitis events and severity of attacks. Although these observations were made in a small number of patients for varying pre-treatment observation periods, and subject to statistical limitations, they suggested that Glybera leads to a clinically relevant reduction of pancreatitis risk in patients with severe or multiple pancreatitis attacks.

Recognizing that LPLD is an orphan condition, the EMA evaluated the totality of available quality, safety and efficacy data in considering our marketing authorization application for Glybera, including reviewing individual patient profiles. On the basis of that review, the EMA concluded that the benefit-risk balance of Glybera is favorable in the treatment of adult patients with familial LPLD diagnosed by genetic testing, with

 

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detectable levels of LPL protein and suffering from severe or multiple pancreatitis episodes despite dietary fat restrictions, and, therefore, recommended granting marketing authorization under exceptional circumstances. Marketing authorization under exceptional circumstances in the European Union is available for products for which the target indications are so rare that comprehensive data on efficacy and safety cannot reasonably be expected to be available prior to commercial launch. Prior to receiving this approval, our initial application for marketing approval for Glybera in the European Union was rejected in June 2011. We requested a re-examination and, following further review, the EMA ultimately considered clinical benefit to be sufficiently established to allow for a positive benefit-risk estimation in an exceptional circumstances setting using a totality of the evidence approach.

To fulfill the key conditions of the approval of Glybera by the EMA, we are required to implement a patient registry prior to commercial launch and to complete an additional, post-approval clinical trial of Glybera, which we intend to commence in the second half of 2014. The principal goal of these programs will be to obtain additional data regarding the safety, efficacy and clinical benefit of Glybera. We also believe that these programs will help us to better define and target the LPLD patient population, as well as to raise awareness of LPLD and of Glybera in the clinician community.

In the European Union, we have been granted orphan drug exclusivity for Glybera for treatment of LPLD until October 2022, subject to the conditions applicable to orphan drug exclusivity. The FDA has also granted orphan drug designation to Glybera for treatment of LPLD.

We met with the FDA in August and December 2013 to discuss the regulatory pathway in the United States for Glybera. In contrast with the European Union, the United States does not have a process to approve marketing of a drug under exceptional circumstances. In our meetings, the FDA advised that it would require data in addition to what we had submitted to obtain marketing approval for Glybera in the European Union. The FDA advised that severe hypertriglyceridemia is currently considered a hallmark of LPLD, and agreed that changes in chylomicron metabolism following a meal may provide data to support the bioactivity of Glybera. However, the FDA also advised that changes in chylomicron metabolism following a meal alone would not be adequate for obtaining marketing approval in the United States at this stage, since it is not yet sufficiently understood how this biological effect translates into clinical meaningfulness. The FDA recommended that we identify the clinical manifestations of LPLD for which Glybera might have the best prospects for demonstrating a meaningful impact in designing an adequate and appropriately controlled trial.

We plan to discuss the details of the EU post-approval trial and patient registry with the FDA, and if applicable to seek to amend the protocols for the post-approval trial and patient registry so that they could also serve as a clinical program with a design that addresses the FDA's requirements. We also plan to file an IND with the FDA for Glybera in the first half of 2014 so that we can include U.S. LPLD patients in the post-approval trial and registry. We believe the patient registry will provide valuable data for the FDA to consider as part of the totality of our U.S. regulatory submissions. Our current expectation, subject to satisfactory completion of regulatory discussions with the FDA, is to have sufficient data from a further clinical trial of Glybera and the patient registry to file a BLA for Glybera with the FDA in 2017. We have begun preliminary preparations for a potential launch in the United States, including commissioning a third party pricing and reimbursement study and have conducted two market research studies directed at key opinion leaders. We have also initiated the development of a diagnostic referral program, engaged in key opinion leader and patient identification efforts and begun networking with key patient organizations in the United States.

 

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Product and Development Pipeline

In addition to Glybera, our development pipeline includes our internal program for hemophilia B, two collaborator-sponsored programs for monogenic diseases, one collaborator-sponsored program for a chronic degenerative disease and several programs in early preclinical development. The following chart provides summary information on the most advanced of these programs:

CHART


(1)
hFIX, GDNF and PBGD transgenes have been exclusively licensed to uniQure.
(2)
The trial commenced in May 2013; gene therapy was produced using mammalian-cell based process.

Below we provide further detail on our most advanced pipeline programs:

Internal program: AMT-060 for hemophilia B.    In collaboration with Chiesi, we are developing AMT-060, a gene therapy for the treatment of hemophilia B, which is a severe blood clotting disorder that can lead to repeated and sometimes life-threatening episodes of external and internal bleeding. The current standard of care for the treatment of hemophilia B is prophylactic protein replacement therapy, requiring frequent intravenous administrations of human Factor IX, or hFIX, often costing approximately $220,000 to $340,000 per patient per year in the United States. We believe that the approximately 60% to 70% of the hemophilia B patient population who have either severe or moderately severe hemophilia would be eligible for treatment with gene therapy.

AMT-060 consists of an AAV5 vector carrying an hFIX transgene that we have exclusively licensed from St. Jude. We are currently conducting pre-IND toxicology animal studies of this product candidate. We plan to file an IND with the FDA and an Investigational Medicinal Product Dossier, or IMPD, with the EMA and then to initiate a Phase I/II, open label, dose escalation clinical trial of this product candidate in the second half of 2014 in 13 to 16 patients in Europe. We expect data from our clinical trial to be available in the second half of 2015.

 

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St. Jude is currently conducting a Phase I/II, open label, dose escalation clinical trial in this indication with a gene therapy consisting of an AAV8 vector carrying the same therapeutic hFIX gene that we are using in AMT-060. In an article published in the New England Journal of Medicine in December 2011 reviewing interim data from six patients in the St. Jude clinical trial, the principal investigators reported that the vector used in the trial consistently led to long-term expression of the hFIX transgene at therapeutic levels in patients with severe hemophilia B, without acute or long-lasting toxicity. We understand from public presentations by the principal investigators for this trial that two additional patients at the highest dose level in this clinical trial have now also demonstrated such long-term expression. We believe that the interim results from this clinical trial constitute proof of concept of the use of this therapeutic gene in treating hemophilia B and may reduce the risks involved in our development of AMT-060.

Collaborator-sponsored programs.    We are also collaborating with third parties that are sponsoring early-stage clinical trials of gene therapy product candidates to which we hold certain rights. We believe that this approach enables us to cost-effectively obtain access to preclinical and early-stage clinical results without expending significant resources of our own. These programs utilize either clinical materials that we have manufactured as part of our collaborations or gene cassettes that we have licensed. We generally have the rights to the data generated in these collaborator-sponsored clinical development programs, but do not control their design or timing. If we decide to progress any of these programs internally, we may need to develop or in-license additional technology. The most advanced of these programs are the following:

    AMT-021 for Acute Intermittent Porphyria.  We and our collaborator Digna Biotech are developing AMT-021 as a gene therapy for acute intermittent porphyria, or AIP, a severe liver disorder. AMT-021 consists of an AAV5 vector carrying a therapeutic porphobilinogen deaminase, or PBGD, gene that we exclusively license from Applied Medical Research Center of the University of Navarra in Spain. Our collaborator Digna Biotech is currently conducting a Phase I clinical trial of AMT-021 in eight patients in Spain. We have manufactured the gene therapy being used in this clinical trial. We understand that, to date, Digna has not observed a reduction in the urinary levels of toxic metabolites in trial participants that might have served as a surrogate marker for efficacy. We understand from Digna Biotech that clinical outcomes data are expected in the second half of 2014. Under an agreement with Digna Biotech, we have an exclusive right to use all preclinical and Phase I clinical trial data from this program.

    AMT-110 for Sanfilippo B Syndrome.  We and our collaborator Institut Pasteur are developing AMT-110 as a gene therapy for Sanfilippo B syndrome, a potentially fatal lysosomal storage disease that results in serious brain degeneration in children. This gene therapy consists of an AAV5 vector carrying a therapeutic a-N-acetylglucosaminidase, or NaGLU, gene. Our collaborator Institut Pasteur is currently conducting a Phase I/II clinical trial of AMT-110 in four patients in France. We have manufactured the gene therapy being used in this clinical trial. We have an agreement in principle with Institut Pasteur to acquire the clinical results and commercial rights under this program following completion of this Phase I/II clinical trial, and are currently in negotiations with Institut Pasteur regarding the terms of a definitive agreement in this regard. We understand from Institut Pasteur that data are expected in the first half of 2015. We believe that if the results of this clinical trial are positive, it will constitute proof of concept of the administration to the brain of a gene therapy for lysosomal storage diseases.

    AAV2/GDNF for Parkinson's Disease.  We and our collaborator the University of California at San Francisco, or UCSF, are developing a gene therapy for Parkinson's disease, a progressive neurodegenerative disorder. UCSF is collaborating with the NIH to conduct a Phase I clinical trial of a gene therapy in this indication consisting of an AAV2 vector carrying a therapeutic gene we have exclusively licensed in the gene therapy field from Amgen, Inc., or Amgen, that expresses a protein called glial cell line-derived neurotrophic factor, or GDNF. This clinical trial is being funded and sponsored by the NIH and will involve 24 patients. UCSF's product candidate has been manufactured by a third party using a mammalian cell-based process. In this clinical trial, the NIH is administering the gene therapy using convection enhanced delivery, which is a process developed by UCSF with the

 

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      goal of achieving more precisely targeted administration than the methods used in earlier approaches, which may result in improved efficacy. We have a license under UCSF's rights to use all preclinical and clinical data from the UCSF program for any future development program. Based on the results of the UCSF program, we may decide to develop an AAV2-based gene therapy containing the GDNF gene manufactured with our insect cell-based manufacturing process.

Potential Additional Pipeline Programs.    We are also conducting early-stage preclinical research into a number of other potential applications of our technologies. Currently these programs focus on utilizing AAV5 in liver and CNS indications. Based on defined criteria for indications that we believe most likely to be well suited to our gene therapy approach, we have prioritized approximately ten additional target diseases. We may seek to develop these programs either independently or with collaborators who are already working in the relevant disease area, including collaborators that may have already conducted pre-clinical or clinical studies.

Our Collaboration with Chiesi

We have entered into two agreements with Chiesi, a family-owned Italian pharmaceutical company with 2012 worldwide revenues of approximately €1.1 billion. One is an agreement for the commercialization of Glybera for LPLD and the second is an agreement for the co-development and commercialization of our hemophilia B program. We have retained full rights in the United States, Canada and Japan under both agreements. We have received €17.0 million in aggregate upfront payments as well as a €14.0 million investment in our ordinary shares. In addition, these agreements provide us with research funding for further development of our hemophilia B product candidate, as well as the potential for commercial milestone payments of up to €42.0 million for Glybera for LPLD.

Under our Glybera commercialization agreement, we will receive payments from Chiesi for the quantities of Glybera we manufacture and supply to them. We are required to pay the cost of goods sold, including royalty and other payments to third parties in connection with the sale of Glybera. Based on our estimates, we anticipate we will retain in the range of 20% to 30% of the net sales of Glybera by Chiesi in the European Union and other countries under our agreement, net of the cost of goods sold, including the royalties and other obligations we owe to third parties. In addition, we are required to repay 20% of the gross amount received from Chiesi related to Glybera sales in repayment of a technical development loan from the Dutch government, which has a current outstanding balance of €5.4 million. Under our hemophilia B co-development agreement, we will also receive payments from Chiesi for any commercial quantities of our hemophilia B product candidate we manufacture and supply to them, if we receive regulatory approval for such product candidate. We estimate that the amount we would retain, net of cost of goods sold, including third party royalties and related amounts, will be between 25% and 35% of the revenues from sales of such product by Chiesi, varying by country of sale.

Our Strategy

Our strategic goal is to transform the paradigm of care for many severe and chronic diseases by moving from the short-term management of symptoms to the potentially curative resolution of the disease through sustained therapeutic gene expression in target tissues. We are building on the capabilities that have enabled us to obtain the first regulatory approval of a gene therapy in the European Union to address a range of diseases for which we believe we can reach the market with a gene therapy ahead of our competitors. We seek to achieve our goal by pursuing the following key objectives:

    Maximize the value of Glybera.  

    Exploit the potential of our gene therapy platform to develop AAV-based gene therapies for additional orphan monogenic diseases and selected chronic degenerative diseases.  

    Leverage our competitive strengths to retain our position as a leading gene therapy company and establish additional collaborations.  

    Continue to invest in our technology platform and expand our modular capabilities.  

 

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Our Corporate Information

Our business was founded in 1998 and was initially operated through our predecessor company, Amsterdam Molecular Therapeutics (AMT) Holding N.V, or AMT. Following the initial rejection of our marketing authorization for Glybera in 2011, we undertook a corporate reorganization, pursuant to which the newly formed uniQure B.V. acquired the entire business and assets of AMT and completed a share-for-share exchange with the shareholders of AMT in the first half of 2012. We intend to re-register as a public limited company in the Netherlands in connection with this offering. Our executive offices are located at Meibergdreef 61, Amsterdam 1105 BA, the Netherlands, and our telephone number is +31 20 566 7394. Our website address is www.uniqure.com. The information contained on, or accessible through, our website is not a part of this prospectus.

Reverse Share Split

Our supervisory board and shareholders have approved a 5-for-1 consolidation of our shares, which will have the effect of a reverse share split, that will be effective prior to the effectiveness of the registration statement of which this prospectus forms a part. We will issue cash in lieu of fractional shares in connection with this reverse split.

All references to ordinary shares, options and warrants, as well as share, per share data and related information have been retroactively adjusted, where applicable, in this prospectus to reflect the reverse share split as if it had occurred at the beginning of the earliest period presented.

Risk Associated with Our Business

Our business is subject to a number of risks of which you should be aware before making an investment decision. These risks are discussed more fully in the "Risk Factors" section of this prospectus. These risks include the following:

    We have a history of operating losses and anticipate that we will continue to incur losses for the foreseeable future. As of September 30, 2013, we had an accumulated deficit of €138.0 million. We will likely need additional funding, and such funding may cause substantial dilution to our shareholders.

    Our financial prospects and ability to generate revenues for the next several years depend heavily on the successful commercialization of Glybera in the European Union in collaboration with our partner Chiesi, and upon our ability to obtain additional marketing approvals and ultimately commercialize Glybera in the United States and other countries, which will not occur for several years, if ever. To obtain marketing approval for Glybera in the United States, we will need to successfully conduct an adequate and appropriately controlled clinical trial, either as part of the EMA-mandated post-approval clinical trial or separately, to obtain data needed to file a BLA for Glybera with the FDA.

    As gene therapies, Glybera and our product candidates are novel technologies and face uncertainty in the regulatory review and approval process. We cannot predict when or if we will obtain marketing approval to commercialize a product candidate, and any approval we may receive may be for a narrower indication than we expect or may be subject to costly post-approval requirements, which could restrict or eliminate the potential commercial success of the product candidate.

    Our product candidates are in early clinical or preclinical development and there is significant risk of failure or delay in these programs. We rely on our collaborators for important aspects of our development program and in many cases we have limited or no control over the design and conduct of the trials our collaborators conduct, or the efforts and resources our collaborators expend.

    The future growth of our business depends in significant part on our ability to enter into in-licenses or acquire rights to new product candidates and technologies, and to enter into additional collaborations in the future. If we are unable to attract collaborators or successfully identify or compete for the rights to new technologies, our prospects for growth could suffer.

 

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    If we fail to obtain or sustain adequate prices and reimbursement for Glybera and other product candidates for which we may receive marketing approval, our ability to market and sell our products would be adversely affected and our financial position would suffer.

    We may be unable to obtain, maintain and protect necessary intellectual property assets, which could harm our ability to compete and impair our business. We are heavily reliant upon licenses of proprietary technology from third parties and these licenses may not provide adequate rights, we may lose or be unable to protect these rights, or we may be unable to acquire additional intellectual property required for our development programs.

    We face substantial competition, and others may discover, develop or commercialize products before or more successfully than we do.

Implications of Being an Emerging Growth Company

We qualify as an "emerging growth company" as defined in the Jumpstart our Business Startups Act of 2012, or the JOBS Act. An emerging growth company may take advantage of specified reduced reporting and other burdens that are otherwise applicable generally to public companies. As an emerging growth company, we are electing to take advantage of the following exemptions:

    providing two years rather than three years of audited financial statements in this prospectus;

    not providing an auditor attestation report on our system of internal control over financial reporting; and

    not complying with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor's report providing additional information about the audit and the financial statements (auditor discussion and analysis).

The JOBS Act permits an "emerging growth company" such as us to take advantage of an extended transition period to comply with new or revised accounting standards applicable to public companies. We are irrevocably electing not to avail ourselves of this extended transition period for complying with new or revised accounting standards and, therefore, we will be subject to the same new or revised accounting standards as other public companies that are not "emerging growth companies."

We may take advantage of these exemptions for up to five years following completion of this offering or such earlier time as we are no longer an emerging growth company. We would cease to be an emerging growth company if we have more than $1.0 billion in annual revenues, have more than $700 million in market value of our ordinary shares held by non-affiliates or issue more than $1.0 billion of non-convertible debt over a three-year period.

 

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THE OFFERING

Ordinary shares offered by us:

  4,600,000 ordinary shares

Ordinary shares to be outstanding immediately after this offering:

 

16,794,906 ordinary shares

Offering price

 

The initial public offering price per ordinary share is expected to be between $13.00 and $15.00.

Listing

 

We have applied for listing of our ordinary shares on the NASDAQ Global Market under the symbol "QURE."

Option to purchase additional shares

 

We have granted to the underwriters an option, which is exercisable within 30 days from the date of this prospectus, to purchase an aggregate of up to an additional 690,000 ordinary shares. See "Underwriting" for more information.

Use of proceeds

 

We currently estimate that we will use the net proceeds from this offering, together with our cash on hand, as follows:

 

to complete the building out and equipping of our manufacturing facility in Lexington, Massachusetts;

 

to support our further clinical development of Glybera, and our application for marketing approval of Glybera and preparation for potential commercial launch in the United States;

 

to fund our share of the costs of our planned Phase I/II clinical trial of AMT-060 in hemophilia B;

 

to advance the development of our other product candidates and research activities, including our collaboration with 4D Molecular Therapeutics;

 

for working capital and for general corporate purposes, including the costs of operating our facilities in Amsterdam and in Lexington, Massachusetts, service on our indebtedness and possibly acquisitions or investments in other businesses, technologies or product candidates.

 

See "Use of Proceeds" for additional information.

Risk factors

 

See "Risk Factors" and other information included in this prospectus for a discussion of risks you should carefully consider before investing in our ordinary shares.

The total number of ordinary shares that will be outstanding immediately after this offering includes:

    an aggregate of 12,194,906 ordinary shares to be outstanding immediately prior to the closing of this offering; and

    4,600,000 ordinary shares to be issued and sold by us in this offering;

and excludes:

    1,691,844 ordinary shares issued under our equity incentive plans issuable upon the exercise of options outstanding as of the date of this prospectus at a weighted average exercise price of €3.90 per share;

    up to 1,531,471 ordinary shares reserved for future issuance under our equity incentive plans immediately following this offering;

 

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    609,744 ordinary shares issuable upon exercise of options granted on January 17, 2014 in connection with our collaboration and license agreement with 4D Molecular Therapeutics, at an exercise price of €0.05 per share; and

    170,802 ordinary shares issuable upon the exercise of warrants outstanding as of the date of this prospectus at an exercise price of €10.10 per share.

Unless otherwise indicated, all information in this prospectus assumes:

    that the underwriters do not exercise their option to purchase an aggregate of up to an additional 690,000 ordinary shares from us;

    our conversion into a public limited company with limited liability (naamloze vennootschap) under the laws of the Netherlands and amendment of our articles of association, which will occur before the completion of this offering;

    the 5-for-1 consolidation of our ordinary shares, which will have the effect of a reverse share split, that will occur prior to the effectiveness of the registration statement of which this prospectus forms a part; and

    the conversion of our class A, class B and class C ordinary shares into an aggregate of 12,194,906 ordinary shares, which will occur at completion of this offering.

Certain of our existing investors and their affiliated entities have indicated an interest in purchasing an aggregate of up to approximately $20 million of our ordinary shares in this offering at the initial public offering price. Assuming an initial public offering price of $14.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, these entities would purchase an aggregate of up to approximately 1,400,000 of the 4,600,000 shares in this offering based on these indications of interest. However, because indications of interest are not binding agreements or commitments to purchase, these entities may determine to purchase fewer shares than they indicate an interest in purchasing or not to purchase any shares in this offering. It is also possible that these entities could indicate an interest in purchasing more of our ordinary shares. In addition, the underwriters could determine to sell fewer shares to any of these entities than the entities indicate an interest in purchasing or not to sell any shares to these entities.

 

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SUMMARY CONSOLIDATED FINANCIAL DATA

The following summary consolidated financial data as of and for the years ended December 31, 2011 and 2012 have been derived from our audited consolidated financial statements included elsewhere in this prospectus. The following summary consolidated financial data as of and for the nine months ended September 30, 2012 and 2013 have been derived from our unaudited consolidated financial statements included elsewhere in this prospectus. The unaudited financial statements have been prepared on the same basis as the audited financial statements and, in the opinion of management, reflect all adjustments, which include only normal recurring adjustments, necessary to state fairly our financial position as of September 30, 2013 and the results of operations for the nine months ended September 30, 2012 and 2013. The summary consolidated financial data below should be read together with those consolidated financial statements as well as the "Selected Consolidated Financial Data" and the "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of this prospectus. Our historical results for any prior period are not necessarily indicative of results to be expected in any future period, and our interim period results are not necessarily indicative of results to be expected for a full year or any other interim period.

Consolidated Statements of Comprehensive Income Data:


 
  YEAR ENDED
DECEMBER 31,
  NINE MONTHS ENDED
SEPTEMBER 30,
 
€ in thousands (except per share data)
  2011   2012   2012   2013  

Revenues:

                         

License revenues

        220  

Collaboration revenues

                1,831  
                   

Total revenues

                2,051  
                   

Cost of goods sold

                (800 )
                   

Gross profit

                1,251  
                   

Other income

  2,192   649   315   686  

Research and development expenses

    (15,500 )   (10,231 )   (5,690 )   (9,856 )

Selling, general and administrative expenses

    (3,807 )   (4,564 )   (4,438 )   (7,612 )

Other losses, net

    (26 )   (45 )   (82 )   (269 )
                   

Operating result

    (17,141 )   (14,191 )   (9,895 )   (15,800 )

Finance income

    277     22     16     48  

Finance expense

    (436 )   (547 )   (545 )   (4,676 )
                   

Net loss

  (17,300 ) (14,716 ) (10,424 ) (20,428 )
                   

Basic and diluted loss per share(1)

 

(3.65

)


(1.70

)


(1.25

)


(1.95

)

Weighted average shares outstanding used in computing per share amounts (in thousands):(1)

                         

Basic and diluted

    4,709     8,637     8,431     10,594  

(1)
As noted above, all share, per share and related information has been retroactively adjusted, where applicable, to reflect the impact of the 5-for-1 consolidation of our shares, which will have the effect of a reverse share split, that will be effective prior to the effectiveness of the registration statement of which this prospectus forms a part.

 

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The following table summarizes our balance sheet data as of September 30, 2013:

    on an actual basis; and

    on an as adjusted basis to give effect to the sale of 4,600,000 ordinary shares by us in this offering, assuming an initial public offering price of $14.00 per ordinary share share, the midpoint of the price range set forth on the cover page of this prospectus, and after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us and the application of such net proceeds as described under "Use of Proceeds."

Consolidated Balance Sheet Data:


 
  AS OF SEPTEMBER 30, 2013  
(€ in thousands)
  ACTUAL   AS ADJUSTED(1)  

Cash and cash equivalents

  31,427   73,785  

Total assets

    43,671     86,029  

Total debt

    8,456     8,456  

Accumulated deficit

    (137,656 )   (138,953 )

Total shareholders' equity (deficit)

    11,321     53,679  

(1)
Each $1.00 increase or decrease in the assumed initial public offering price of $14.00 per ordinary share would increase or decrease, respectively, the amount of cash and cash equivalents, working capital, total assets and total shareholders' equity by $4.3 million, assuming the number of ordinary shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting the underwriting discounts and commissions and estimated offering expenses payable by us. We may also increase or decrease the number of ordinary shares we are offering. An increase or decrease of 1,000,000 in the number of ordinary shares we are offering would increase or decrease, respectively, the amount of cash, cash equivalents and short-term investments, working capital, total assets and shareholders' equity by approximately $13.0 million, assuming the assumed initial public offering price per ordinary share, as set forth on the cover page of this prospectus, remains the same. The as adjusted information is illustrative only, and we will adjust this information based on the actual initial public offering price and other terms of this offering determined at pricing.

 

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RISK FACTORS

Investing in our ordinary shares involves a high degree of risk. You should carefully consider the risks and uncertainties described below together with all of the other information contained in this prospectus, including our financial statements and the related notes appearing at the end of this prospectus, before deciding to invest in our ordinary shares. If any of the following risks actually occurs, our business, prospects, operating results and financial condition could suffer materially. In such event, the trading price of our ordinary shares could decline and you could lose part or all of your investment.


Risks Related to Our Financial Position and Need for Additional Capital

We have incurred significant losses to date, expect to incur losses over the next several years and may never achieve or maintain profitability.

We have incurred significant losses to date. We had a net loss of €20.4 million in the first nine months of 2013, €14.7 million in 2012 and €17.3 million in 2011. As of September 30, 2013, we had an accumulated deficit of €138.0 million. To date, we have financed our operations primarily through the sale of equity securities and convertible debt and, to a lesser extent, through milestone payments, subsidies and grants from governmental agencies and fees for services. We have devoted substantially all of our financial resources and efforts to research and development, including preclinical studies and clinical trials. Our product, Glybera, received marketing approval under exceptional circumstances from the European Commission in October 2012. We plan in the future to apply for marketing approval for Glybera in the United States and other countries and will be required to conduct one or more additional clinical trials of Glybera. We are still in the early stages of development of the other product candidates in our pipeline. We expect to continue to incur significant expenses and losses over the next several years. Our net losses may fluctuate significantly from quarter to quarter and year to year. We anticipate that our expenses will increase substantially as we:

    complete our EMA-mandated post-approval clinical trial of Glybera and implement an LPLD patient registry;

    conduct a clinical trial of Glybera, either as part of the EMA-mandated post-approval clinical trial or separately, to obtain data needed to file a BLA for Glybera with the FDA;

    seek marketing approval for Glybera in the United States and other countries;

    initiate a Phase I/II clinical trial of AMT-060 for hemophilia B in collaboration with Chiesi;

    advance the preclinical and clinical development of our other product candidates, most of which are at relatively early stages of development, and seek to discover and develop additional product candidates;

    seek marketing approval for any product candidates that successfully complete clinical trials;

    establish a sales, marketing and medical affairs infrastructure in the United States;

    complete the building out and equipping of our manufacturing facility in Lexington, Massachusetts to expand our manufacturing capabilities for Glybera and our pipeline of product candidates;

    fund the ongoing operations of our Lexington facility;

    maintain, expand and protect our intellectual property portfolio, including in-licensing additional intellectual property rights from third parties;

    hire additional personnel, particularly in our manufacturing, research, clinical development, medical affairs, commercial and quality control groups;

    add operational, financial and management information systems and related finance and compliance personnel; and

    operate as a public company.

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We are only in the preliminary stages of most of these activities. We and our collaborators may never succeed in these activities and, even if we do, may never generate revenues that are significant enough to achieve profitability.

Even if we do achieve profitability, we may not be able to sustain or increase profitability. Our failure to become and remain profitable would depress the value of our company and could impair our ability to expand our business, maintain our research and development efforts, diversify our product offerings or even continue our operations. A decline in the value of our company could also cause you to lose part or all of your investment.

Our financial results will substantially depend on the commercial success of sales of Glybera.

We anticipate that our collaborator Chiesi will commercially launch Glybera in the European Union in the first half of 2014 and that revenues from sales of Glybera will be one of the principal sources of funds for our business for at least the next several years. Because our business is currently dependent on Glybera, failure to achieve anticipated revenues from this product would have an adverse effect on our results of operations and cause the value of our ordinary shares to decline. A number of factors, some of which are out of our control, may adversely affect the commercial success of Glybera, including the following:

    our collaborator Chiesi may not successfully commercialize Glybera in the European Union and other specified countries in the Chiesi territory;

    the post-approval requirements imposed by the EMA in connection with Glybera's approval under exceptional circumstances may be costly or may eventually lead to withdrawal of approval;

    we may never be able to obtain marketing approval for Glybera in the United States or other countries;

    Glybera may fail to achieve market acceptance by physicians, patients, third party payors and others in the medical community;

    other alternative treatments for LPLD may be developed and gain commercial acceptance, eroding Glybera's market share;

    the limited label we have received for Glybera in the European Union may limit our addressable market, and other regulatory agencies may approve Glybera only with a similarly limited label;

    we may be unable to establish or maintain sales, marketing and medical affairs capabilities for the commercialization of Glybera in the United States, even if we receive FDA approval; and

    coverage, pricing and reimbursement levels may be lower than we expect.

Even if our commercialization of Glybera or other product candidates for which we obtain marketing approval is successful, we may not be financially successful due to our obligations to third parties.

We have obtained exclusive or non-exclusive rights from third parties under a range of patents and other technology that we are exploiting in Glybera and our development programs. Our agreements with these third parties generally grant us a license to make, use, sell, offer to sell and import products covered by the licensed patent rights in exchange for our payment of some combination of an upfront amount, annual fees, royalties, a portion of amounts we receive from our sublicensees and payments upon the achievement of specified development, regulatory or commercial milestones. For example, we are contractually obligated to pay royalties and other obligations to third parties on net sales of Glybera by us, Chiesi or other sublicensees or on other amounts we receive, including from Chiesi or other sublicensees for their sales of Glybera. We also received a technical development loan from the Dutch government, which requires repayment based on the timing and amount of revenues we receive from the sale of Glybera. These financial obligations to third parties are an expense to us, which could adversely affect our financial position.

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We will likely need to raise additional funding, particularly if we experience delays in implementing our development programs or commercialization efforts. Additional funding may not be available on acceptable terms, or at all, and any failure to obtain capital when needed may force us to delay, limit or terminate our product development efforts or other operations.

We expect to incur significant expenses in connection with our ongoing activities and expect that we will likely need to obtain substantial additional funding in connection with our continuing operations. We have based our estimate of our financing requirements on assumptions that may prove to be wrong, and we could use our capital resources sooner than we currently expect. Our future capital requirements will depend on many factors, including:

    the commercial success of Glybera, including the timing and amount of revenues generated, as well as our cost of goods sold;

    our collaboration agreements remaining in effect and our ability to obtain research and development funding and achieve milestones under these agreements;

    the progress and results of our current and planned clinical trials and those of our collaborators;

    the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our additional product candidates;

    the number and development requirements of other product candidates that we pursue;

    the cost, timing and outcome of regulatory review of our product candidates, particularly for approval of Glybera in the United States;

    the cost and timing of future commercialization activities by us or our collaborators, including product manufacturing, marketing, sales and distribution, for Glybera and any of our product candidates for which we receive marketing approval in the future;

    the amount and timing of revenues, if any, we receive from commercial sales of any product candidates for which we receive marketing approval in the future;

    the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending any intellectual property-related claims;

    the extent to which we acquire or in-license other products or technologies; and

    the cost and progress of the build-out of our Lexington, Massachusetts manufacturing facility.

Adequate capital may not be available to us when needed or may not be available on acceptable terms. Further, our ability to obtain debt financing may be limited by covenants we have made under our Loan and Security Agreement with Hercules Technology Growth Capital, Inc., or Hercules, and our pledge to Hercules of substantially all of our assets as collateral. These covenants, with certain exceptions, limit our ability to incur additional indebtedness and liens, pay dividends, make acquisitions, or sell or dispose of property and assets. Additionally, they require us to maintain cash equivalents on deposit in the United States of at least the lesser of (1) 100% of the then outstanding principal amount or (2) 50% of all the worldwide cash and cash equivalents. If we are unable to raise capital when needed or on attractive terms, we could be forced to delay, reduce or eliminate our research and development programs or any future commercialization efforts, which would have a negative impact on our financial condition.

In addition, we may wish to seek additional capital due to favorable market conditions or strategic considerations, even if we believe we have sufficient funds for our current or future operating plans.

Raising additional capital may cause dilution to our shareholders, including purchasers in this offering, restrict our operations or require us to relinquish rights to our technologies or product candidates.

To the extent that we raise additional capital through the sale of equity or convertible debt securities, your ownership interest will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect your rights as an ordinary shareholder. Debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends.

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If we raise additional funds through collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, products or product candidates or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to develop and market products or product candidates that we would otherwise prefer to develop and market ourselves.

Our existing and any future indebtedness could adversely affect our ability to operate our business.

As of September 30, 2013, we had recognized a liability of €7.3 million ($9.8 million) of outstanding borrowings under our Loan and Security Agreement with Hercules, which we are required to repay in monthly installments through October 1, 2016. We do not intend to use the net proceeds of this offering to prepay these obligations. We could in the future incur additional debt obligations beyond our borrowings from Hercules. Our existing loan obligations, together with other similar obligations that we may incur in the future, could have significant adverse consequences, including:

    requiring us to dedicate a portion of our cash resources to the payment of interest and principal, reducing money available to fund working capital, capital expenditures, product development and other general corporate purposes;

    increasing our vulnerability to adverse changes in general economic, industry and market conditions;

    subjecting us to restrictive covenants that may reduce our ability to take certain corporate actions or obtain further debt or equity financing;

    limiting our flexibility in planning for, or reacting to, changes in our business and the industry in which we compete; and

    placing us at a competitive disadvantage compared to our competitors that have less debt or better debt servicing options.

We may not have sufficient funds, and may be unable to arrange for additional financing, to pay the amounts due under our existing loan obligations. Failure to make payments or comply with other covenants under our existing debt could result in an event of default and acceleration of amounts due. Under our agreement with Hercules, the occurrence of an event that would reasonably be expected to have a material adverse effect on our business, operations, assets or condition is an event of default. If an event of default occurs and the lender accelerates the amounts due, we may not be able to make accelerated payments, and the lender could seek to enforce security interests in the collateral securing such indebtedness, which includes substantially all of our assets. In addition, the covenants under our existing debt, and the pledge of our assets as collateral, could limit our ability to obtain additional debt financing.

Our business operations may be negatively affected by the strategic restructuring we undertook in 2012.

At the end of 2011, following the initial rejection of our application for marketing approval for Glybera in the European Union, our predecessor entity, Amsterdam Molecular Therapeutics, or AMT, initiated a strategic restructuring in order to conserve resources and improve its financial position. As part of this effort, AMT significantly reduced personnel, programs and spending. As a result, we lost many talented employees, including employees with an extensive understanding of our clinical programs as well as our regulatory and financial affairs. In the fourth quarter of 2011, total staff was reduced from 92 to 49. Since that time, we have hired a number of new staff, and total employee headcount as of December 31, 2013 was 87. In addition, we have engaged 33 consultants and contract workers. Nevertheless, this loss of talent and institutional knowledge has adversely affected our operations during the past year and may result in delays in preparing regulatory filings, completing clinical trials and other related activities, and could negatively impact our future business operations.

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Risks Related to the Development of Our Product Candidates

We may not be successful in our efforts to use our gene therapy technology platform to build a pipeline of additional product candidates.

A key element of our strategy is to use our gene therapy technology platform to expand our pipeline of gene therapies and to progress these product candidates through clinical development together with our collaborators. Although we currently have a pipeline of programs at various stages of development, we may not be able to identify or develop product candidates that are safe and effective. Even if we are successful in continuing to build our pipeline, the potential product candidates that we identify may not be suitable for clinical development, including as a result of being shown to have harmful side effects or other characteristics that indicate that they are unlikely to receive marketing approval and achieve market acceptance. Research programs to identify new product candidates require substantial technical, financial and human resources. We or our collaborators may focus our efforts and resources on potential programs or product candidates that ultimately prove to be unsuccessful. If we do not continue to successfully develop and commercialize product candidates based upon our technology, we may face difficulty in obtaining product revenues in future periods, which could result in significant harm to our financial position and adversely affect our share price.

Our strategy of obtaining rights to key technologies through in-licenses may not be successful.

We seek to expand our product pipeline in part by in-licensing the rights to key technologies, including those related to gene delivery and gene cassettes. The future growth of our business will depend in significant part on our ability to in-license or otherwise acquire the rights to additional product candidates or technologies, particularly through our collaborations with academic research institutions. However, we may be unable to in-license or acquire the rights to any such product candidates or technologies from third parties on acceptable terms or at all. The in-licensing and acquisition of these technologies is a competitive area, and a number of more established companies are also pursuing strategies to license or acquire product candidates or technologies that we may consider attractive. These established companies may have a competitive advantage over us due to their size, cash resources and greater clinical development and commercialization capabilities. In addition, companies that perceive us to be a competitor may be unwilling to license rights to us. Furthermore, we may be unable to identify suitable product candidates or technologies within our area of focus. If we are unable to successfully obtain rights to suitable product candidates or technologies, our business, financial condition and prospects could suffer.

We may encounter substantial delays in our clinical trials or fail to demonstrate the safety and efficacy of our product candidates.

Clinical development is expensive, time-consuming and uncertain as to outcome. Our product candidates are in early clinical or preclinical development, and there is a significant risk of failure or delay in each of these programs. In several of our programs, we intend to transition a collaborator's program to a different viral vector or to our insect-cell based manufacturing process, which could result in additional development challenges and delays. We cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, if at all. A failure of one or more clinical trials can occur at any stage of testing. Events that may prevent successful or timely completion of clinical development include:

    delays in reaching a consensus with regulatory agencies on study design;

    delays in reaching agreement on acceptable terms with prospective clinical research organizations, or CROs, and clinical trial sites;

    delays in obtaining required Institutional Review Board, or IRB, approval at each clinical trial site;

    delays in recruiting suitable patients to participate in our clinical trials, particularly due to the rare nature of many of our target orphan monogenic diseases;

    imposition of a clinical hold by regulatory agencies after an inspection of our clinical trial operations or trial sites;

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    failure by CROs, other third parties or us to adhere to clinical trial requirements;

    failure to perform in accordance with the FDA's good clinical practices, or GCP, or applicable regulatory guidelines in other countries;

    delays in the testing, validation, manufacturing and delivery of our product candidates to the clinical sites;

    delays in having patients complete participation in a study or return for post-treatment follow-up;

    clinical trial sites or patients dropping out of a study;

    occurrence of serious adverse events associated with a product candidate that are viewed to outweigh its potential benefits; or

    changes in regulatory requirements and guidance that require amending or submitting new clinical protocols.

Any inability to successfully complete preclinical and clinical development could result in additional costs to us or impair our ability to generate revenues from product sales, regulatory and commercialization milestones and royalties. In addition, if we make manufacturing or formulation changes to our product candidates, including changes in the vector or manufacturing process used, we may need to conduct additional studies to bridge our modified product candidates to earlier versions. Clinical trial delays could also shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do, which could impair our ability to successfully commercialize our product candidates and may harm our business and results of operations.

If clinical trials of our product candidates fail to satisfactorily demonstrate safety and efficacy to regulatory authorities, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of our product candidates.

Before obtaining marketing approval from regulatory authorities for the sale of our product candidates, we must conduct extensive clinical trials to demonstrate the safety and efficacy of the product candidates in humans. In addition, we have an agreement in principle with Institut Pasteur to acquire the clinical results and commercial rights under our Sanfilippo B program following completion of the ongoing Phase I/II clinical trial, and are currently in negotiations with Institut Pasteur regarding the terms of a definitive agreement in this regard. If we are unable to reach agreement with Institut Pasteur regarding such rights, we would have to conduct additional clinical development ourselves and may experience delays in progressing this clinical program. It is impossible to predict when or if any of our product candidates will prove effective or safe in humans or will receive marketing approval. If the results of our clinical trials are inconclusive or if there are safety concerns or adverse events associated with our product candidates, we may:

    be delayed in or altogether prevented from obtaining marketing approval for our product candidates;

    obtain approval for indications or patient populations that are not as broad as intended or desired;

    obtain approval with labeling that includes significant use or distribution restrictions or safety warnings;

    be subject to changes with the way the product is administered;

    be required to perform additional clinical trials to support approval or be subject to additional post-marketing testing requirements;

    have regulatory authorities withdraw their approval of the product or impose restrictions on its distribution in the form of a modified risk evaluation and mitigation strategy;

    be subject to the addition of labeling statements, such as warnings or contraindications;

    be sued; or

    experience damage to our reputation.

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Any of these events could prevent us from achieving or maintaining market acceptance of our product candidates and impair our ability to commercialize our products.

Because of the nature of the gene therapies we are developing, regulators may require us to demonstrate long-term gene expression or clinical efficacy, which may require longer clinical trial periods or longer patient follow-up than is typically required in the case of other therapies.

We may experience delays or difficulties in the enrollment of patients in clinical trials, particularly for orphan indications, which may delay or prevent our receipt of necessary regulatory approvals.

Identifying and qualifying patients to participate in clinical trials of our product candidates is critical to our success. The timing of our clinical trials and those of our collaborators depends on the speed at which we or they can recruit patients to participate in such trials. We or our collaborators may not be able to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA, the EMA or similar regulatory authorities outside the United States and the European Union. In particular, because several of our programs are focused on the treatment of patients with orphan diseases, our ability to enroll eligible patients in these trials may be limited or slower than we anticipate in light of the small patient populations involved. For example, we reduced the number of patients enrolled in our second Phase II/III clinical trial of Glybera from the 16 patients originally planned to five patients due to slow recruitment. In addition, our potential competitors, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions, may seek to develop competing therapies, which would further limit the small patient pool available for our studies. Patient enrollment may be affected by other factors including:

    the severity of the disease under investigation;

    design of the study protocol;

    the eligibility criteria for the study;

    the perceived risks, benefits and convenience of administration of the product candidate being studied;

    our efforts to facilitate timely enrollment in clinical trials;

    the patient referral practices of physicians; and

    the proximity and availability of clinical trial sites to prospective patients.

An inability by us or our collaborators to locate and enroll a sufficient number of patients for clinical trials may result in our failure to initiate or continue clinical trials for our product candidates, or may cause significant delays in such trials and could require us or our collaborators to abandon one or more clinical trials altogether. Enrollment delays may also result in increased development costs for our product candidates, which could cause the value of our company to decline.

Our progress in early-stage clinical trials may not be indicative of long-term efficacy in late-stage clinical trials, and our progress in trials for one product candidate may not be indicative of progress in trials for other product candidates.

With the exception of Glybera, the product candidates in our pipeline are at early-stages of development. Study designs and results from previous studies are not necessarily predictive of our future clinical study designs or results, and initial results may not be confirmed upon full analysis of the complete study data. Our product candidates may fail to show the desired safety and efficacy in later stages of clinical development despite having successfully advanced through initial clinical studies.

A number of companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials even after achieving promising results in early-stage clinical trials. If a larger population of patients does not experience positive results, if these results are not reproducible, or if our products show diminishing activity over time, our products may not receive approval from the EMA or

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FDA. Data obtained from preclinical and clinical activities are subject to varying interpretations, which may delay, limit or prevent regulatory approval. In addition, we may encounter regulatory delays or rejections as a result of many factors, including changes in regulatory policy during the period of product development. Failure to confirm favorable results from earlier trials by demonstrating the safety and effectiveness of our products in late stage clinical trials with larger patient populations could have a material adverse effect on our business that would cause our share price to decline.

Progress in trials of Glybera and its approval in the European Union do not indicate that we will make similar progress in additional trials for Glybera or in trials for our other product candidates. While Glybera uses an AAV1 vector for gene delivery, the rest of the product candidates in our pipeline use other AAV vector variants, such as AAV5 or AAV2. Also, while Glybera is injected directly into the muscles of the leg, the rest of the products in our pipeline target other tissues. Due to these variations, trials for our other product candidates may be less successful than the trials for Glybera.

If serious adverse events occur or unacceptable side effects are identified in any gene therapy products or product candidates, whether ours or those of our competitors, we may need to abandon or limit the sale or development of Glybera or our product candidates.

Glybera or our product candidates may prove to have undesirable or unintended side effects, toxicities or other characteristics that may preclude our obtaining additional marketing approval or prevent or limit commercial use. In our clinical development program for Glybera, there were a total of 48 serious adverse events, two of which were determined to be related to Glybera, a pulmonary embolism and fever. In our partner's clinical development program for AIP, there was one serious adverse event that was determined by the investigator not to be treatment-related. If Glybera or any of our product candidates or those of other parties are associated with undesirable side effects in clinical trials or have characteristics that are unexpected, we may need to abandon their development or limit development to more narrow uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective.

Negative public opinion and increased regulatory scrutiny of gene therapy and genetic research may damage public perception of Glybera and our product candidates or adversely affect our ability to conduct our business or obtain further marketing approvals for Glybera and marketing approvals for our product candidates.

Public perception may be influenced by claims that gene therapy is unsafe, and gene therapy may not gain the acceptance of the public or the medical community. In particular, our success will depend upon physicians specializing in the treatment of those diseases that our product candidates target prescribing treatments that involve the use of our product candidates in lieu of, or in addition to, existing symptomatic treatments they are already familiar with and for which greater clinical data may be available.

A generalized public backlash developed against gene therapy following the death in September 1999 of an 18-year-old who had volunteered for a gene therapy experiment at the University of Pennsylvania. Researchers at the university had infused the volunteer's liver with a gene aimed at reversing a rare metabolic disease of the liver. The procedure triggered an extreme immune-system reaction that caused multiple-organ failure in a very short time, leading to the first death to occur as a direct result of a gene therapy experiment. In addition, in two gene therapy studies in 2003, 20 subjects treated for X-linked severe combined immunodeficiency using a murine gamma-retroviral vector showed correction of the disease. However, the studies were terminated after five subjects developed leukemia.

Although none of our current product candidates utilize the gamma-retroviruses used in the 2003 studies, our product candidates do use a viral vector delivery system. The risk of cancer remains a concern for gene therapy and we cannot assure that it will not occur in any of our planned or future clinical studies. In addition, there is the potential risk of delayed adverse events following exposure to gene therapy products

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due to persistent biological activity of the genetic material or other components of products used to carry the genetic material.

Adverse events in our clinical trials or those conducted by other parties, even if not ultimately attributable to our product candidates, and the resulting publicity could result in increased governmental regulation, unfavorable public perception, potential regulatory delays in the testing or approval of our potential product candidates, stricter labeling requirements for those product candidates that are approved and a decrease in demand for any such product candidates. If any such adverse events occur, commercialization of Glybera or further advancement of our clinical trials could be halted or delayed, which would have a material adverse effect on our business and operations.


Risks Related to the Regulatory Approval of Our Product Candidates

Even if we complete the necessary preclinical tests and clinical trials, we cannot predict when or if we will obtain marketing approval to commercialize a product candidate, and any approval we receive may be for a more narrow indication than we expect.

We cannot commercialize a product until the appropriate regulatory authorities have reviewed and approved the product candidate. The development and commercialization of our product candidates, including their design, testing, manufacture, safety, efficacy, purity, recordkeeping, labeling, storage, approval, advertising, promotion, sale and distribution, are subject to comprehensive regulation by the EMA and other regulatory agencies of the member states of the European Union, by the FDA and other regulatory agencies in the United States, and similar regulatory authorities outside the European Union and the United States. Failure to obtain marketing approval for a product candidate in a specific jurisdiction will prevent us from commercializing the product candidate in that jurisdiction.

We have not received approval to market any of our products or product candidates from regulatory authorities in the United States. We received marketing authorization for Glybera from the European Commission in October 2012 under exceptional circumstances for a subset of LPLD patients, after our initial application was rejected in June 2011. We plan to file an IND with the FDA for Glybera in the first half of 2014. The results of our prior clinical trials of Glybera will not be sufficient to obtain FDA approval, and the FDA may not ultimately approve Glybera for marketing in the United States. Based on our meetings with the FDA in August and December 2013, we believe that to obtain marketing approval for Glybera in the United States, we will need to successfully conduct an adequate and appropriately controlled clinical trial. We have not yet completed the design of this trial or prepared or submitted a protocol for this trial to the FDA. We will seek to amend the protocol for our EU post-approval trial of Glybera so that such trial also could serve as such a trial. The FDA may require preclinical testing or clinical trials beyond this clinical trial as a basis for marketing approval of Glybera, which would be expensive and time consuming. If we fail to obtain marketing approval of Glybera in the United States on our anticipated timeframe, or obtain only limited approval for a specific patient population, our business could be materially adversely affected.

The process of obtaining marketing approval for our product candidates in the European Union, the United States and other countries is expensive and may take many years, if approval is obtained at all. Additional clinical trials may be required and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved. Changes in marketing approval policies during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application. Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application, may decide that our data are insufficient for approval, may require additional preclinical, clinical or other studies and may not complete their review in a timely manner. The FDA does not maintain a regulatory approval process similar to the EMA's marketing authorization under exceptional circumstances, which may make it more difficult to obtain marketing authorization for Glybera or other product candidates in the United States. Further, any marketing approval we ultimately obtain may be for

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only limited indications, or be subject to stringent labeling or other restrictions or post-approval commitments that render the approved product not commercially viable. For example, we received marketing authorization for Glybera in the European Union only for a restricted patient population and other regulatory agencies may approve Glybera only with a similarly limited label, which limits our addressable market. Further, Glybera received marketing approval subject to post-approval restrictions including the requirement to conduct a post-approval clinical study, and if we fail to adequately satisfy these post-approval requirements the EMA may withdraw its approval.

If we experience delays in obtaining approval or if we fail to maintain approval of Glybera in the European Union or obtain approval of Glybera in the United States or elsewhere or of any of our product candidates in the United States or other countries, the commercial prospects for Glybera or our other product candidates may be harmed and our ability to generate revenues will be materially impaired.

The European Commission authorized marketing of Glybera under exceptional circumstances, and only after its subsidiary committees had made negative decisions involving the use of Glybera for the treatment of all patients with LPLD.

The process for obtaining approval of Glybera in the European Union was protracted and complicated by initial decisions against approval by the committees charged with review of our marketing authorization application. In their initial decision in June 2011, both the Committee for Advanced Therapeutics, or CAT, and the Committee for Human Medicinal Products, or CHMP, determined that the benefit-risk balance for Glybera was negative for the treatment of all patients with LPLD.

In June 2012, the CAT gave a positive opinion and the CHMP then reassessed Glybera and recommended approval for adult patients diagnosed with familial LPLD and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. This was a more restricted patient population than we had sought in our original application. The European Commission granted this approval in October 2012, subject to certain conditions including additional post-marketing studies for efficacy.

Our receipt of marketing authorization under exceptional circumstances in the European Union does not provide any assurance that we will be able to obtain marketing authorization for Glybera elsewhere, including in the United States, or for our other gene therapies in any country.

Our product, Glybera, was approved in Europe through a special regulatory scheme allowing for marketing of certain products under exceptional circumstances. A similar pathway to approval does not exist in the United States. As a result, approval of Glybera in Europe does not guarantee or increase the likelihood of approval of Glybera by the FDA in the United States.

The FDA does not maintain a regulatory approval process similar to the EMA's marketing authorization under exceptional circumstances, which may make it more difficult to obtain approval for Glybera in the United States. In the United States, the FDA will generally only approve a product on the basis of two full clinical studies that contain substantial evidence of the safety and efficacy of the proposed new product. Clinical trials in the United States must be conducted in accordance with GCP requirements. A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of an IND. Each institution participating in the clinical trial is subject to the initial approval, continuing review, and at least annual reapproval, by an IRB.

Given the differences between the regulatory schemes for approval of new products in Europe and the United States, approval of Glybera in the European Union does not assure or increase the likelihood of approval of the product in the United States. In addition, we are in discussions with the FDA regarding the regulatory pathway for Glybera in the United States, and must design an adequate and appropriately controlled clinical trial of Glybera to support a BLA filing. This could involve additional time, which may delay our U.S. clinical program for Glybera. If we fail to obtain marketing approval in the United States on

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our anticipated timeframe, or obtain only limited approval for a specific patient population, our business could be materially adversely affected.

The FDA will require us to conduct comparability studies evaluating the products manufactured at our Amsterdam facility with those to be manufactured at our Lexington, Massachusetts facility, which is currently under construction. Those studies and their results could substantially delay or preclude our ability to commercialize Glybera and our product candidates in the United States.

The FDA maintains strict requirements governing the manufacturing process for biologics. When a manufacturer seeks to modify or change that process, the FDA typically requires the applicant to conduct non-clinical and, depending on the magnitude of the changes, potentially clinical comparability studies that evaluate the potential differences in the product resulting from the change in the manufacturing process. In connection with any application we may file with the FDA seeking marketing approval for Glybera or any of our other product candidates in the United States, we will be required to conduct comparability studies assessing product manufactured at our facility in Amsterdam with product to be manufactured at our facility in Lexington, Massachusetts, which we are currently building out and equipping. The FDA may be especially concerned about the need for such a comparability study for Glybera if the clinical studies on which we rely for approval of our application only involved product manufactured at our facility in the Netherlands and if we intend to market only product manufactured in Lexington in the United States.

Delays in designing and completing a comparability study to the satisfaction of the FDA could delay or preclude our development and commercialization plans and, thereby, limit our revenues and growth. For example, for Glybera, we may attempt to show comparability of the product manufactured at the different facilities through the use of non-clinical data, such as potency assays and animal studies. There is a risk that such data may not show acceptable comparability of the product manufactured at the different sites to the satisfaction of FDA. In addition, in the event that the FDA does not accept such non-clinical comparability data, we may need to conduct a study involving dosing of patients with product from our Lexington facility. That study may result in a delay of the approval or launch of Glybera in the United States.

We are subject to potentially costly post-approval requirements in the European Union that may restrict or eliminate the commercial success of Glybera.

As part of our marketing approval under exceptional circumstances in the European Union, the EMA has imposed ongoing requirements for a potentially costly post-approval study and market surveillance. Specifically, as a condition to approval we are required to complete a post-approval clinical trial and implement a disease registry for long term surveillance of patients, as well as implement risk management procedures, distribute educational materials to healthcare professionals and patients, comply with certain notification obligations and undergo annual reassessment, the outcome of which could eventually lead to a withdrawal of the approval. The expense and uncertain result of these post-approval requirements may delay, limit or terminate our commercialization plan for Glybera and adversely affect our financial position.

The risks associated with the marketing approval process are heightened by our products' status as gene therapies.

Glybera has been evaluated as a gene therapy by the EMA. We believe that all of our current product candidates, including Glybera, will be viewed as gene therapy products by the EMA, FDA and other regulatory authorities. Gene therapies are relatively new treatments and regulators do not have extensive experience or standard review and approval processes for gene therapies. The FDA has never approved a gene therapy product as safe and effective and, unlike the EMA, does not have an exceptional circumstances approval pathway. The EMA has approved only one gene therapy, Glybera, for a subset of LPLD patients, under exceptional circumstances, and only did so by a vote of 17 to 15 and after twice denying approval. Given the novelty and complexity of our technology, we intend to discuss with the EMA,

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the FDA and other regulatory authorities the appropriate scientific analysis and evaluation of our methods to support applications for marketing approval for our product candidates. The application process will take time and resources, may require independent third-party analysis and may still not be accepted by the EMA, FDA or other regulatory authorities.

The EMA and FDA have demonstrated caution in their regulation of gene therapy treatments, and ethical and legal concerns about gene therapy and genetic testing may result in additional regulations or restrictions on the development and commercialization of our product candidates that are difficult to predict. For example, the EMA advocates a risk-based approach to the development of a gene therapy product. Agencies at both the U.S. federal and state level, as well as congressional committees and foreign governments, have sometimes expressed interest in further regulating biotechnology. Such action may delay or prevent commercialization of some or all of our product candidates. For example, in 2003, the FDA suspended 27 gene therapy trials involving several hundred patients after learning that a child treated in France had developed a condition resembling leukemia. Although the FDA was not aware that any of the patients treated in the 27 American trials had suffered illnesses similar to that of the infant in France, it nevertheless took precautions. This temporary halt, the largest such action involving gene therapy trials, was a setback for the field.

Regulatory requirements affecting gene therapy have changed frequently and may continue to change. For example, the European Commission conducted a public consultation in early 2013 on the application of EU legislation that governs advanced therapy medicinal products, including gene therapy products, that could result in changes in the data we need to submit to the EMA in order for our product candidates to gain regulatory approval. In addition, divergent scientific opinions among the various bodies involved in the review process may result in delays and require additional resources and may ultimately result in rejection. For further discussion about the regulation we face in Europe and the United States, please see "Business—Government Regulation and Reimbursement."

In the United States, the FDA has established the Office of Cellular, Tissue and Gene Therapies within the Agency's Center for Biologics Evaluation and Research, or CBER, to consolidate the review of gene therapy and related products, and the Cellular, Tissue and Gene Therapies Advisory Committee to advise CBER on its review. Gene therapy clinical trials conducted at institutions that receive funding for recombinant DNA research from the NIH are also subject to review by the NIH Office of Biotechnology Activities' Recombinant DNA Advisory Committee, or the RAC. Although the FDA decides whether individual protocols may proceed, the RAC review process can impede the initiation of a clinical trial, even if the FDA has reviewed the study and approved its initiation. In addition, the FDA can put an IND on clinical hold even if the RAC has provided a favorable review. Also, before a clinical trial can begin at an NIH-funded institution, that institution's institutional review board, or IRB, and its Institutional Biosafety Committee will review the proposed clinical trial to assess the safety of the study. Adverse developments in clinical trials of gene therapy products conducted by others may cause the FDA or other regulatory bodies to change the requirements for approval of any of our product candidates.

The FDA and the EMA have issued various guidance documents pertaining to gene therapy products, with which we likely must comply to gain regulatory approval of any of our product candidates in the United States or European Union, respectively. Those guidance documents may require us, for example, to observe the subjects of our clinical trials for a longer period than normal following completion of a trial, or to undertake more extensive preclinical assessments, in particular concerning our vector and transgene expression cassette system, before beginning clinical trials at all. We also may need to conduct environmental risk assessments and special long term studies to monitor the safety and efficacy of our products. The close regulatory scrutiny of gene therapy products may result in delays and increased costs, and may ultimately lead to any gene therapy product not being approved.

These regulatory review committees and advisory groups and the new guidelines they promulgate may lengthen the regulatory review process, require us to perform additional studies, increase our development

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costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and commercialization of these product candidates or lead to significant post-approval limitations or restrictions. As we advance our product candidates, we will be required to consult with these regulatory and advisory groups, and comply with applicable guidelines. If we fail to do so, we may be required to delay or discontinue development of our product candidates. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product to market could decrease our ability to generate sufficient product revenues to maintain our business.

If we are not able to obtain or maintain orphan product exclusivity for any of our product candidates for which we seek this status, or if our competitors are able to obtain orphan product exclusivity before we do, we may not be able to obtain approval for our competing products for a significant period of time.

Regulatory authorities in some jurisdictions, including the European Union and the United States, may designate drugs for relatively small patient populations as orphan drugs. Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is a drug intended to treat a rare disease or condition, which is generally defined as a patient population of fewer than 200,000 individuals annually in the United States or not more than five in 10,000 people in the European Union. Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of market exclusivity, which precludes the EMA or FDA from approving another marketing application for the same drug for the same indication for that time period. The applicable period is seven years in the United States and ten years in the European Union following marketing approval. The EU exclusivity period can be reduced to six years if a drug no longer meets the criteria for orphan drug designation, for example if the drug is sufficiently profitable so that market exclusivity is no longer justified.

Orphan drug exclusivity may be lost if the EMA or FDA determines that the request for designation was materially defective, or if the manufacturer is unable to assure sufficient quantity of the drug to meet the needs of patients with the rare disease or condition or if the incidence and prevalence of patients who are eligible to receive the drug in these markets materially increase. Although we have obtained orphan designation for Glybera in the European Union and the United States, even after an orphan drug is approved, the same drug can subsequently be approved for the same condition if the competent regulatory agency concludes that the later drug is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.

If we lose orphan drug exclusivity or if our competitors obtain orphan drug exclusivity before we do, we may be precluded from obtaining marketing authorization or we may lose out on the potential benefits of market exclusivity.

Fast track designation by the FDA may not lead to a faster development or regulatory review or approval process, and it does not increase the likelihood that any of our product candidates will receive marketing approval in the United States.

We may in the future seek fast track designation for Glybera or other product candidates as appropriate in the United States. If a drug is intended for the treatment of a serious or life-threatening condition or disease and the drug demonstrates the potential to address unmet medical needs for this condition, the drug sponsor may apply for FDA fast track designation. The FDA has broad discretion whether or not to grant this designation, so even if we believe a particular product candidate is eligible for this designation, we cannot assure you that the FDA would decide to grant it. Even if we do apply for and receive fast track designation, we may not experience a faster development, review or approval process compared to conventional FDA procedures. The FDA may withdraw fast track designation if it believes that the designation is no longer supported by data from our clinical development program.

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Breakthrough therapy designation by the FDA may not lead to a faster development or regulatory review or approval process, and it does not increase the likelihood that any of our product candidates will receive marketing approval in the United States.

We may in the future apply for breakthrough therapy designation for Glybera or other product candidates in the United States. A breakthrough therapy is defined as a product that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and for which preliminary clinical evidence indicates substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. For drugs and biologics that have been designated as breakthrough therapies, interaction and communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while minimizing the number of patients placed in ineffective control regimens. Products designated as breakthrough therapies by the FDA are also eligible for accelerated approval.

Designation as a breakthrough therapy is within the discretion of the FDA. Accordingly, even if we believe one of our products or product candidates meets the criteria for designation as a breakthrough therapy, the FDA may disagree. In any event, the receipt of a breakthrough therapy designation for a product or product candidate may not result in a faster development process, review or approval compared to products considered for approval under conventional FDA procedures and, in any event, does not assure ultimate approval by the FDA. In addition, even if one or more of our products or product candidates qualify as breakthrough therapies, the FDA may later decide that the products no longer meet the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Any of our product candidates for which we obtain marketing approval in the future could be subject to post-marketing restrictions or other regulatory requirements.

Glybera and any of our product candidates for which we obtain marketing approval in the future, as well as the manufacturing process, post-approval studies and measures, labeling, advertising and promotional activities for such products, will be subject to continued requirements of and review by the FDA, EMA and other regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, requirements relating to manufacturing, quality control, quality assurance and corresponding maintenance of records and documents and recordkeeping. Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the product may be marketed or to the conditions of approval, including the requirement to develop and implement a risk evaluation and mitigation strategy. For example, the EMA's approval of Glybera was contingent upon our agreeing to post-approval obligations described elsewhere in this prospectus.

The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of a product. The FDA and other agencies, including the Department of Justice, closely regulate and monitor the post-approval marketing and promotion of products to ensure that they are manufactured, marketed and distributed only for the approved indications and in accordance with the provisions of the approved label. The FDA imposes stringent restrictions on manufacturers' communications regarding off-label use and if we do not market our products for their approved indications, we may be subject to an enforcement action for off-label marketing. Violations of the Federal Food, Drug, and Cosmetic Act and other statutes, including the False Claims Act, relating to the promotion of prescription drugs may lead to investigations alleging violations of federal and state health care fraud and abuse laws, as well as state consumer protection laws. Similar regulations apply in many other foreign jurisdictions.

In addition, later discovery of previously unknown adverse events or other problems with our products, or failure to comply with regulatory requirements, may yield various adverse results, including:

    restrictions on such products or manufacturing processes;

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    restrictions on the labeling or marketing of a product;

    restrictions on product distribution or use;

    requirements to conduct post-marketing studies or clinical trials;

    warning letters;

    withdrawal of the products from the market;

    refusal to approve pending applications or supplements to approved applications that we submit;

    recall of products;

    fines, restitution or disgorgement of profits or revenues;

    suspension or withdrawal of marketing approvals;

    refusal to permit the import or export of our products;

    product seizure; and

    injunctions or the imposition of civil or criminal penalties.

Non-compliance with EU requirements regarding safety monitoring or pharmacovigilance can also result in significant financial penalties. Similarly, failure to comply with the European Union's requirements regarding the protection of personal information can also lead to significant penalties and sanctions.

Any government investigation of alleged violations of law could require us to expend significant time and resources and could generate negative publicity. The occurrence of any event or penalty may inhibit our ability or that of our collaborators to commercialize Glybera and any other products and generate revenues, and may also adversely affect our ability to obtain FDA approval. Failure to maintain marketing approval for Glybera in the European Union or to obtain regulatory approval for Glybera in other jurisdictions may also adversely affect our ability to develop other product candidates, given the general applicability of our technology platform to the development of our current and future product candidates.


Risks Related to the Commercialization of Glybera and Our Product Candidates

If we or our collaborators are unable to commercialize Glybera or our other product candidates or experience significant delays in doing so, our business will be materially harmed.

Our ability to generate product revenues will depend heavily on the successful commercialization of Glybera and development and eventual commercialization of other product candidates. The success of our product candidates will depend on several factors, including the following:

    successful completion of preclinical studies and clinical trials;

    receipt of marketing approvals from applicable regulatory authorities;

    obtaining and maintaining patent and trade secret protection and non-patent, orphan drug exclusivity for our product candidates;

    completing the build-out of, and obtaining regulatory approval for, our new manufacturing facility in Lexington, Massachusetts;

    launching commercial sales of our products, if and when approved, whether alone or in collaboration with others;

    identifying and engaging effective distributors or other third party resellers on acceptable terms in certain jurisdiction where we plan to utilize third parties for the marketing and sale of Glybera or other candidate products;

    acceptance of our products, if and when approved, by patients, the medical community and third party payors;

    effectively competing with other therapies;

    obtaining and maintaining healthcare coverage and adequate reimbursement; and

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    complying with post-approval requirements of the EMA and maintaining a continued acceptable overall safety profile based on the EMA's risk-benefit analysis.

Failure to achieve or implement any of these elements could result in significant delays or an inability to successfully commercialize Glybera or our product candidates, which could materially harm our business.

The affected populations for Glybera and our other product candidates may be smaller than we or third parties currently project, which may affect the addressable markets for Glybera and our other product candidates.

Our projections of the number of people who have the diseases we are seeking to treat, as well as the subset of people with these diseases who have the potential to benefit from treatment with Glybera or our product candidates, are estimates based on our knowledge and understanding of these diseases. The total addressable market opportunity for Glybera and our product candidates will ultimately depend upon a number of factors including the diagnosis and treatment criteria included in the final label, if approved for sale in specified indications, acceptance by the medical community, patient access and product pricing and reimbursement. Prevalence estimates are frequently based on information and assumptions that are not exact and may not be appropriate, and the methodology is forward-looking and speculative. The process we have used in developing an estimated prevalence range for the indications we are targeting has involved collating limited data from multiple sources. Accordingly, the prevalence estimates included in this prospectus should be viewed with caution. Further, the data and statistical information used in this prospectus, including estimates derived from them, may differ from information and estimates made by our competitors or from current or future studies conducted by independent sources.

The use of such data involves risks and uncertainties and is subject to change based on various factors. Our estimates may prove to be incorrect and new studies may change the estimated incidence or prevalence of the diseases we seek to address. The number of patients with the diseases we are targeting in the European Union, the United States and elsewhere may turn out to be lower than expected or may not be otherwise amenable to treatment with our products, or new patients may become increasingly difficult to identify or access, all of which would adversely affect our results of operations and our business.

Glybera, and any other product candidate that receives marketing approval in the future, may fail to achieve the degree of market acceptance by physicians, patients, third-party payors and others in the medical community necessary for commercial success.

Doctors may be reluctant to accept a gene therapy as a treatment option or, where available, choose to continue to rely on existing symptomatic treatments. If Glybera does not achieve an adequate level of acceptance, we may not generate significant revenues from this product and we may never achieve profitability. The degree of market acceptance of Glybera, as well as of any of our product candidates that receive marketing approval in the future, will depend on a number of factors, including:

    the efficacy and potential advantages of our therapies compared with alternative treatments;

    our ability to convince payors of the long-term cost-effectiveness of our therapies and, consequently, the availability of third-party coverage and adequate reimbursement;

    the limitations on use and label requirements imposed by regulators;

    the convenience and ease of administration of our gene therapies, which in the case of Glybera requires spinal anaesthesia and multiple intramuscular injections, compared to alternative treatments;

    the willingness of the target patient population to try new therapies, especially a gene therapy, and of physicians to administer these therapies;

    the strength of marketing and distribution support;

    the prevalence and severity of any side effects; and

    any restrictions on the use of our products.

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In the case of Glybera in the European Union, we are required to put in place a restricted access program to ensure that the product is used appropriately when the diagnosis is confirmed, mandating that the product only be supplied to doctors who have received the appropriate educational materials and only be used to treat patients participating in a registry to monitor the outcome of patients treated with Glybera. These requirements may further limit our ability to gain sufficient market acceptance.

If our collaboration with Chiesi is not successful, we may not effectively commercialize Glybera in the European Union and other countries covered by our partnership with Chiesi.

We have entered into a collaboration with Chiesi for the commercialization of Glybera in the European Union, China, Russia and other specified countries. As a result, we are dependent on the efforts of Chiesi to successfully commercialize Glybera in these countries. There is a risk that Chiesi:

    may not perform its obligations as expected;

    may have difficulties gaining acceptance of the use of Glybera in the clinical community and achieving satisfactory pricing and reimbursement of Glybera;

    may terminate, or may elect not to continue or renew, our commercialization arrangements based on changes in its strategic focus or available funding, or external factors, such as an acquisition, that divert resources or create competing priorities; and

    may not commit sufficient resources to the marketing and distribution of Glybera.

In addition, we are required to manufacture Glybera for sale by Chiesi. Should we encounter manufacturing problems, we may fail to adequately supply Glybera to Chiesi. If any of these circumstances related to our collaboration with Chiesi are realized, they may adversely affect the commercial success of Glybera in the European Union and other countries covered by our partnership with Chiesi.

We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we do.

The development and commercialization of new biotechnology and biopharmaceutical products, including gene therapies, is highly competitive. We may face competition with respect to Glybera and our current product candidates, as well as with respect to any product candidates that we may seek to develop or commercialize in the future, from large and specialty pharmaceutical companies and biotechnology companies worldwide, who currently market and sell products or are pursuing the development of products for the treatment of many of the disease indications for which we are developing our product candidates. Potential competitors also include academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization. In recent years, there has been a significant increase in commercial and scientific interest and financial investment in gene therapy as a therapeutic approach, which has intensified the competition in this area.

We are aware of several companies focused on developing gene therapies in various indications, including AGTC, Asklepios, Audentes Therapeutics, BioMarin, bluebird bio, Dimension/Regen X, Oxford BioSciences, Sangamo BioScience, and Spark Therapeutics, as well as several companies addressing other methods for modifying genes and regulating gene expression. We may also face competition with respect to the treatment of some of the diseases that we are seeking to target with our gene therapies from protein pharmaceuticals under development at pharmaceutical and biotechnology companies, including Pfizer, Baxter, Bayer, Novo Nordisk, Genzyme, Shire, BioMarin and Biogen Idec. We must also compete with existing standards of care, therapies and symptomatic treatments, as well as any new therapies that may become available in the future for the indications we are targeting.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than the products that we develop. Our competitors also may obtain EMA, FDA or other

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regulatory approval for their products more rapidly than we do, which could result in our competitors establishing a strong market position before we are able to enter the market. Because we expect that gene therapy patients may generally require only a single administration, we believe that the first gene therapy product to enter the market for a particular indication will likely enjoy a significant commercial advantage, and may also obtain market exclusivity under applicable orphan drug regimes.

Many of the companies with which we are competing or may compete in the future have significantly greater financial resources and expertise than we do in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products. Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in more resources being concentrated among a smaller number of our competitors. Smaller and other early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Even if we are successful in achieving regulatory approval to commercialize a product candidate faster than our competitors, it is conceivable that we may face competition from biosimilars. In the United States, the Biologics Price Competition and Innovation Act of 2009 authorized the FDA to approve products that are "highly similar," or biosimilar, to or "interchangeable" with an FDA-approved biological product following expiration of a 12 year period of exclusivity. In the European Union, a competitor may reference data from biological products already approved, but will not be able to get on the market until ten years after the time of approval, although that may be extended to 11 years under specified circumstances. If competitors are able to obtain marketing approval for biosimilars after the applicable period of non-patent exclusivity expires, the attendant competitive pressure and consequences. Expiration or successful challenge of our applicable patent rights could also trigger competition from other products.


Risks Related to Our Dependence on Third Parties for Glybera and our Product Pipeline

We rely on third parties for important aspects of our development programs. If these parties do not perform successfully or if we are unable to maintain any of our collaboration arrangements, our business could be adversely affected.

We have entered into collaborations with other companies and academic research institutions with respect to important elements of our commercial and development programs. For example, we have collaboration agreements with Chiesi, for both commercialization of Glybera in the European Union and certain other countries and co-development and commercialization of our hemophilia B program, and development programs with Digna Biotech, Institut Pasteur and UCSF. We believe that these arrangements provide us with access to important technologies and capabilities, and in many cases to data from our collaborators' preclinical and clinical development programs. Our collaboration with Chiesi has also provided us with important funding for our Glybera and hemophilia B development programs.

Our existing collaborations, and any future collaborations we enter into, may pose a number of risks, including the following:

    collaborators have significant discretion in determining the efforts and resources that they will apply to these collaborations;

    in our current collaborations, we generally have limited or no control over the design or conduct of clinical trials sponsored by our collaborators;

    if our collaborators do not conduct the clinical trials they sponsor in accordance with regulatory requirements or stated protocols, we will not be able to rely on the data produced in such trials in our further development efforts;

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    collaborators may not perform their obligations as expected;

    collaborators may also have relationships with other entities, some of which may be our competitors;

    collaborators may not pursue development and commercialization of any product candidates or may elect not to continue or renew development or commercialization programs based on clinical trial results, changes in the collaborators' strategic focus or available funding, or external factors, such as an acquisition, that divert resources or create competing priorities;

    collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, stop a clinical trial or abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product candidate for clinical testing;

    collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our products or product candidates if the collaborators believe that competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours;

    our collaboration arrangements may impose restrictions on our ability to undertake other development efforts that may appear to be attractive to us;

    product candidates discovered in collaboration with us may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to cease to devote resources to the commercialization of our product candidates;

    a collaborator with marketing and distribution rights to Glybera or one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of such product or products;

    disagreements with collaborators, including disagreements over proprietary rights, contract interpretation or the preferred course of development, could cause delays or termination of the research, development or commercialization of product candidates, lead to additional responsibilities for us, or result in litigation or arbitration, any of which would be time-consuming and expensive;

    collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation;

    collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and potential liability; and

    collaborations may in some cases be terminated for the convenience of the collaborator and, if terminated, we could be required to expend additional funds to pursue further development or commercialization of the applicable product or product candidates.

If our collaborations do not result in the successful development and commercialization of products or if one of our collaborators terminates its agreement with us, we may not receive any future research funding or milestone or royalty payments under the collaboration. If we do not receive the funding we expect under these agreements, our development of our product candidates could be delayed and we may need additional resources to develop our product candidates. All of the risks relating to product development, regulatory approval and commercialization described in this prospectus also apply to the activities of our development collaborators.

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If we are unable to enter into additional collaborations in the future, or if our new collaborations are not successful, we may not be able to develop or market our product candidates or obtain a strategic position in the development of new gene therapies.

We believe collaborations enable us to gain access to early-stage clinical programs and related data, as well as to promising transgenes and other intellectual property, with limited financial investment by us. Part of our strategy is to leverage our experience and expertise in gene therapy research and development, as well as our proprietary manufacturing capabilities, to be an attractive collaborator for academic research institutions and biotechnology and pharmaceutical companies seeking to advance their programs into larger, late-stage clinical trials that require commercial-scale manufacturing. We face significant competition from other gene therapy, biotechnology and pharmaceutical companies, and we may be unable to attract suitable collaborators or reach agreements with them on acceptable terms, which could limit our access to attractive development programs.

For some of our product candidates, particularly for chronic and degenerative diseases that will require large clinical trials and a retail sales force to address the market, we may in the future collaborate with pharmaceutical and biotechnology companies for development and potential commercialization. We face significant competition in seeking appropriate collaborators. Our ability to reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator's resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator's evaluation of a number of factors. Many of our agreements with our licensors, including our agreements with the NIH, require us to obtain consent from the licensor before we can enter into arrangements involving the sublicensing of technology we have licensed from such licensors. Our licensors may withhold such consent, or may provide such consent only if we agree to reduce our rights or increase our financial or other obligations to them. Obtaining such consent may also hamper our ability to enter into collaboration arrangements on a timely basis.

If we are unable to reach agreements with suitable collaborators on a timely basis, on acceptable terms, or at all, we may have to curtail the development of a product candidate, reduce or delay its development or one or more of our other development programs, delay its potential commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense. If we elect to fund and undertake development or commercialization activities on our own, we may need to obtain additional expertise and additional capital, which may not be available to us on acceptable terms or at all. If we fail to enter into collaborations and do not have sufficient funds or expertise to undertake the necessary development and commercialization activities, we may not be able to further develop our product candidates or bring them to market or continue to develop our product platform, and our business may be materially and adversely affected.

We do not currently have a sales or marketing infrastructure and have no experience in the sale, marketing or distribution of pharmaceutical products. To achieve commercial success for Glybera in the European Union and certain other countries, we are dependent on Chiesi's sales and marketing infrastructure. We may enter into similar arrangements with other parties in respect of the commercialization of products in other jurisdictions. Entering into arrangements with other third parties to perform these services may result in lower product revenues and profitability, if any, than if we were to market, sell and distribute Glybera or other products ourselves. In addition, we may not be successful in entering into arrangements with third parties in the future to sell, market and distribute our product candidates, including Glybera in other territories, or may be unable to do so on terms that are favorable to us. We likely will have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our products effectively.

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Risks Related to Our Manufacturing

Gene therapies, including Glybera, are complex and difficult to manufacture. We could experience production problems that result in delays in our development or commercialization schedules or otherwise adversely affect our business.

We manufacture Glybera and clinical supplies of our product candidates ourselves in our facility in Amsterdam and plan to commence production in the facility we are currently building out in Lexington, Massachusetts. The insect-cell based manufacturing process we use to produce Glybera and our other product candidates is highly complex and in the normal course is subject to production difficulties. A number of factors could cause production interruptions, including equipment malfunctions, facility contamination, labor problems, raw material shortages or contamination, natural disasters, disruption in utility services, terrorist activities, human error or disruptions in the operations of our suppliers.

Our viral vectors require processing steps that are more complex than those required for most chemical pharmaceuticals. Moreover, unlike chemical pharmaceuticals, the physical and chemical properties of a biologic such as ours generally cannot be adequately characterized prior to manufacturing the final product. As a result, an assay of the finished product is not sufficient to ensure that the product will perform in the intended manner. Accordingly, we employ multiple steps to attempt to control our manufacturing process to assure that the process works and the product or product candidate is made strictly and consistently in compliance with the process. Problems with the manufacturing process, even minor deviations from the normal process, could result in product defects or manufacturing failures that result in lot failures, product recalls, product liability claims and insufficient inventory. We may encounter problems achieving adequate or clinical-grade materials that meet EMA, FDA or other applicable standards or specifications with consistent and acceptable production yields and costs.

In addition, the EMA, FDA and other regulatory bodies may require us to submit samples of any lot of any approved product together with the protocols showing the results of applicable tests at any time. Under some circumstances, the EMA, FDA or other regulatory bodies may require that we not distribute a lot until the agency authorizes its release. Slight deviations anywhere in the manufacturing process, including stability and quality control, may result in unacceptable changes in the products that could result in lot failures or product recalls. Lot failures or product recalls could cause us to delay product launches or clinical trials, which could be costly to us and otherwise harm our business.

We also may encounter problems hiring and retaining the experienced specialist personal needed to operating our manufacturing process, which could result in delays in our production or difficulties in maintaining compliance with applicable regulatory requirements.

Any problems in our manufacturing process or facilities could make us a less attractive collaborator for academic research institutions and other parties, which could limit our access to additional attractive development programs.

Any contamination in our manufacturing process, shortages of raw materials or failure of any of our key suppliers to deliver necessary components of our platform could result in delays in our clinical development or marketing schedules.

Given the nature of biologics manufacturing, there is a risk of contamination. Any contamination could materially adversely affect our ability to produce our gene therapies, including Glybera, on schedule and could therefore harm our results of operations and cause reputational damage.

Some of the raw materials required in our manufacturing process are derived from biological sources. Such raw materials are difficult to procure and may also be subject to contamination or recall. A material shortage, contamination, recall, or restriction on the use of biologically derived substances in the manufacture of Glybera or our product candidates could adversely impact or disrupt the commercial

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manufacturing of Glybera or the production of clinical material, which could materially and adversely affect our operating results and development timelines.

We rely on single suppliers for the supply and manufacture of certain components of our technology. Specifically, we have only one source of supply for some of the materials used in the chromatography step of our manufacturing process. We are not currently seeking to establish secondary suppliers for these materials. We may not be successful in establishing secondary suppliers on acceptable terms, if at all, should our suppliers discontinue supply of these materials. Further, these suppliers are not required to give us advance notice in the event they discontinue supply of the relevant materials. Should our ability to procure these material components from our sole suppliers be compromised, our ability to continuously operate would be impaired until an alternative supplier is sourced, qualified and tested, which could limit our ability to produce a commercial supply of Glybera, delay the development programs of Glybera and our other product candidates and harm our business.

Delays in completing and receiving regulatory approvals for our new U.S. manufacturing facility could delay our development and commercialization plans and thereby limit our revenues and growth.

We are expending significant funds for the build-out of our leased 53,000 square foot manufacturing facility in Lexington, Massachusetts. This project may result in unanticipated delays and cost more than expected due to a number of factors, including regulatory requirements. If construction or regulatory approval of our new facility is delayed, we may not be able to manufacture sufficient quantities of Glybera or our product candidates, which would limit our commercialization and development activities and our opportunities for growth. Cost overruns associated with this facility could also require us to raise additional funds from external sources, which may be unavailable on favorable terms or at all.

Our manufacturing facility in Amsterdam is, and our facility in Lexington will be, subject to significant government regulations and approvals, which are often costly. If we fail to comply with these regulations or maintain these approvals, our business will be materially harmed.

Our manufacturing facility in Amsterdam is, and our new facility in Lexington will be, subject to ongoing regulation and periodic inspection by the EMA, FDA and other regulatory bodies to ensure compliance with current Good Manufacturing Practices, or cGMP. Any failure to follow and document our adherence to such cGMP regulations or other regulatory requirements may lead to significant delays in the availability of products for commercial use or clinical study, may result in the termination of or a hold on a clinical study, or may delay or prevent filing or approval of marketing applications for our products. In addition, if we alter our manufacturing process for gene therapies, including Glybera, or during the development of a product candidate, the EMA, FDA or other regulatory authorities may require additional testing and clinical studies to ensure adequate safety and efficacy.

To monitor our compliance with applicable regulations, the EMA, FDA and comparable agencies in other jurisdictions routinely conduct inspections of our facilities and may identify potential deficiencies for us to address. For example, the FDA issues what are referred to as "FDA Form 483s" that set forth observations and concerns that are identified during its inspections. We may receive Form 483s in the future. Failure to satisfactorily address the concerns or potential deficiencies identified in a Form 483 could result in us being issued a warning letter, a notice of what the FDA believes to be significant regulatory violations requiring prompt corrective actions. If we fail to adequately respond to a warning letter, or otherwise fail to comply with applicable regulatory requirements, we could be subject to enforcement, remedial and/or punitive actions by the FDA or other regulatory authorities.

Failure to comply with applicable regulations could also result in the EMA, FDA or other applicable authorities taking various actions, including:

    levying fines and other civil penalties;

    imposing consent decrees or injunctions;

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    a requirement to suspend or put on hold one or more of our clinical trials;

    suspending or withdrawing regulatory approvals;

    delaying or refusing to approve pending applications or supplements to approved applications;

    suspending manufacturing activities or product sales, imports or exports;

    requiring us to communicate with physicians and other customers about concerns related to actual or potential safety, efficacy, and other issues involving our products;

    mandating product recalls or seizing products;

    imposing operating restrictions; and

    seeking criminal prosecutions.

Any of the foregoing could materially harm our business.

Our use of viruses, chemicals and other hazardous materials requires us to comply with regulatory requirements and exposes us to significant potential liabilities.

Our development and manufacturing processes involve the use of viruses, chemicals and other hazardous materials, and produce waste products. Accordingly, we will be subject to federal, state and local laws and regulations in the United States, and are subject to comparable regulations in the Netherlands, governing the use, manufacture, distribution, storage, handling, treatment and disposal of these materials. In addition to ensuring the safe handling of these materials, applicable requirements require increased safeguards and security measures for many of these agents, including controlling access and screening of entities and personnel who have access to them, and establishing a comprehensive national database of registered entities. In the event of an accident or failure to comply with environmental, occupational health and safety and export control laws and regulations, we could be held liable for damages that result, and any such liability could exceed our assets and resources.


Risks Related to Our Intellectual Property

We license intellectual property from third parties, and such licenses may not provide adequate rights, may not be available in the future on commercially reasonable terms or at all, or our licensors may be unable to obtain and maintain patent protection for the technology or products that we license from them.

We currently are heavily reliant upon licenses of proprietary technology from third parties that is important or necessary to the development of our technology and products, including technology related to our manufacturing process, our vector platform, our gene cassettes and the therapeutic genes of interest we are using. These and other licenses may not provide adequate rights to use such technology in all relevant fields of use. Licenses to additional third-party technology that may be required for our development programs may not be available in the future or may not be available on commercially reasonable terms, which could have a material adverse effect on our business and financial condition.

In some circumstances, we may not have the right to control the preparation, filing and prosecution of patent applications, or to maintain the patents, covering technology that we license from third parties. In addition, some of our agreements with our licensors require us to obtain consent from the licensor before we can enforce patent rights, and our licensor may withhold such consent or may not provide it on a timely basis. Therefore, we cannot be certain that these patents and applications will be prosecuted and enforced in a manner consistent with the best interests of our business. In addition, if third parties who license patents to us fail to maintain such patents, or lose rights to those patents, the rights we have licensed may be reduced or eliminated.

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Our intellectual property licenses with third parties may be subject to disagreements over contract interpretation, which could narrow the scope of our rights to the relevant intellectual property or technology or increase our financial or other obligations to our licensors.

The agreements under which we currently license intellectual property or technology from third parties are complex, and certain provisions in such agreements may be susceptible to multiple interpretations. The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business and financial condition. For example, we have an exclusive license from the NIH for "the development and sale of AAV5 based therapeutic products to be delivered to the brain or liver for treatment of human diseases originating in the brain or liver," other than arthritis-related diseases. We also have a non-exclusive license from the NIH for the development and sale of AAV5 based therapeutic products to treat human diseases other than those covered by our exclusive license.

We believe that our exclusive license from the NIH includes the systemic administration of AAV5-based therapeutic products so long as such therapeutic products are "to be delivered to the brain or liver for treatment of human diseases originating in the brain or liver." However, Sangamo BioSciences, Inc., or Sangamo, has announced that it has broad worldwide licenses to use AAV vectors, including AAV5 and AAV6, for research, development and commercialization of therapies for hemophilia A and B, Huntington's disease and other targets. We believe Sangamo's view may be that our exclusive license excludes systemic administration because Sangamo interprets the phrase "to be delivered to" to require direct administration into the brain or liver. Our view is that the phrase "to be delivered to" indicates the ultimate destination of the therapy and not the location where it is first introduced into the body. Although we think our interpretation is correct, there can be no assurance that a court would agree with our interpretation regarding the meaning of this phrase. If our interpretation of the phrase "to be delivered to" is incorrect, then others may obtain licenses from the NIH that may enable them to compete with us in the systemic administration of AAV5-based therapeutics for treatment of human diseases originating in the brain or liver, which could harm our business.

If we fail to comply with our obligations in our intellectual property licenses with third parties, we could lose rights that are important to our business.

We in-license intellectual property from third parties that is material to Glybera and all of our product candidates, including technology related to our manufacturing process, our vector platform, and the therapeutic gene cassettes we are using. Our licensing arrangements with third parties impose diligence, development and commercialization timelines, milestone payment, royalty, insurance and other obligations on us. If we fail to comply with these obligations, our counterparties may have the right to terminate these agreements, in which case we might not be able to develop, manufacture or market any product that is covered by these agreements or may face other penalties under the agreements. Such an occurrence could materially adversely affect the value of the product candidate being developed under any such agreement. Termination of these agreements or reduction or elimination of our rights under these agreements may result in our having to negotiate new or amended agreements with less favorable terms, or cause us to lose our rights under these agreements, including our rights to important intellectual property or technology.

If we are unable to obtain and maintain patent protection for our technology and products, our ability to successfully commercialize our products may be impaired.

We rely upon a combination of in-licensed and owned patents, trade secret protection and confidentiality agreements to protect our intellectual property. Our success depends in large part on our ability to obtain and maintain this protection in the European Union, the United States and other countries, in part by filing patent applications related to our novel technologies and product candidates. Our patents may not provide us with any meaningful commercial protection, prevent competitors from competing with us or otherwise

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provide us with any competitive advantage. Our competitors may be able to circumvent our owned or licensed patents by developing similar or alternative technologies or products in a non-infringing manner.

The patent prosecution process is expensive and time-consuming, and we may not be able to file and prosecute all necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection.

The patent position of biotechnology and pharmaceutical companies generally is highly uncertain, involves complex legal and factual questions and has in recent years been the subject of much litigation. In addition, the laws of foreign countries may not protect our rights to the same extent as the laws of the United States. For example, EU patent law with respect to the patentability of methods of treatment of the human body is more limited than U.S. law. Publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after their priority date, or in some cases at all. Therefore, we cannot know with certainty whether we were the first to make the inventions or that we were the first to file for patent protection of the inventions claimed in our owned or licensed patents or pending patent applications. As a result, the issuance, scope, validity, enforceability and commercial value of our patent rights are highly uncertain. Our pending and future patent applications may not result in patents being issued that protect our technology or products, in whole or in part, or which effectively prevent others from commercializing competitive technologies and products. Changes in either the patent laws or interpretation of the patent laws in the European Union, the United States or other countries may diminish the value of our patents or narrow the scope of our patent protection.

If the scope of the patent protection we obtain is not sufficiently broad, our ability to successfully commercialize our technology and products may be impaired.

The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, and our owned and licensed patents may be challenged in the courts or patent offices in the European Union, the United States or elsewhere. Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and products. Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

Recent patent reform legislation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents. In September 2011, the Leahy-Smith America Invents Act, or the Leahy-Smith Act, was signed into law. The Leahy-Smith Act includes a number of significant changes to U.S. patent law. These include provisions that affect the way patent applications are prosecuted and may also affect patent litigation. The U.S. Patent and Trademark Office recently developed new regulations and procedures to govern administration of the Leahy-Smith Act, and many of the substantive changes to patent law associated with the Leahy-Smith Act and, in particular, the first to file provisions, only became effective in March 2013. Accordingly, it is not clear what, if any, impact the Leahy-Smith Act will have on the operation of our business. However, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business and financial condition.

Moreover, since September 2012, third parties now have standing to submit documents to the U.S. Patent and Trademark Office that relate to pending patent applications, known as pre-issuance submissions, for

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consideration during examination of a patent application. In addition, third parties may now challenge issued patents through inter partes reviews and post-grant reviews which include trials before a panel of administrative patent judges. We may be subject to such pre-issuance submissions, inter partes reviews or post-grant reviews, or become involved in opposition, re-examination, interference or derivation proceedings challenging our patent rights or the patent rights of others. An adverse determination in any such examination, proceeding or litigation could reduce the scope of, or invalidate, our patent rights, allow third parties to commercialize our technology or products and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize products without infringing third party patent rights. In addition, if the breadth or strength of protection provided by our patents and patent applications is threatened, it could dissuade companies from collaborating with us to license, develop or commercialize current or future product candidates.

We may become involved in lawsuits to protect or enforce our patents or other intellectual property, which could be expensive, time consuming and unsuccessful.

Competitors may infringe our owned or licensed patents or other intellectual property. To counter infringement or unauthorized use, we may be required to file infringement claims, which can be expensive and time consuming. Any claims we assert against perceived infringers could provoke these parties to assert counterclaims against us alleging that we infringe their patents. In addition, in a patent infringement proceeding, a court may decide that a patent of ours is invalid or unenforceable, in whole or in part, construe the patent's claims narrowly or refuse to stop the other party from using the technology at issue on the grounds that our patents do not cover the technology in question. An adverse result in any litigation proceeding could put one or more of our patents at risk of being invalidated or interpreted narrowly.

Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses, and could distract our technical and management personnel from their normal responsibilities. In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our ordinary shares. Such litigation or proceedings could substantially increase our operating losses and reduce the resources available for development activities or any future sales, marketing or distribution activities. We may not have sufficient financial or other resources to conduct such litigation or proceedings adequately. Some of our competitors may be able to sustain the costs of such litigation or proceedings more effectively than we can because of their greater financial resources. Uncertainties resulting from the initiation and continuation of patent litigation or other proceedings could compromise our ability to compete in the marketplace. Third parties may initiate legal proceedings alleging that we are infringing their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.

Our commercial success depends upon our ability, and the ability of our collaborators, to develop, manufacture, market and sell our product candidates and use our proprietary technologies without infringing the proprietary rights of third parties. There is considerable intellectual property litigation in the biotechnology and pharmaceutical industries. We may become party to, or threatened with, future adversarial proceedings or litigation regarding intellectual property rights with respect to our products and technology, including interference or derivation proceedings before the U.S. Patent and Trademark Office. Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future.

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Third parties may assert their intellectual property rights against us, which could require us to defend lawsuits, obtain licenses, and cease or delay commercializing certain product candidates.

If we are found to infringe a third party's intellectual property rights, we could be required to obtain a license from such third party to continue developing and marketing our products and technology. However, we may not be able to obtain any required license on commercially reasonable terms or at all. Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors access to the same technologies licensed to us. We could be forced, including by court order, to cease commercializing the infringing technology or product. In addition, we could be found liable for monetary damages, including treble damages and attorneys' fees if we are found to have wilfully infringed a patent. A finding of infringement could prevent us from commercializing our product candidates or force us to cease some of our business operations, which could materially harm our business. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar negative impact on our business.

For example, we are aware of patents owned by third parties that relate to some aspects of our programs that are still in development. In some cases, because we have not determined the final methods of manufacture, the method of administration or the therapeutic compositions for these programs, we cannot determine whether rights under such third party patents will be needed. In addition, in some cases, we believe that the claims of these patents are invalid or not infringed, or will expire before commercialization. However, if such patents are needed and found to be valid and infringed, we could be required to obtain licenses, which might not be available on commercially reasonable terms, or to cease or delay commercializing certain product candidates, or to change our programs to avoid infringement.

Our reliance on third parties may require us to share our trade secrets, which could increase the possibility that a competitor will discover them or that our trade secrets will be misappropriated or disclosed.

Because we collaborate with various organizations and academic research institutions on the advancement of our gene therapy platform, we must, at times, share trade secrets with them. We seek to protect our proprietary technology in part by entering into confidentiality agreements and, if applicable, materials transfer agreements, collaborative research agreements, consulting agreements or other similar agreements with our collaborators, advisors and consultants prior to beginning research or disclosing proprietary information. These agreements typically limit the rights of the third parties to use or disclose our confidential information, such as trade secrets. Despite the contractual provisions employed when working with third parties, the need to share trade secrets and other confidential information increases the risk that such trade secrets become known by our competitors, are inadvertently incorporated into the technology of others, or are disclosed or used in violation of these agreements. Given that our proprietary position is based, in part, on our know-how and trade secrets, a competitor's discovery of our trade secrets or other unauthorized use or disclosure would impair our competitive position and may have a material adverse effect on our business.

In addition, these agreements typically restrict the ability of our collaborators, advisors and consultants to publish data potentially relating to our trade secrets. Our academic collaborators typically have rights to publish data, provided that we are notified in advance and may delay publication for a specified time in order to secure our intellectual property rights arising from the collaboration. In other cases, publication rights are controlled exclusively by us, although in some cases we may share these rights with other parties. We also conduct joint research and development programs that may require us to share trade secrets under the terms of our research and development partnerships or similar agreements.

Some courts inside and outside the United States are less willing or unwilling to protect trade secrets. If any of our trade secrets were to be lawfully obtained or independently developed by a competitor, we would have no right to prevent them, or those to whom they communicate it, from using that technology or information to compete with us.

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Risks Related to Pricing and Reimbursement

We face uncertainty related to insurance coverage of and pricing and reimbursement for Glybera and any product candidates for which we may receive marketing approval.

We anticipate that the cost of treatment using Glybera or our other product candidates will be significant. We expect that most patients and their families will not be capable of paying for our products themselves. There will be no commercially viable market for Glybera or our other product candidates without reimbursement from third-party payors, such as government health administration authorities, private health insurers and other organizations. Even if there is a commercially viable market, if the level of third-party reimbursement is below our expectations, our revenues and gross margins will be adversely affected and our business will be harmed.

Government authorities and other third party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels. Reimbursement systems vary significantly by country and by region, and reimbursement approvals must be obtained on a country-by-country basis. Government authorities and third party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications and procedures. Increasingly, third party payors require drug companies to provide them with predetermined discounts from list prices, are exerting influence on decisions regarding the use of particular treatments and are limiting covered indications. If coverage and adequate reimbursement are not available or reimbursement is available only at limited levels, we may not be able to successfully commercialize Glybera or any product candidate for which we obtain marketing approval.

The pricing review period and pricing negotiations for new medicines take considerable time and have uncertain results. Pricing review and negotiation often begins only after the receipt of regulatory marketing approval, and some authorities require approval of the sale price of a product before it can be marketed. In some markets, particularly the countries of the European Union, prescription pharmaceutical pricing remains subject to continuing direct governmental control and to drug reimbursement programs even after initial approval is granted, and price reductions may be imposed. Prices of medical products may also be subject to varying price control mechanisms or limitations as part of national health systems if products may be considered not to be cost-effective or where the drug company's profits are deemed excessive. In addition, pricing and reimbursement decisions in certain countries can lead to mandatory price reductions or additional reimbursement restrictions in other countries. As a result of these restrictions, Glybera, as well as any product candidates for which we may obtain marketing approval in the future, may be subject to price regulations that delay or prohibit our or our partners' commercial launch of the product. In addition, we or our collaborators may elect to reduce the price of our products in order to increase the likelihood of obtaining reimbursement approvals. In the event that countries impose prices which are not sufficient to allow us or our collaborators to generate a profit, we or our collaborators may refuse to launch the product in such countries or withdraw the product from the market. If pricing is set at unsatisfactory levels, or if the price decreases, our business could be harmed, possibly materially. If we fail to obtain and sustain an adequate level of coverage and reimbursement for our products by third party payors, our ability to market and sell our products would be adversely affected and our business would be harmed.

Due to the generally limited addressable market for our target orphan indications and the potential for Glybera and our product candidates to offer therapeutic benefit in a single administration, we face uncertainty related to pricing and reimbursement for these product candidates.

The relatively small market size for orphan indications and the potential for long-term therapeutic benefit from a single administration present particular challenges to pricing review and negotiation for Glybera and our product candidates for which we may obtain marketing authorization. The patient populations for Glybera and our product candidates targeted at orphan disease are relatively small. If we are unable to obtain adequate levels of reimbursement relative to the small market size in our target orphan indications,

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our ability to support our development and commercial infrastructure and to successfully market and sell Glybera and other product candidates for which we may obtain marketing approval will be adversely affected.

We also anticipate that Glybera and many or all of our gene therapy product candidates may provide long-term, and potentially curative benefit with a single administration. This is a different paradigm than that of other pharmaceutical therapies, which often require an extended course of treatment or frequent administration. As a result, governments and other payors may be reluctant to provide the significant level of reimbursement that we seek at the time of administration of our gene therapies or may seek to tie reimbursement to clinical evidence of continuing therapeutic benefit over time. Although we anticipate that Glybera will need to be administered only once, there may be situations in which we may need to readminister Glybera, which may further complicate the pricing and reimbursement for Glybera. In addition, in light of the anticipated cost of these therapies, governments and other payors may be particularly restrictive in making coverage decisions. These factors could limit our commercial success and harm our business.

Recently enacted and future legislation and related market pricing pressures may affect the coverage and pricing and reimbursement we may obtain for our products.

A primary trend in the U.S. healthcare industry and elsewhere is cost containment. In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability to profitably sell any products for which we obtain marketing approval. We expect that existing, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we receive for any approved product. Any reduction in reimbursement from government programs may result in a similar reduction in payments from private payors. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenues, attain profitability, or commercialize our products.


Risks Related to Other Legal Compliance Matters

Our relationships with customers and third-party payors will be subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.

Healthcare providers, physicians and third-party payors will play a primary role in the recommendation and prescription of any products for which we obtain marketing approval. Our future arrangements with third-party payors and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute any products for which we obtain marketing approval.

Within the European Union, the control of unlawful marketing activities is a matter of national law in each of the member states. We could face civil, criminal and administrative sanctions if any member state determines that we have breached our obligations under its national laws. Industry associations also closely monitor the activities of member companies. If these organizations or authorities name us as having breached our obligations under their regulations, rules or standards, our reputation would suffer and our business and financial condition could be adversely affected. Similarly, failure to comply with the European Union's requirements regarding the protection of personal information can also lead to significant penalties and sanctions.

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If we market a product in the United States in the future, we will be subject to various federal and state laws and regulations including:

    the federal Anti-Kickback Statute, which prohibits, among other things, persons from knowingly and wilfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward, or in return for, either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made under a federal healthcare program such as Medicare and Medicaid;

    the federal False Claims Act, which imposes criminal and civil penalties, including civil whistleblower or qui tam actions, against individuals or entities for knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false or fraudulent or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government;

    the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters and also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;

    federal law that requires applicable manufacturers of covered drugs to report payments and other transfers of value to physicians and teaching hospitals;

    the U.S. Foreign Corrupt Practices Act, which prohibits the offering to pay, paying or promising to pay or authorizing the payment of money or anything of value to a foreign official in order to influence any act or decision of the foreign official or secure any improper advantage in order to obtain or retain business; and

    certain state laws that require pharmaceutical companies to comply with the pharmaceutical industry's voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government and require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures. State and foreign laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not pre-empted by HIPAA, thus complicating compliance efforts.

We will also be subject to similar local laws in jurisdictions in which we may seek or obtain marketing authorization, or in which we may have operations or sales. Efforts to ensure that our business arrangements with third parties will comply with applicable laws and regulations will involve substantial costs. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our operations, or the activities of our collaborators, distributors or other third-party agents are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, exclusion of products from government funded healthcare programs and the curtailment or restructuring of our operations. If any of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs.

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If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could harm our business.

We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Our operations involve the use of hazardous and flammable materials, including chemicals and biological materials. Our operations also produce hazardous waste products. We cannot eliminate the risk of contamination or injury from these materials. In the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties for failure to comply with such laws and regulations.

Although we maintain employer's liability insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, this insurance may not provide adequate coverage against potential liabilities. We do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us in connection with our storage or disposal of biological, hazardous or radioactive materials.

In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may impair our research, development or production efforts. Our failure to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions.

Product liability lawsuits against us could cause us to incur substantial liabilities and to limit commercialization of Glybera and any products that we may develop in the future.

We face an inherent risk of product liability related to the testing of our product candidates in human clinical trials and will face an even greater risk when we commercially sell Glybera and any other products that we may develop. If we cannot successfully defend ourselves against claims that our product candidates or products caused injuries, we will incur substantial liabilities. Regardless of merit or eventual outcome, liability claims may result in:

    decreased demand for any product candidates or products that we develop or sell;

    injury to our reputation and significant negative media attention;

    negative publicity or public opinion surrounding gene therapy;

    withdrawal of clinical trial participants;

    significant costs to defend the related litigation;

    substantial monetary awards to trial participants or patients;

    loss of revenue;

    reduced resources of our management to pursue our business strategy; and

    the inability to further develop or commercialize any products that we develop.

We currently hold €6,000,000 in clinical trial insurance coverage in the aggregate, with a per incident limit of €400,000 to €450,000, with respect to the clinical studies we conduct. Such coverage may not be adequate to cover all liabilities that we may incur. We may need to increase our insurance coverage as we expand our clinical trials and commercialize Glybera. In addition, insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise.

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Risks Related to Employee Matters and Managing Growth

Our future success depends on our ability to retain key executives and technical staff and to attract, retain and motivate qualified personnel.

We are highly dependent on the research and development, clinical and business development expertise of our Chief Executive Officer, Jörn Aldag, our Chief Medical Officer, Christian Meyer, M.D., and our Vice President, Research and Development, Harald Petry, as well as the other principal members of our management, scientific and clinical team. Although we have entered into employment agreements with our senior managment, each of them may terminate their employment on relatively short notice. We do not maintain "key person" insurance for any of our senior management or employees.

Substantially all share options outstanding under our 2012 plan will vest in full upon the closing of this offering, including those held by our senior management and key employees. Following this offering, therefore, our outstanding options will no longer have retention value, and we may not have appropriate adequate equity incentives in place to retain or motivate these key personnel.

The loss of the services of our senior management or other key employees could impede the achievement of our research, development and commercialization objectives and seriously harm our ability to successfully implement our business strategy. Furthermore, replacing senior management and key employees may be difficult and may take an extended period of time because of the limited number of individuals in our industry with the breadth and depth of skills and experience required to successfully develop, gain regulatory approval of and commercialize gene therapy products. Competition to hire from this limited pool is intense, and we may be unable to hire, train, retain or motivate these key personnel on acceptable terms.

In connection with our corporate restructuring in 2012, we lost many talented employees, including employees with an extensive understanding of our clinical programs as well as our regulatory and financial affairs. This reduction in headcount may adversely affect our ability in the future to attract and retain other qualified staff.

We also experience competition for the hiring of scientific and clinical personnel from universities and research institutions. In addition, we rely on consultants and advisors, including scientific and clinical advisors, to assist us in formulating our research and development and commercialization strategy. Our consultants and advisors may have commitments under employment, consulting or advisory contracts with other entities that may limit their availability to us. If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth strategy will be limited.

We plan to expand our key capabilities and, as a result, may encounter difficulties in managing our growth, which could disrupt our operations. If we are unable to establish such capabilities we may not be successful in commercializing Glybera or our other product candidates in the United States or other countries, even if we receive marketing approval.

If we receive marketing approval, we intend to build a sales, marketing and medical affairs infrastructure to market Glybera and potentially other product candidates in the United States and other countries. We currently have no experience building and training an internal sales force. We expect in the future to experience significant growth in the number of our employees and the scope of our operations, particularly in the areas of manufacturing, clinical development, regulatory affairs and sales, marketing and distribution. To manage our anticipated future growth, we will be required to implement and improve our managerial, operational and financial systems, expand our facilities and recruit and train additional qualified personnel. Recruiting and training a sales force is expensive and time-consuming and could delay any ultimate launch of Glybera or other product candidates for which we are able to obtain marketing approval in the United States and other markets. Due to our limited financial resources and the limited experience of our management team in running a company with this level of anticipated growth, we may not be able to effectively manage the expansion of our operations or recruit and train additional qualified personnel.

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If the commercial launch of Glybera or any other product candidate for which we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses. This may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing personnel. Factors that may inhibit our efforts to commercialize Glybera or other product candidates on our own include:

    our inability to recruit, train and retain adequate numbers of effective sales, marketing and medical affairs personnel;

    the inability of sales, marketing and medical affairs personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe our gene therapies;

    the lack of complementary products to be offered by our sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines; and

    unforeseen costs and expenses associated with creating an independent sales and marketing organization.

If we do not successfully establish sales, marketing and medical affairs capabilities, either on our own or in collaboration with third parties, we will not be successful in commercializing Glybera or other product candidates in the United States.


Risks Related to this Offering and Ownership of our Ordinary Shares

There has been no public market for our ordinary shares prior to this offering, and you may not be able to resell our ordinary shares at or above the price you paid, or at all.

Prior to this initial public offering, there was no established public market for our ordinary shares. Our predecessor entity, Amsterdam Molecular Therapeutics, was previously listed on EuroNext Amsterdam. Since our acquisition of the business of AMT in 2012 as part of a corporate reorganization, there has been very limited liquidity for our ordinary shares through an electronic trading platform in the Netherlands. We have applied for listing of our ordinary shares on the NASDAQ Global Market. If an active trading market for our ordinary shares does not develop after this offering, the market price and liquidity of our ordinary shares will be materially and adversely affected.

The initial public offering price for our ordinary shares will be determined by negotiations between us and the underwriters and may bear no relationship to the market price for our ordinary shares after the initial public offering. We cannot assure you that an active trading market for our ordinary shares will develop or that the market price of our ordinary shares will not decline below the initial public offering price.

The price of our ordinary shares may be volatile and fluctuate substantially, which could result in substantial losses for purchasers of our ordinary shares in this offering.

Our share price is likely to be volatile. The stock market in general and the market for smaller biopharmaceutical companies in particular have experienced extreme volatility that has often been unrelated to the operating performance of particular companies. As a result of this volatility, you may not be able to sell your ordinary shares at or above the initial public offering price. The market price for our ordinary shares may be influenced by many factors, including:

    the success of competitive products or technologies;

    results of clinical trials of our product candidates or those of our competitors;

    public perception of gene therapy;

    regulatory delays and greater government regulation of potential products due to adverse events;

    regulatory or legal developments in the European Union, the United States and other countries;

    developments or disputes concerning patent applications, issued patents or other proprietary rights;

    the recruitment or departure of key personnel;

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    the level of expenses related to any of our product candidates or clinical development programs;

    the results of our efforts to discover, develop, acquire or in-license additional product candidates or products;

    actual or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts;

    variations in our financial results or those of companies that are perceived to be similar to us;

    changes in the structure of healthcare payment systems;

    market conditions in the pharmaceutical and biotechnology sectors; and

    general economic, industry and market conditions.

After this offering, our senior managers, directors and principal shareholders, if they choose to act together, will continue to have the ability to control all matters submitted to shareholders for approval.

Upon the closing of this offering, our management board and supervisory board members, and senior management, combined with our shareholders who owned more than 5% of our outstanding ordinary shares before this offering, will, in the aggregate, beneficially own approximately 57% of our share capital. Assuming an initial public offering price of $14.00 per share, which is the midpoint of the price range on the cover of this prospectus, if our 5% shareholders and their affiliated entities purchase all of the $20 million of our ordinary shares they have indicated an interest in purchasing in this offering, the percentage of our ordinary shares beneficially owned by our management board and supervisory board members, senior management and shareholders who owned more than 5% of our outstanding ordinary shares before this offering will, in the aggregate, increase to approximately 66% of our ordinary shares. As a result, if these shareholders were to choose to act together, they would be able to control all matters submitted to our shareholders for approval, as well as our management and affairs. For example, these persons, if they choose to act together, would control the election of supervisory board directors and approval of any merger, consolidation or sale of all or substantially all of our assets.

Provisions of our articles of association or Dutch corporate law might deter acquisition bids for us that might be considered favorable and prevent or frustrate any attempt to replace or remove the management board and supervisory board.

Certain provisions of our articles of association may make it more difficult for a third party to acquire control of us or effect a change in our management board or supervisory board. These provisions include:

    staggered three-year terms of our supervisory directors;

    a provision that our managing directors and supervisory directors may only be removed at a general meeting of shareholders by a two-thirds majority of votes cast representing more than half of the issued share capital of the company (unless the removal was proposed by the supervisory board); and

    a requirement that certain matters, including an amendment of our articles of association, may only be brought to our shareholders for a vote upon a proposal by our management board that has been approved by our supervisory board.

We do not expect to pay dividends in the foreseeable future.

We have not paid any dividends since our incorporation. Even if future operations lead to significant levels of distributable profits, we currently intend that earnings, if any, will be reinvested in our business and that dividends will not be paid until we have an established revenue stream to support continuing dividends. Under Dutch law, we may only pay dividends if our shareholders' equity exceeds the sum of the paid-up and called-up share capital plus the reserves required to be maintained by Dutch law or by our articles of association. In addition, our loan agreement with Hercules contains, and any other loan facilities that we may enter into may contain, restrictions on our ability, or that of our subsidiaries, to pay dividends. Subject to such restrictions, a proposal for the payment of cash dividends in the future, if any, will be at the discretion of our management board, subject to the approval of our supervisory board, and will depend upon

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such factors as earnings levels, capital requirements, contractual restrictions, our overall financial condition and any other factors deemed relevant by our management board. Accordingly, investors cannot rely on dividend income from our ordinary shares and any returns on an investment in our ordinary shares will likely depend entirely upon any future appreciation in the price of our ordinary shares.

We expect that only a relatively small percentage of our ordinary shares will be publicly traded following this offering, which may limit the liquidity of your investment and may have a material adverse effect on the price of our ordinary shares.

After this offering, approximately 43% of our ordinary shares will be held by parties other than our management board and supervisory board members and senior management, existing shareholders holding 5% or more of our ordinary shares, and their respective affiliates, or approximately 34% if our 5% shareholders and their affiliated entities purchase all of the $20 million of our ordinary shares they have indicated an interest in purchasing in this offering, assuming an initial public offering price of $14.00 per share, which is the midpoint of the price range on the cover of this prospectus. As a result, we expect that only a relatively small number of our ordinary shares will be actively traded in the public market following this offering. Reduced liquidity may have a material adverse effect on the price of our ordinary shares.

You will not be able to trade our ordinary shares on any exchange outside the United States.

Our ordinary shares will be listed only in the United States on the NASDAQ Global Market and we have no plans to list our ordinary shares in any other jurisdiction. As a result, a holder of our ordinary shares outside the United States may not be able to effect transactions in our ordinary shares as readily as the holder may if our securities were listed on an exchange in that holder's home jurisdiction.

The sale of a substantial number of our ordinary shares following this offering may cause the market price of our ordinary shares to decline.

Sales of a substantial number of shares in the public market may occur at any time after the expiration of the lock-up agreements described in the "Underwriting" section of this prospectus. Our sale or the resale by our shareholders of shares, or a market expectation of such sales, after this offering may cause the market price of our ordinary shares to decline. After this offering, we will have outstanding 16,794,906 ordinary shares. Of these, the 4,600,000 ordinary shares sold in this offering will be freely transferable without restriction. The remaining 12,194,906 ordinary shares, or 73% of our outstanding shares after this offering, are currently restricted as a result of securities laws or lock-up agreements but will be able to be sold, subject to any applicable volume limitations under U.S. federal securities laws with respect to affiliate sales, in the future as set forth in "Shares Eligible for Future Sale" and "Underwriting" below.

We are an "emerging growth company," and the reduced disclosure requirements applicable to emerging growth companies may make our ordinary shares less attractive to investors.

We are an "emerging growth company," as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act, and may remain an emerging growth company for up to five years. For so long as we remain an emerging growth company, we are permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that are not emerging growth companies. These exemptions include:

    being permitted to provide only two years of audited financial statements in this prospectus, in addition to any required unaudited interim financial statements, with correspondingly reduced "Management's Discussion and Analysis of Financial Condition and Results of Operations" disclosure;

    not being required to comply with the auditor attestation requirements in the assessment of our internal control over financial reporting; and

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    not being required to comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor's report providing additional information about the audit and the financial statements;

We have taken advantage of reduced reporting burdens in this prospectus. In particular, in this prospectus, we have provided only two years of audited financial statements. We cannot predict whether investors will find our ordinary shares less attractive if we rely on these exemptions. If some investors find our ordinary shares less attractive as a result, there may be a less active trading market for our ordinary shares and our share price may be more volatile.

We will be a foreign private issuer and, as a result, we will not be subject to U.S. proxy rules and will be subject to Exchange Act reporting obligations that, to some extent, are more lenient and less frequent than those of a U.S. domestic public company.

Upon consummation of this offering, we will report under the Securities Exchange Act of 1934, as amended, or the Exchange Act, as a non-U.S. company with foreign private issuer status. Because we qualify as a foreign private issuer under the Exchange Act and although we are subject to Dutch laws and regulations with regard to such matters and intend to furnish quarterly financial information to the SEC, we are exempt from certain provisions of the Exchange Act that are applicable to U.S. domestic public companies, including:

    the sections of the Exchange Act regulating the solicitation of proxies, consents or authorizations in respect of a security registered under the Exchange Act;

    the sections of the Exchange Act requiring insiders to file public reports of their stock ownership and trading activities and liability for insiders who profit from trades made in a short period of time; and

    the rules under the Exchange Act requiring the filing with the Securities and Exchange Commission of quarterly reports on Form 10-Q containing unaudited financial and other specified information, or current reports on Form 8-K, upon the occurrence of specified significant events.

In addition, foreign private issuers are not be required to file their annual report on Form 20-F until 120 days after the end of each fiscal year, while U.S. domestic issuers that are accelerated filers are required to file their annual report on Form 10-K within 75 days after the end of each fiscal year. Foreign private issuers are also exempt from the Regulation Fair Disclosure, aimed at preventing issuers from making selective disclosures of material information. As a result of the above, you may not have the same protections afforded to shareholders of companies that are not foreign private issuers.

We may lose our foreign private issuer status which would then require us to comply with the Exchange Act's domestic reporting regime and cause us to incur significant legal, accounting and other expenses.

We are a foreign private issuer and therefore we are not required to comply with all of the periodic disclosure and current reporting requirements of the Exchange Act applicable to U.S. domestic issuers. In order to maintain our current status as a foreign private issuer, either:

    a majority of our ordinary shares must be either directly or indirectly owned of record by non-residents of the United States; or

    a majority of our "executive officers" or directors may not be U.S. citizens or residents, more than 50 percent of our assets cannot be located in the United States and our business must be administered principally outside the United States.

If we lost this status, we would be required to comply with the Exchange Act reporting and other requirements applicable to U.S. domestic issuers, which are more detailed and extensive than the requirements for foreign private issuers.

We may also be required to make changes in our corporate governance practices in accordance with various SEC and NASDAQ rules. The regulatory and compliance costs to us under U.S. securities laws if we are

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required to comply with the reporting requirements applicable to a U.S. domestic issuer may be significantly higher than the cost we would incur as a foreign private issuer. As a result, we expect that a loss of foreign private issuer status would increase our legal and financial compliance costs and would make some activities more time consuming and costly. We also expect that if we were required to comply with the rules and regulations applicable to U.S. domestic issuers, it would make it more difficult and expensive for us to obtain director and officer liability insurance, and we may be required to accept reduced coverage or incur substantially higher costs to obtain coverage. These rules and regulations could also make it more difficult for us to attract and retain qualified members of our supervisory board.

We have broad discretion in the use of the net proceeds from this offering and may not use them effectively.

Our management will have broad discretion in the application of the net proceeds from this offering and could spend the proceeds in ways that do not improve our results of operations or enhance the value of our ordinary shares. The failure by our management to apply these funds effectively could result in financial losses that could have a material adverse effect on our business, cause the price of our ordinary shares to decline and delay the development of our product candidates. Pending their use, we may invest the net proceeds from this offering in a manner that does not produce income or that loses value.

We will incur increased costs as a result of operating as a public company, and our management will be required to devote substantial time to new compliance initiatives and corporate governance practices.

As a public company, and particularly after we are no longer an emerging growth company, we will incur significant legal, accounting and other expenses that we did not incur as a private company. We currently estimate that we will incur incremental annual costs of approximately $1.5 million associated with operating as a public company, although it is possible that our actual incremental annual costs will be higher than we currently estimate. The Sarbanes-Oxley Act of 2002, the Dodd-Frank Wall Street Reform and Consumer Protection Act, the listing requirements of The NASDAQ Global Market and other applicable securities rules and regulations impose various requirements on public companies, including establishment and maintenance of effective disclosure and financial controls and corporate governance practices. Our management and other personnel will need to devote a substantial amount of time to these compliance initiatives.

These rules and regulations are often subject to varying interpretations, in many cases due to their lack of specificity, and, as a result, their application in practice may evolve over time as new guidance is provided by regulatory and governing bodies. This could result in continuing uncertainty regarding compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices and control environment process improvements.

If we fail to implement and maintain an effective system of internal controls, we may be unable to accurately report our results of operations or prevent fraud or fail to meet our reporting obligations, and investor confidence and the market price of our ordinary shares may be materially and adversely affected.

Prior to this offering, we were a private company with limited accounting personnel and other resources with which to address our internal controls and procedures. Our independent registered public accounting firm has not conducted an audit of our internal control over financial reporting. However, in connection with the audit of our consolidated financial statements as of and for year ended December 31, 2012 and the review of our consolidated financial statements as of and for the nine months ended September 30, 2013, we and our independent registered public accounting firm identified three material weaknesses in our internal control over financial reporting. A significant deficiency is a control deficiency, or a combination of control deficiencies, that adversely affects our ability to initiate, authorize, record, process, or report external financial data reliably in accordance with IFRS such that there is more than a remote likelihood that a misstatement of our annual or interim financial statements that is more than inconsequential will not be

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prevented or detected by our employees. A material weakness is a significant deficiency, or combination of significant deficiencies, that results in more than a remote likelihood that a material misstatement of our annual or interim financial statement will not be prevented or detected by our employees. In response, we have begun the process of evaluating our internal control over financial reporting, although we may not complete our review until after this offering is completed. We have also taken several remedial actions to address these material weaknesses. For details, see "Management's Discussion and Analysis of Financial Condition and Results of Operations—Internal Control Over Financial Reporting."

Furthermore, it is possible that, had our independent registered public accounting firm conducted an audit of our internal control over financial reporting, such firm might have identified additional material weaknesses and deficiencies. Upon the completion of this offering, we will become a public company in the United States subject to the Sarbanes-Oxley Act of 2002. Section 404 of the Sarbanes-Oxley Act of 2002, or Section 404, will require that we include a report of management on our internal control over financial reporting in our annual report on Form 20-F beginning with our annual report for the fiscal year ending December 31, 2015. In addition, once we cease to be an "emerging growth company" as such term is defined in the JOBS Act, our independent registered public accounting firm must attest to and report on the effectiveness of our internal control over financial reporting. Our management may conclude that our internal control over financial reporting is not effective. Moreover, even if our management concludes that our internal control over financial reporting is effective, our independent registered public accounting firm, after conducting its own independent testing, may issue a report that is qualified if it is not satisfied with our internal controls or the level at which our controls are documented, designed, operated or reviewed, or if it interprets the relevant requirements differently from us. In addition, after we become a public company, our reporting obligations may place a significant strain on our management, operational and financial resources and systems for the foreseeable future. We may be unable to timely complete our evaluation, testing and any required remediation.

During the course of documenting and testing our internal control procedures in order to satisfy the requirements of Section 404, we may identify other weaknesses and deficiencies in our internal control over financial reporting. In addition, if we fail to maintain the adequacy of our internal control over financial reporting, as these standards are modified, supplemented or amended from time to time, we may not be able to conclude on an ongoing basis that we have effective internal control over financial reporting in accordance with Section 404. If we fail to achieve and maintain an effective internal control environment, we could experience material misstatements in our financial statements and fail to meet our reporting obligations, which would likely cause investors to lose confidence in our reported financial information. This could in turn limit our access to capital markets, harm our results of operations, and lead to a decline in the trading price of our ordinary shares. Additionally, ineffective internal control over financial reporting could expose us to increased risk of fraud or misuse of corporate assets and subject us to potential delisting from the NASDAQ Global Market, regulatory investigations and civil or criminal sanctions. We may also be required to restate our financial statements for prior periods.

You will experience immediate and substantial dilution in the net tangible book value of the ordinary shares you purchase.

The initial public offering price per ordinary share will be substantially higher than the net tangible book value per ordinary share prior to the offering. Consequently, when you purchase ordinary shares in the offering at the assumed initial public offering price, you will incur immediate dilution of $12.96 per ordinary share. See "Dilution."

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We intend to rely on NASDAQ Stock Market rules that permit us to comply with applicable Dutch corporate governance practices, rather than the corresponding domestic U.S. corporate governance practices, and therefore your rights as a shareholder will differ from the rights you would have as a shareholder of a domestic U.S. issuer.

As a foreign private issuer whose ordinary shares are listed on the NASDAQ Global Market, we are permitted in certain cases to follow Dutch corporate governance practices instead of the corresponding requirements of the NASDAQ Marketplace Rules. A foreign private issuer that elects to follow a home country practice instead of NASDAQ requirements must submit to NASDAQ in advance a written statement from an independent counsel in such issuer's home country certifying that the issuer's practices are not prohibited by the home country's laws. In addition, a foreign private issuer must disclose in its annual reports filed with the Securities and Exchange Commission each such requirement that it does not follow and describe the home country practice followed instead of any such requirement. We intend to follow Dutch corporate governance practices with regard to the quorum requirements applicable to meetings of shareholders and the provision of proxy statements for general meetings of shareholders, rather than the corresponding domestic U.S. corporate governance practices. In accordance with Dutch law and generally accepted business practices, our articles of association do not provide quorum requirements generally applicable to general meetings of shareholders. Although we do intend to provide shareholders with an agenda and other relevant documents for the general meeting of shareholders, Dutch law does not have a regulatory regime for the solicitation of proxies and the solicitation of proxies is not a generally accepted business practice in the Netherlands. Accordingly, our shareholders may not be afforded the same protection as provided under NASDAQ's corporate governance rules.

We do not comply with all the provisions of the Dutch Corporate Governance Code. This may affect your rights as a shareholder.

As a Dutch company we are subject to the Dutch Corporate Governance Code, or DCGC. The DCGC contains both principles and best practice provisions for management boards, supervisory boards, shareholders and general meetings of shareholders, financial reporting, auditors, disclosure, compliance and enforcement standards. The DCGC applies to all Dutch companies listed on a government-recognized stock exchange, whether in the Netherlands or elsewhere, including the NASDAQ Global Market. The principles and best practice provisions apply to our management board and supervisory board, in relation to their role and composition, conflicts of interest and independence requirements, board committees and remuneration, shareholders and the general meeting of shareholders, for example, regarding anti-takeover protection and obligations of the company to provide information to its shareholders; and financial reporting, including external auditor and internal audit requirements. We do not comply with all the provisions of the DCGC. This may affect your rights as a shareholder and you may not have the same level of protection as a shareholder in a Dutch company that fully complies with the DCGC.


Risks for U.S. Holders

We cannot assure you that we will not be classified as a passive foreign investment company for any taxable year, which may result in adverse U.S. federal income tax consequence to U.S. holders.

Based on our estimated gross income and average value of our gross assets, taking into account the assumed initial public offering price of our shares in this offering and the expected price of our shares following the offering, and the nature of our business, we do not expect to be considered a "passive foreign investment company," or PFIC, for U.S. federal income tax for the 2013 tax year or in the foreseeable future. A corporation organized outside the United States generally will be classified as a PFIC for U.S. federal income tax purposes in any taxable year in which at least 75% of its gross income is passive income or on average at least 50% of the gross value of its assets is attributable to assets that produce passive income or are held for the production of passive income. Passive income for this purpose generally includes dividends, interest, royalties, rents and gains from commodities and securities transactions. Our status in

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any taxable year will depend on our assets and activities in each year, and because this is a factual determination made annually after the end of each taxable year, there can be no assurance that we will not be considered a PFIC for the current taxable year or any future taxable year. The market value of our assets may be determined in large part by reference to the market price of our ordinary shares, which is likely to fluctuate after the offering, and may fluctuate considerably given that market prices of biotechnology companies have been especially volatile. If we were to be treated as a PFIC for any taxable year during which a U.S. holder held our ordinary shares, however, certain adverse U.S. federal income tax consequences could apply to the U.S. holder. See "Taxation—Taxation in the United States—Passive foreign investment company considerations."

Any U.S. or other foreign judgments you may obtain against us may be difficult to enforce against us in the Netherlands.

We are incorporated under the laws of the Netherlands. We currently have only limited operations in the United States. Most of our assets are currently located in the Netherlands.

The majority of our managing directors, supervisory directors and senior management reside outside the United States. As a result, it may not be possible for investors to effect service of process within the United States upon such persons or to enforce judgments against them or us in U.S. courts, including judgments predicated upon the civil liability provisions of the federal securities laws of the United States. In addition, it is not clear whether a Dutch court would impose civil liability on us or any of our managing directors or supervisory directors in an original action based solely upon the federal securities laws of the United States brought in a court of competent jurisdiction in the Netherlands.

The United States and the Netherlands currently do not have a treaty providing for the reciprocal recognition and enforcement of judgments, other than arbitration awards, in civil and commercial matters. Consequently, a final judgment for payment given by a court in the United States, whether or not predicated solely upon U.S. securities laws, would not automatically be recognized or enforceable in the Netherlands. In order to obtain a judgment which is enforceable in the Netherlands, the party in whose favor a final and conclusive judgment of the U.S. court has been rendered will be required to file its claim with a court of competent jurisdiction in the Netherlands. Such party may submit to the Dutch court the final judgment rendered by the U.S. court. If and to the extent that the Dutch court finds that the jurisdiction of the U.S. court has been based on grounds which are internationally acceptable and that proper legal procedures have been observed, the Dutch court will, in principle, give binding effect to the judgment of the U.S. court, unless such judgment contravenes principles of public policy of the Netherlands. Dutch courts may deny the recognition and enforcement of punitive damages or other awards. Moreover, a Dutch court may reduce the amount of damages granted by a U.S. court and recognize damages only to the extent that they are necessary to compensate actual losses or damages. Enforcement and recognition of judgments of U.S. courts in the Netherlands are solely governed by the provisions of the Dutch Civil Procedure Code.

Based on the lack of a treaty as described above, U.S. investors may not be able to enforce against us or our management board or supervisory board members, representatives or certain experts named herein who are residents of the Netherlands or countries other than the United States any judgments obtained in U.S. courts in civil and commercial matters, including judgments under the U.S. federal securities laws.

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The rights and responsibilities of our shareholders and directors are governed by Dutch law and differ in some important respects from the rights and responsibilities of shareholders under U.S. law.

Our corporate affairs are governed by our articles of association and by the laws governing companies incorporated in the Netherlands. The rights of our shareholders and the responsibilities of members of our supervisory board and management board under Dutch law are different than under the laws of some U.S. jurisdictions. In the performance of their duties, our supervisory board and management board are required by Dutch law to consider the interests of uniQure, its shareholders, its employees and other stakeholders and not only those of our shareholders.

In addition, the rights of holders of shares and many of the rights of shareholders as they relate to, for example, the exercise of shareholder rights, are governed by Dutch law and our articles of association and differ from the rights of shareholders under U.S. law. For example, Dutch law does not grant appraisal rights to a company's shareholders who wish to challenge the consideration to be paid upon a merger or consolidation of the company. See "Description of Share Capital—Comparison of Dutch corporate law and our Articles of Association and Delaware corporate law."

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SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS AND INDUSTRY DATA

This prospectus contains forward-looking statements that involve substantial risks and uncertainties. All statements contained in this prospectus, other than statements of historical fact, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. The forward-looking statements in this prospectus include, among other things, statements about:

    the timing of commencement of and receipt of data from our planned clinical trials;

    the timing of the ongoing and planned clinical trials conducted by our collaborators and other third parties;

    our ongoing and planned discovery and development of product candidates;

    our expectations regarding the timing or likelihood of regulatory filings and approvals for our product candidates;

    our ability to expand our sales, marketing and medical affairs infrastructure;

    our ability to successfully commercialize Glybera and our product candidates;

    the potential advantages of Glybera and our product candidates;

    our estimates regarding the market opportunities for our product candidates;

    the rate and degree of market acceptance and clinical benefit of Glybera and our product candidates;

    our expectations regarding milestone, royalty and expense reimbursement payments under our licensing arrangements;

    our estimates of the net amount will we retain from sales of Glybera;

    the timing and cost of the build-out of our manufacturing facility in Lexington, Massachusetts;

    our ability to establish and maintain collaborations;

    our ability to develop, acquire or in-license additional product candidates and other key intellectual property;

    our future intellectual property position; and

    our estimates regarding expenses, future revenues, capital requirements and needs for additional financing.

We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. We have included important factors in the cautionary statements included in this prospectus, particularly in the "Risk Factors" section, that we believe could cause actual results or events to differ materially from the forward-looking statements that we make. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make.

You should read this prospectus and the documents that we have filed as exhibits to the registration statement of which this prospectus is a part completely and with the understanding that our actual future results may be materially different from what we expect. We do not assume any obligation to update any forward-looking statements.

This prospectus includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties. Industry publications and third party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. Although we believe these industry publications and third party research, surveys and studies are reliable, we have not independently verified such data.

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USE OF PROCEEDS

We estimate that we will receive net proceeds from this offering of $56.4 million (€41.8 million), based upon an assumed initial public offering price of $14.00 per ordinary share (the midpoint of the estimated price range set forth on the cover page of this prospectus), after deducting underwriting discounts and any offering expenses payable by us. If the underwriters exercise their option to purchase additional shares, we estimate that the net proceeds of the offering will be $65.4 million (€48.4 million).

A $1.00 increase (decrease) in the assumed initial public offering price of $14.00 per ordinary share would increase (decrease) the net proceeds to us from this offering by approximately $4.3 million, assuming the number of ordinary shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting underwriting discounts and commissions and estimated offering expenses payable by us. Similarly, each increase (decrease) of one million ordinary shares in the number of ordinary shares offered by us would increase (decrease) the net proceeds to us from this offering by approximately $13.0 million, assuming the assumed initial public offering price remains the same and after deducting underwriting discounts and commissions and estimated offering expenses payable by us.

As of September 30, 2013, we had cash and cash equivalents of €31.4 million ($42.4 million). We currently estimate that we will use the net proceeds from this offering, together with our cash on hand, as follows:

    approximately €11.0 million ($15.0 million) to complete the building out and equipping of our manufacturing facility in Lexington, Massachusetts;

    approximately €6.0 million ($8.0 million) to support our further clinical development of Glybera, and our application for marketing approval of Glybera and preparation for potential commercial launch in the United States;

    approximately €4.0 million ($5.0 million) to fund our share of the costs related to our planned Phase I/II clinical trial of AMT-060 in hemophilia B;

    approximately €8.0 million ($11.0 million) to advance the development of our other product candidates and research activities, including financing our collaboration with 4D Molecular Therapeutics; and

    the remainder for working capital and for general corporate purposes, including the costs of operating our facilities in Amsterdam and Lexington, Massachusetts, service on our indebtedness and potentially for acquisitions or investments in other businesses, technologies or product candidates.

This expected use of net proceeds from this offering represents our intentions based upon our current plans and business conditions, which could change in the future as our plans and business conditions evolve. The amounts and timing of our actual expenditures may vary significantly depending on numerous factors, including the progress of our development, the status of and results from clinical trials, as well as any collaborations that we may enter into with third parties for our product candidates, and any unforeseen cash needs. As a result, our management retains broad discretion over the allocation of the net proceeds from this offering. We have no current agreements, commitments or understandings for any material acquisitions or licenses of any products, businesses or technologies.

Pending our use of the net proceeds from this offering, we intend to invest the net proceeds in a variety of capital preservation investments, including term deposits, short-term, investment-grade, interest-bearing instruments and U.S. government securities.

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DIVIDEND POLICY

We have never declared or paid any dividends on our ordinary shares, and we currently do not plan to declare dividends on our ordinary shares in the foreseeable future. Under Dutch law, we may only pay dividends if our shareholders' equity exceeds the sum of the paid-up and called-up share capital plus the reserves required to be maintained by Dutch law or by our articles of association. In addition, our loan agreement with Hercules contains, and any other loan facilities that we may enter into may contain, restrictions on our ability, or that of our subsidiaries, to pay dividends. Subject to such restrictions, a proposal for the payment of cash dividends in the future, if any, will be at the discretion of our management board, subject to the approval of our supervisory board, and will depend upon such factors as earnings levels, capital requirements, contractual restrictions, our overall financial condition and any other factors deemed relevant by our management board.

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CAPITALIZATION

The following table sets forth our cash and cash equivalents and capitalization as of September 30, 2013:

    on an actual basis, reflecting the 5-for-1 consolidation of our shares, which will have the effect of a reverse share split, that will be effective prior to the effectiveness of this registration statement, as noted above; and

    on an as adjusted basis to give effect to the sale of 4,600,000 ordinary shares by us in this offering, assuming an initial public offering price of $14.00 per ordinary share, the midpoint of the price range set forth on the cover page of this prospectus, and after deducting the estimated underwriting discounts and commissions and estimated offering expenses payable by us and the application of such net proceeds as described under "Use of Proceeds."

This table should be read together with our consolidated financial statements and the related notes and the "Management's Discussion and Analysis of Financial Condition and Results of Operations" section of this prospectus.


 
  AS OF SEPTEMBER 30, 2013  
(in thousands, except share and per share data)
  ACTUAL   AS ADJUSTED(1)  

Cash and cash equivalents

  31,427   73,785  
           

Total debt

    8,456     8,456  

Shareholders' equity:

             

Share capital

             

Ordinary shares

    609     839  

Share premium

    142,444     185,869  

Other reserves

    5,924     5,924  

Accumulated deficit

    (137,656 )   (138,953 )
           

Total shareholders' equity

    11,321     53,679  
           

Total capitalization

  19,777   62,135  
           

(1)
Each $1.00 increase or decrease in the assumed initial public offering price of $14.00 per ordinary share would increase or decrease, respectively, the amount of cash and cash equivalents, working capital, total assets and total shareholders' equity by $4.3 million, assuming the number of ordinary shares offered by us, as set forth on the cover page of this prospectus, remains the same and after deducting the underwriting discounts and commissions and estimated offering expenses payable by us. We may also increase or decrease the number of ordinary shares we are offering. An increase or decrease of 1,000,000 in the number of ordinary shares we are offering would increase or decrease, respectively, the amount of cash, cash equivalents and short-term investments, working capital, total assets and stockholders' equity by approximately $13.0 million, assuming the assumed initial public offering price per ordinary share, remains the same. The as adjusted information is illustrative only, and we will adjust this information based on the actual initial public offering price and other terms of this offering determined at pricing.

The table above excludes:

    1,691,844 ordinary shares issued under our equity incentive plans issuable upon the exercise of options outstanding as of the date of this prospectus at a weighted average exercise price of €3.90 per share;

    up to 1,531,471 ordinary shares reserved for future issuance under our equity incentive plans following this offering;

    609,744 ordinary shares issuable upon exercise of options granted on January 17, 2014 in connection with our collaboration and license agreement with 4D Molecular Therapeutics, at an exercise price of €0.05 per share; and

    170,802 ordinary shares issuable upon the exercise of warrants outstanding as of the date of this prospectus at an exercise price of €10.10 per ordinary share.

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DILUTION

If you invest in our ordinary shares, your interest will be diluted to the extent of the difference between the initial public offering price per share and the net tangible book value per share after this offering.

Our net tangible book value as of September 30, 2013, was €4.6 million ($6.1 million), or €0.37 ($0.50) per ordinary share. Net tangible book value per ordinary share represents the amount of our total tangible assets less our total liabilities, divided by the number of ordinary shares outstanding as of September 30, 2013, after giving effect to the 5-for-1 consolidation of our ordinary shares, which will have the effect of a reverse share split and will occur prior to the effectiveness of the registration statement of which this prospectus forms a part. Because the reclassification of our ordinary A, B, and C shares into ordinary shares will occur on a one-to-one basis at the completion of the initial public offering, the reclassification will not result in additional dilution.

After giving effect to the sale by us of 4,600,000 ordinary shares in this offering at an assumed initial public offering price of $14.00 per ordinary share (€10.37 per ordinary share) (the midpoint of the estimated price range on the cover page of this prospectus), and after deducting underwriting discounts and commissions and estimated offering expenses payable by us, our pro forma net tangible book value as of September 30, 2013, would have been €46.9 million ($63.3 million), or €0.77 per ordinary share ($1.04 per ordinary share), giving effect to the 5-for-1 consolidation of our ordinary shares. This amount represents an immediate increase in net tangible book value of €0.40 per ordinary share ($0.54 per ordinary share) to our existing shareholders and an immediate dilution in net tangible book value of €9.60 per ordinary share ($12.96 per ordinary share), or 93% per ordinary share, to new investors purchasing ordinary shares in this offering at the assumed initial public offering price. We determine dilution by subtracting the pro forma net tangible book value per share after this offering from the amount of cash that a new investor paid for an ordinary share. The following table illustrates this dilution on a per share basis:


Assumed initial public offering price per ordinary share

  $ 14.00   10.37  

Net tangible book value per ordinary share as of September 30, 2013

    0.50     0.37  

Increase per ordinary share attributable to new investors in this offering

    0.54     0.40  

Pro forma net tangible book value per ordinary share as of September 30, 2013 after giving effect to this offering

    1.04     0.77  

Dilution per ordinary share to new investors

    12.96     9.60  

A $1.00 increase (decrease) in the assumed initial public offering price of $14.00 per ordinary share would increase (decrease) the pro forma net tangible book value by $0.07 (€0.05 per ordinary share) per ordinary share and increase (decrease) the dilution to new investors by $0.93 per ordinary share (€0.69 per ordinary share), assuming the number of ordinary shares offered by us, as set forth on the cover page of this prospectus, remains the same, and after deducting underwriting discounts and commissions and estimated expenses payable by us. If the underwriters exercise their option to purchase additional ordinary shares from us in full, the pro forma net tangible book value per ordinary share would be $1.19 per ordinary share (€0.88 per ordinary share), and the dilution in pro forma net tangible book value per ordinary share to investors in this offering would be $12.81 per ordinary share (€9.50 per ordinary share).

The table below summarizes as of the date of this prospectus, the number of our ordinary shares, after giving effect to the 5-for-1 consolidation of our ordinary shares, which will have the effect of a reverse share split, the total consideration and the average price per share (a) paid to us by existing shareholders and (b) to be paid by new investors purchasing our ordinary shares in this offering at an assumed initial public offering price of $14.00 per ordinary share, the midpoint of the estimated price range set forth on the cover

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page of this prospectus, before deducting underwriting discounts and commissions and estimated offering expenses.


 
  SHARES PURCHASED   TOTAL CONSIDERATION    
   
 
 
  AVERAGE
PRICE
PER SHARE
 
 
  NUMBER   PERCENT   AMOUNT   PERCENT  

Existing shareholders

    12,194,906     73 % $ 80,271,348   59,481,069     55 % $ 6.58   4.88  

New investors

    4,600,000     27     64,400,000     47,720,400     45     14.00     10.37  
                                   

Total

    16,794,906     100.0 % $ 144,671,348   107,201,469     100.0 %            
                                   

The total number of ordinary shares reflected in the discussion and tables above is based on 12,194,906 ordinary shares outstanding as of the date of this prospectus.

The table above excludes:

    1,691,844 ordinary shares issued under our equity incentive plans issuable upon the exercise of options outstanding as of the date of this prospectus at a weighted average exercise price of €3.90 per ordinary share;

    up to 1,531,471 ordinary shares reserved for future issuance under our equity incentive plans following this offering;

    609,744 ordinary shares issuable upon exercise of options granted on January 17, 2014 in connection with our collaboration and license agreement with 4D Molecular Therapeutics, at an exercise price of €0.05 per share; and

    170,802 ordinary shares issuable upon the exercise of warrants outstanding as of the date of this prospectus at an exercise price of €10.10 per ordinary share.

If the underwriters exercise their option to purchase additional ordinary shares in full, the percentage of ordinary shares beneficially owned by existing shareholders would decrease to approximately 70% of the total number of ordinary shares outstanding after this offering, and the number of ordinary shares held by new investors will be increased to 5,290,000 ordinary shares, or approximately 30% of the total number of ordinary shares outstanding after this offering.

To the extent options are exercised and awards are granted under these plans, there may be dilution to our shareholders. We may also choose to raise additional capital due to market conditions or strategic considerations even if we believe we have sufficient funds for our current or future operating plans. To the extent that we raise additional capital through the sale of equity or convertible debt securities, the issuance of these securities could result in further dilution to our shareholders.

Certain of our existing investors and their affiliated entities have indicated an interest in purchasing an aggregate of up to approximately $20 million of our ordinary shares in this offering at the initial public offering price. Assuming an initial public offering price of $14.00 per share, which is the midpoint of the price range set forth on the cover page of this prospectus, these entities would purchase an aggregate of up to approximately 1,400,000 of the 4,600,000 shares in this offering based on these indications of interest. However, because indications of interest are not binding agreements or commitments to purchase, these entities may determine to purchase fewer shares than they indicate an interest in purchasing or not to purchase any shares in this offering. It is also possible that these entities could indicate an interest in purchasing more of our ordinary shares. In addition, the underwriters could determine to sell fewer shares to any of these entities than the entities indicate an interest in purchasing or not to sell any shares to these entities.

The foregoing discussion and tables do not reflect any potential purchases by these entities or their affiliated entities.

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SELECTED CONSOLIDATED FINANCIAL DATA

The following selected consolidated financial data as of and for the years ended December 31, 2011 and 2012 have been derived from our audited consolidated financial statements included elsewhere in this prospectus. The following selected consolidated financial data as of and for the nine months ended September 30, 2012 and 2013 have been derived from our unaudited consolidated financial statements included elsewhere in this prospectus. The unaudited financial statements have been prepared on the same basis as the audited financial statements and, in the opinion of management, reflect all adjustments, which include only normal recurring adjustments, necessary to state fairly our financial position as of September 30, 2013 and the results of operations for the nine months ended September 30, 2012 and 2013.

Our historical results for any prior period are not necessarily indicative of results to be expected in any future period, and our interim period results are not necessarily indicative of results to be expected for a full year or any other interim period. The information set forth below should be read in conjunction with the "Management's Discussion and Analysis of Financial Condition and Results of Operations" section of this prospectus and with our consolidated financial statements and notes thereto included elsewhere in this prospectus.

Consolidated Statements of Comprehensive Income Data:


 
  YEAR ENDED
DECEMBER 31,
  NINE MONTHS ENDED
SEPTEMBER 30,
 
€ in thousands (except share and per share data)
  2011   2012   2012   2013  

Revenues:

                         

License revenues

        220  
                   

Collaboration revenues

                1,831  
                   

Total revenues

                2,051  
                   

Cost of goods sold

                (800 )
                   

Gross profit

                1,251  
                   

Other income

  2,192   649   315   686  

Research and development expenses

    (15,500 )   (10,231 )   (5,690 )   (9,856 )

Selling, general and administrative expenses

    (3,807 )   (4,564 )   (4,438 )   (7,612 )

Other losses, net

    (26 )   (45 )   (82 )   (269 )
                   

Operating result

    (17,141 )   (14,191 )   (9,985 )   (15,800 )

Finance income

    277     22     16     48  

Finance expense

    (436 )   (547 )   (545 )   (4,676 )
                   

Net loss

  (17,300 ) (14,716 ) (10,424 ) (20,428 )
                   

Basic and diluted loss per share(1)

  (3.65 ) (1.70 ) (1.25 ) (1.95 )

Weighted average shares outstanding used in computing per share amounts:(1)

                         

Basic and diluted

    4,709     8,637     8,431     10,594  

(1)
As noted above, all share, per share and related information has been retroactively adjusted, where applicable, to reflect the impact of the 5-for-1 consolidation of our shares, which will have the effect of a reverse share split, that will be effective prior to the effectiveness of the registration statement of which this prospectus forms a part.

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The following table sets forth selected balance sheet data as of the dates indicated:

Consolidated Balance Sheet Data:


 
  AS OF DECEMBER 31,    
 
 
  AS OF
SEPTEMBER 30,
2013
 
(€ in thousands)
  2010   2011   2012  

Cash and cash equivalents

  17,859   1,100   263   31,427  

Total assets

    22,703     5,804     5,567     43,671  

Total debt

    4,621     4,544     1,498     8,456  

Accumulated deficit

    (88,205 )   (105,505 )   (117,234 )   (137,656 )

Total shareholders' equity (deficit)

    13,659     (2,593 )   (448 )   11,321  

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EXCHANGE RATE INFORMATION

Our business to date has been conducted primarily in the European Union, and we prepare our consolidated financial statements in euros. In this prospectus, translations from euros to U.S. dollars were made at the rate of €0.741 to $1.00, the official exchange rate quoted as of September 30, 2013 by the European Central Bank. Such U.S. dollar amounts are not necessarily indicative of the amounts of U.S. dollars that could actually have been purchased upon exchange of euros at the dates indicated. On January 22, 2014, the exchange rate was €0.737 to $1.00. The following table presents information on the exchange rates between the euro and the U.S. dollar for the periods indicated:


(€ per U.S. dollar)
  PERIOD END   AVERAGE   LOW   HIGH  

Year Ended December 31:

                         

2009

    0.694     0.717     0.661     0.796  

2010

    0.748     0.754     0.687     0.837  

2011

    0.773     0.718     0.672     0.776  

2012

    0.758     0.778     0.743     0.827  

2013

    0.725     0.753     0.724     0.783  

2014 (through January 22)

    0.737     0.735     0.732     0.739  

Month Ended:

                         

July 2013

    0.753     0.765     0.752     0.780  

August 2013

    0.755     0.751     0.746     0.757  

September 2013

    0.740     0.749     0.738     0.762  

October 2013

    0.733     0.733     0.724     0.741  

November 2013

    0.735     0.741     0.735     0.748  

December 2013

    0.725     0.731     0.724     0.739  

January 2014 (through January 22)

    0.737     0.735     0.732     0.739  

This prospectus also contains amounts that we have paid or may be required to pay in Canadian dollars. On January 17, 2014, the exchange rate quoted by the Federal Reserve Bank of New York was C$1.096 to $1.00.

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MANAGEMENT'S DISCUSSION AND ANALYSIS OF
FINANCIAL CONDITION AND RESULTS OF OPERATIONS

You should read the following discussion and analysis of our financial condition and results of operations together with the information under "Selected Financial Information" and our consolidated audited and unaudited interim financial statements, including the notes thereto, included elsewhere in this prospectus. The following discussion is based on our financial statements prepared in accordance with International Financial Reporting Standards, or IFRS, as issued by the International Accounting Standards Board, or IASB, which might differ in material respects from generally accepted accounting principles in other jurisdictions. The following discussion includes forward-looking statements that involve risks, uncertainties and assumptions. Our actual results may differ materially from those anticipated in these forward-looking statements as a result of many factors, including but not limited to those described under "Risk Factors".

Overview

We are a leader in the field of gene therapy and have developed the first and currently the only gene therapy product to receive regulatory approval in the European Union. Our first product, Glybera, was approved by the European Commission in October 2012 under exceptional circumstances for the treatment of a subset of patients with lipoprotein lipase deficiency, or LPLD, a potentially life-threatening, orphan metabolic disease. We expect to launch Glybera commercially in selected European countries in the first half of 2014 through our collaboration with Chiesi, which we entered into in April 2013. We retain full commercial rights to Glybera in the United States. In August and December 2013, we met with the FDA to discuss the regulatory pathway for Glybera in the United States and we plan to file an IND with the FDA for Glybera in the first half of 2014. We are developing a pipeline of additional AAV-based gene therapies through multiple collaborations designed to accelerate the development and commercialization of these programs. We develop our gene therapies using our innovative, modular technology platform, including our proprietary, cost-effective manufacturing process.

Our business was founded in 1998 by scientists who were investigating LPLD at the Academic Medical Center of the University of Amsterdam, or the AMC. In our early years we received funding and subsidized rent from the AMC, government grants, income for cGMP contract manufacturing of biologics for third parties, and small amounts of equity financing. Since our first institutional venture capital financing in 2006, we have funded our operations primarily through private and public placements of equity securities, and and other convertible debt securities, in the aggregate amount of €137.5 million ($179.9 million). During this period, we have also received total other income, consisting principally of government grants and subsidies, of €5.9 million, and total nonrefundable collaboration funding of €17.0 million. Our predecessor entity, Amsterdam Molecular Therapeutics (AMT) N.V., or AMT, completed an initial public offering of its ordinary shares on Euronext Amsterdam in 2007. We acquired the business of AMT in the first half of 2012, as described below.

The total amounts described above include the following funds received in 2013:

    €12.0 million in convertible loan financing, which we received in the first quarter of 2013, and which was converted into equity in July 2013;

    $10.0 million (€7.5 million) in venture debt financing, which we received in the second quarter of 2013;

    €17.0 million in upfront payments from Chiesi under our collaboration agreements for Glybera and hemophilia B, which we received in July 2013; and

    €14.0 million in equity funding from Chiesi, which we received in July 2013.

As of September 30, 2013, we had cash and cash equivalents of €31.4 million. To date, we have not generated any revenues from royalties or product sales. We do not expect to generate royalty or revenues from product sales prior to the commercial launch of Glybera by Chiesi.

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We had a net loss of €20.4 million in the first nine months of 2013, €14.7 million in 2012 and €17.3 million in 2011. As of September 30, 2013, we had an accumulated deficit of €138.0 million. We anticipate that our expenses will increase substantially in the future as we:

    complete our EMA-mandated post-approval clinical trial of Glybera and implement an LPLD patient registry;

    conduct a clinical trial of Glybera, either as part of the EMA-mandated post-approval clinical trial or separately, to obtain data needed to file a BLA for Glybera with the FDA;

    seek marketing approval for Glybera in the United States and other countries;

    initiate a Phase I/II clinical trial of AMT-060 for hemophilia B in collaboration with Chiesi;

    advance the preclinical and clinical development of our other product candidates, most of which are at relatively early stages of development, and seek to discover and develop additional product candidates;

    seek marketing approval for any product candidates that successfully complete clinical trials;

    establish a sales, marketing and medical affairs infrastructure in the United States;

    complete the building out and equipping of our manufacturing facility in Lexington, Massachusetts to expand our manufacturing capabilities for Glybera and our pipeline of product candidates;

    fund the ongoing operations of our Lexington facility;

    fund expenses in connection with our new collaboration with 4D Molecular Therapeutics;

    maintain, expand and protect our intellectual property portfolio, including in-licensing additional intellectual property rights from third parties;

    hire additional personnel, particularly in our manufacturing, research, clinical development, medical affairs, commercial and quality control groups;

    add operational, financial and management information systems and related finance and compliance personnel; and

    operate as a public company.

Accounting for our Corporate Reorganization and Strategic Restructuring

At the end of 2011, following the initial rejection of the application for marketing approval for Glybera in the European Union, AMT initiated a strategic restructuring in order to reduce its cost base, conserve resources and improve its financial position. As part of this effort, AMT significantly reduced personnel, programs and expenditures. As a result, we lost a number of employees, including employees with an extensive understanding of our clinical programs as well as our regulatory and financial affairs. AMT implemented a strategic restructuring in the fourth quarter of 2011, as a result of which total staff was reduced from 92 to 49. AMT incurred significant restructuring expenses in connection with this reduction in staff, which were recorded in full during the fourth quarter of 2011. Since that time, we have hired a number of new staff. As of December 31, 2013, we had a total of 87 employees and engaged 33 consultants and contract workers.

In the first half of 2012, we completed a corporate reorganization pursuant to which uniQure acquired the entire business of the AMT group. Pursuant to IFRS, this reorganization was treated as a reverse acquisition of AMT and accordingly, for accounting purposes, AMT was treated as the acquirer. As a result, the historical financial statements of AMT are treated as the financial statements of uniQure. See Note 1 to the audited consolidated financial statements included elsewhere in this prospectus for further details.

At the time AMT originally prepared its audited financial statements for 2011, the business of AMT was in liquidation and therefore the related financial statements were prepared on a liquidation basis rather than a going concern basis. As of December 31, 2011, it was regarded as probable that the business and assets of AMT would be disposed of, and therefore AMT's assets and liabilities were recorded as assets and liabilities held for sale and its operating results were recorded as discontinued operations. Following the corporate

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reorganization described above, we restated the financial information of AMT as of and for the year ended December 31, 2011 on a going concern basis. See Note 5 to the 2012 audited consolidated financial statements included elsewhere in this prospectus for further details.

Collaboration and License Agreements

Chiesi Agreements

In April 2013 we entered into two collaboration agreements with Chiesi. In July 2013, we received an aggregate of €17.0 million in upfront payments from Chiesi under these agreements, as well as a €14.0 million investment in our ordinary shares.

Glybera agreement

Under the Glybera agreement, we granted Chiesi the exclusive right to commercialize Glybera for LPLD in the European Union and other specified countries, excluding the United States. In July 2013 we received a €2.0 million upfront payment in recognition of our past expenditures incurred in developing the product. In addition, we are eligible to earn up to €42.0 million in commercial milestone payments based on annual sales of Glybera.

We will receive payments for the quantities of Glybera we manufacture and supply to Chiesi, payable in part upon order and in part upon delivery of such product quantities. We will bear the cost of goods sold for the Glybera we deliver, including the royalties and related payments to third parties we must make under the license agreements covering various aspects of the technology underlying the composition and manufacture of Glybera. See "Business—Strategic Collaboration: Chiesi". We estimate that the amount we will retain, net of cost of goods sold, including such third party royalties and related amounts, will be between 20% and 30% of the revenues from sales of Glybera by Chiesi, varying by country of sale. We believe that the amount that we will retain from net sales of Glybera in the European Union will initially be at the lower end of this range and will increase toward the higher end of that range beginning in 2015, upon the expiration of an in-licensed patent on which we pay royalties. In addition, we are required to pay 20% of the gross amount we receive from Chiesi in respect of Glybera product sales to the Dutch government, in repayment of a technical development loan in the outstanding amount of €5.4 million as of September 30, 2013, until the earlier of repayment in full of such amount and 2017, as described below. See "Business—Internal Program: Glybera—Glybera Commercialization Plan" and "—Intellectual Property—Licenses."

Hemophilia B agreement

Under the Hemophilia B agreement, we granted to Chiesi an exclusive license, for the European Union and specified countries other than the United States, to co-develop and exclusively commercialize AMT-060, a gene therapy product for the treatment of hemophilia B. We received a €15.0 million upfront payment under this agreement. Of this amount, €5.0 million related to the future development of our hemophilia B product candidate and €10.0 million related to the use of our manufacturing capacity for our hemophilia B product candidate. In addition, we will share equally with Chiesi specified development expenses attributable to the hemophilia B program according to a defined development plan and budget, including expenses associated with preclinical and clinical studies as well as development and regulatory milestone payments associated with existing in-license agreements. We will receive payments from Chiesi for commercial quantities of our hemophilia B product candidate we manufacture and supply to them, if we receive regulatory approval for such product candidate. We estimate that the amount we would retain, net of cost of goods sold, including third party royalties and related amounts, will be between 25% and 35% of the revenues from sales of such product by Chiesi, varying by country of sale. We and Chiesi have agreed to negotiate a separate supply and distribution agreement in respect of the potential commercialization of our hemophilia B product candidate prior to dosing the first patient in any pivotal study. We are not entitled to any milestone payments under this co-development agreement. See "Business—Strategic Collaboration: Chiesi."

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Strategic Collaboration: 4D Molecular Therapeutics

In January 2014, we entered into a collaboration and license agreement with 4D for the discovery and optimization of next-generation AAV vectors. Under this agreement, we have an exclusive license to 4D's existing and certain future know-how and other intellectual property for the delivery of AAV vectors to CNS or liver cells for the diagnosis, treatment, palliation or prevention of all diseases or medical conditions. Under this collaboration, the 4D team, including Dr. David Schaffer, 4D's co-founder and Professor of Chemical and Biomolecular Engineering at the University of California, Berkeley, will establish a laboratory, which we will fund, at a cost of approximately $3.0 million in aggregate over the next three years, to identify next generation AAV vectors. We are also required to make payments for pre-clinical, clinical and regulatory milestones under the collaboration as well as to pay single-digit royalties. In addition, we have granted options to purchase an aggregate of 609,744 ordinary shares in connection with this collaboration, and will recognize resulting share-based payment expense over the next three years. To the extent that the collaboration is successful, we may also incur additional third party costs in developing any product candidates and also in preparing, filing and prosecuting additional patent applications. See "Business—Strategic Collaboration: 4D Molecular Therapeutics".

License Agreements

We have obtained exclusive or non-exclusive rights from third parties under a range of patents and other technology that we are exploiting in Glybera and our development programs. Our agreements with these third parties generally grant us a license to make, use, sell, offer to sell and import products covered by the licensed patent rights in exchange for our payment of some combination of an upfront amount, annual fees, royalties, a portion of amounts we receive from our sub-licensees and payments upon the achievement of specified development, regulatory or commercial milestones. Our potential aggregate financial obligations under these agreements are material. Some of the agreements may also specify the extent of the efforts we must use to develop and commercialize licensed products. See "Business—Intellectual Property—Licenses."

Financial Operations Overview

Revenues

To date, we have not generated any revenues from royalties or product sales. We do not expect to generate royalty or product revenues prior to the commercial launch of Glybera by Chiesi. When and if Chiesi generates commercial sales of Glybera, we will record the gross amounts we receive from Chiesi as product revenues. We will record the related expenses, including third party royalties and related payments, as cost of goods sold.

During the nine months ended September 30, 2013, we recognized collaboration revenues of €1.8 million in respect of development activities that were reimbursable by Chiesi under our co-development agreement for hemophilia B. We expect to continue to recognize such collaboration revenues going forward, in accordance with our contractual agreements.

During the nine months ended September 30, 2013, we also recognized license revenues of €0.2 million. This amount reflects the amortization during the period of the non-refundable upfront payments we received from Chiesi under our collaboration agreements. The balance of €16.8 million of these license revenues will be recognized on a straight-line basis through the remaining period of the intellectual property protection of our manufacturing technologies, which is currently expected to be until September 2032.

The timing of our operating cash flows may vary from the recognition of the related amounts, as we defer the recognition of some upfront payments, including the upfront payments under our Chiesi agreements, and recognize these as revenue when earned or over a defined period, while we treat other revenue, such as milestone payments or service fees, as earned when received. We expect our revenues to vary from quarter to quarter and year to year, depending upon, among other things, the commercial success of Glybera, our

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success in obtaining marketing approval for Glybera in the United States and additional countries, the structure and timing of milestone events, the number of milestones achieved, the level of revenues earned for ongoing development efforts, any new collaboration arrangements we may enter into and the terms we are able to negotiate with our collaborators. We currently intend to sell Glybera in the United States, if approved, ourselves, in which case we would recognize revenues in the full amount of the sales price. In addition, because LPLD is an orphan disease and we expect that the number of patients that will be treated with Glybera is relatively small, and because we currently expect that we will receive a one-time payment for a single patient treatment, we anticipate that revenues from Glybera may vary significantly from period to period. Further, because we currently anticipate that LPLD patients will require only a single administration with Glybera, we do not expect to earn recurring revenue from treated patients. We therefore believe that period to period comparisons should not be relied upon as indicative of our future revenues.

Other Income

Our other income consists principally of government grants, subsidies and investment credits that support our research efforts in defined research and development projects, which we refer to as grants. These grants generally provide for reimbursement of our approved expenses incurred as defined in various grants. We recognize grants when expenses are incurred in accordance with the terms and conditions of the grant and the collectability of the receivable is reasonably assured. Because we have limited or no control over the timing of receipt of grants, the amount of other income varies from period to period and is not indicative of underlying trends in our operations.

We have received grants from the Dutch government and from the European Union. We have also participated in collaborations and consortia in which our collaborators and fellow consortium members have received grants from governmental authorities, which have enabled us to access preclinical and clinical data while minimizing the expenses we incur.

We have received a research and development subsidy from the Dutch government in the form of reimbursement of payroll taxes related to relevant employees. The amount we receive is tied directly to the number of employees and number of hours devoted to specified research and development programs, and therefore varies directly with the size of our workforce and direction of our research and development programs. We have no obligation to repay these amounts.

Some of the grants we have received are repayable under specified circumstances. In particular, we would be required to repay some grants if we successfully commercialize a supported program within a specified timeframe. None of the grants we have received to date relate to programs that we currently anticipate commercializing, other than the technical development loan in respect of Glybera, described under "Costs of Goods Sold" below. Accordingly, we do not currently expect that we will be required to repay any of these grants.

Other income also includes amounts we receive as payment or reimbursement for expenses of manufacturing and development of AMT-110 under our collaboration agreement with Institut Pasteur.

Cost of Goods Sold

Cost of goods sold includes the purchase price of raw materials, directly attributable labor costs and directly related charges by third party service providers, and the royalties and other related payments to third parties we must make under the license agreements covering various aspects of the technology underlying the composition and manufacture of Glybera.

We also include in cost of goods sold amounts that we are required to repay to the Dutch government in respect of a technical development loan that we received in the period from 2000 to 2005 to support the early development of Glybera. As of September 30, 2013, the total amount of principal and interest outstanding was €5.4 million. Under the terms of this contingent commitment, we are required to make

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repayments based on the timing and amount of revenues we receive from product sales of Glybera. In connection with our receipt of upfront payments from Chiesi for the commercialization of Glybera, we repaid €0.8 million of this loan in September 2013, which we recorded as cost of goods sold although no product sales occurred. No further payments will be made until sales of Glybera commence. We expect to pay to the Dutch government 20% of any gross amounts we receive from Chiesi in connection with sales of Glybera, as and when received, until the earlier of such time as the loan is repaid in full or December 31, 2017. Amounts that remain outstanding as of December 31, 2017, if any, would be forgiven. We have not recorded any liability for these amounts. To the extent we generate revenues from the sale of Glybera, we will recognize a liability and a corresponding charge to cost of goods sold in future periods.

Should we obtain marketing approval in the United States for Glybera, we expect that our costs of goods sold for sales of Glybera in the United States would be significantly lower than our costs of goods sold for sales of Glybera in the European Union due principally to the existence of lower royalty obligations on U.S. sales.

Research and Development Expenses

Research and development expenses consist principally of expenses associated with employees, manufacturing facilities, clinical development, collaboration with third parties, license fees, laboratory consumables and depreciation.

During the period from 2006, when we received our first significant venture capital equity investment, to September 30, 2013, we incurred an aggregate of €101.1 million in research and development expenses. We expect that our total research and development expenses in 2013 were in the range of €12.0 million to €14.0 million. In addition, we began to capitalize our development expenses related to Glybera from March 21, 2013. We capitalized €2.1 million of such expenses in the first nine months of 2013, which we expect to begin amortizing once sales of Glybera commence, over the period through September 2032. We allocate our direct research and development expenses to our various programs on the basis of actual external expenses incurred in respect of each program and our allocation of time spent by our research and development team on each program. We do not allocate our overhead expenses to specific development programs. Our research and development expenses mainly relate to the following key programs:

    Glybera.  We are undertaking preparations for the EMA-mandated post-approval clinical trial and patient registry. In addition, we are undertaking preparations for the submission of an IND with the FDA in the first half of 2014. We bear all of the costs of this program outside of the territories covered by the Chiesi agreement. Certain costs, including the patient registry for territories covered by the Chiesi agreement, will be shared equally with Chiesi.

    Hemophilia B.  We plan to initiate a Phase I/II clinical trial of AMT-060 for the treatment of hemophilia B in the second half of 2014 in collaboration with Chiesi. Under our co-development agreement, we and Chiesi will each bear half of the development costs of this program.

    Acute intermittent porphyria (AIP).  We have incurred costs related to the development and manufacture of clinical supplies of AMT-021 for the treatment of AIP provided to our collaboration partner, Digna Biotech, for its ongoing Phase I clinical trial in this indication.

    CNS programs.  We have incurred costs related to the development and manufacture of clinical supplies of AMT-110 for the treatment of Sanfilippo B provided to our collaboration partner, Institut Pasteur, for its ongoing Phase I/II clinical trial. We also incur expenses related to the research and preclinical activities related to our other CNS programs.

    Technology platform development and other research.  We incur significant research and development costs related to our gene delivery and manufacturing technology platform that are applicable across all of our programs, as well as our other research programs, including intellectual property expenses, depreciation expenses and facility costs. These costs are not allocated to specific projects.

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The table below sets forth our direct research and development expenses by program for the years ended December 31, 2011 and 2012 and the nine-month periods ended September 30, 2012 and 2013:


 
  YEAR ENDED
DECEMBER 31,
  NINE MONTHS ENDED
SEPTEMBER 30,
 
(€ in thousands, except percentages)
  2011   2012   CHANGE   2012   2013   CHANGE  
 
   
   
  %
   
   
  %
 

Glybera program*

    4,381     1,055     (76 )   651     1,665     156  

Hemophilia B program

    671     1,131     69     674     1,510     124  

AIP program

    1,383     1,055     (24 )   896     219     (76 )

CNS programs

    363     922     154     564     804     43  

Technology platform development and research programs

    8,702     6,068     (30 )   2,905     5,658     95  
                           

Total

    15,500     10,231     (34 )   5,690     9,856     73  
                               

*
Excludes capitalized development expenses.

Our research and development expenses may vary substantially from period to period based on the timing of our research and development activities, including regulatory approvals and enrollment of patients in clinical trials. We expect that our research and development expenses will increase significantly as we increase our staff, conduct further clinical development of Glybera, advance the research and development of our other product candidates and commence manufacturing at our manufacturing facility in Lexington, Massachusetts. The successful development of our product candidates is highly uncertain. At this time, we cannot reasonably estimate the nature, timing or estimated costs of, or any cash inflows resulting from, the development of any of our product candidates. This is due to numerous risks and uncertainties associated with developing gene therapies, including the uncertainty of:

    the scope, rate of progress and expense of our research and development activities;

    clinical trial and early-stage results;

    the terms and timing of regulatory approvals;

    the expense of filing, prosecuting, defending and enforcing patent claims and other intellectual property rights; and

    our and our collaborators' ability to market, commercialize and achieve market acceptance for Glybera or any other product candidate that we may develop in the future.

A change in the outcome of any of these variables with respect to the development of Glybera or any other product candidate that we may develop could mean a significant change in the expenses and timing associated with the development of Glybera or such product candidate. For example, if the FDA or another regulatory authority were to require us to conduct preclinical and clinical studies for Glybera or any other product candidate beyond those which we currently anticipate will be required for the completion of clinical development, or if we experience significant delays in enrollment in any clinical trials, we could be required to expend significant additional financial resources and time on the completion of our clinical development. See "Risk Factors—Risks Related to the Development of Our Product Candidates" and "—Risks Related to the Regulatory Approval of Our Product Candidates".

We have incurred significant expenses in the development of Glybera. Under applicable accounting principles, we capitalize development expenses upon receipt of marketing approval for a product candidate, provided that we have the technical, scientific and financial resources to complete the development and commercialization of the program. We received marketing approval from the European Commission for Glybera for a subset of LPLD patients in October 2012. Because we did not have sufficient financial resources at that time to complete the development of Glybera, including the post-approval activities

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required by the EMA prior to commercial launch, we did not capitalize the development expenses related to Glybera during the year ended December 31, 2012. Following our receipt of an additional €10.0 million in convertible debt financing in the first quarter of 2013, we determined that we had sufficient financial resources to complete these post-approval activities, and accordingly began to capitalize the related development expenses in the first quarter of 2013.

Over the period through 2016, we anticipate that we will incur external expenses related to the further development of Glybera, including implementation of the patient registry, initiation and conduct of the post-approval clinical trial and additional development work to seek FDA approval, of approximately €7.0 million; in addition, we will incur significant related employee expenses. See "Risk Factors—Risks Related to the Development of Our Product Candidates" and "—Risks Related to the Regulatory Approval of Our Product Candidates."

In addition, in connection with the collaboration and license agreement we entered into with 4D Molecular Therapeutics during January 2014, we will incur additional expenses as we fund a joint research effort with 4D. Further, we granted options to purchase an aggregate of 609,744 of our ordinary shares to two consultants who will be providing services to us in connection with that agreement. The fair value of these options will vest over a future service period, and will have a significant impact on our expenses recognized. Finally, to the extent certain pre-clinical, clinical and regulatory milestones are met, we will make milestone payments to 4D. See "Business—Strategic Collaboration: 4D Molecular Therapeutics."

Selling, General and Administrative Expenses

Our selling, general and administrative expenses have consisted to date principally of employee, office, consultancy and other administrative expenses. We expect that our selling, general and administrative expenses will increase significantly in the future as our business expands and we add personnel, particularly in our medical affairs, commercial, quality control, finance and compliance groups, and as we commence manufacturing operations in our facility in Lexington, Massachusetts. We also expect to incur additional expenses associated with operating as a public company, including expenses for additional personnel, additional legal, accounting and audit fees, directors' and officers' liability insurance premiums and expenses related to investor relations. In future periods, we will include in selling, general and administrative expenses our sales expenses related to the commercialization of Glybera in the European Union, including our market access and medical affairs efforts, as well as the costs related to the sales and marketing efforts we intend to undertake in the United States in advance of potential marketing approval for Glybera from the FDA.

Other Losses—Net

Other losses—net consists of foreign exchange losses that do not relate to borrowings. We are exposed to foreign exchange risk arising from various currency exposures, primarily with respect to the U.S. dollar and, to a lesser extent, the British pound, as we acquire certain materials and pay for certain licenses and other services in these two currencies. We have not established any formal practice to manage the foreign exchange risk against our functional currency.

Finance Income

Our finance income consists of interest income earned on our cash and cash equivalents and gains on our derivative instruments, described below. We deposit our cash and cash equivalents primarily in savings and deposit accounts with original maturities of three months or less. Savings and deposit accounts have historically generated only minimal interest income.

We have entered into various financing arrangements with our investors, including convertible notes issued in 2009, 2012 and 2013, all of which were converted into ordinary shares in July 2013. See "Related Party Transactions" for further detail. Each of the convertible notes consists of a debt element and an

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embedded financial derivative element. Derivatives are initially recognized at fair value on the date a derivative contract is entered into and are subsequently measured at fair value through profit and loss. The resulting gain is recognized in the consolidated income statement and accounted for as finance income.

Finance Expense

Finance expense consists primarily of interest due on our convertible notes, losses on the fair value measurements of our derivative instruments, and, to a lesser extent, the interest component of finance leases.

Results of Operations

Overview

Our results of operations in the periods under review were significantly affected by the corporate reorganization and strategic restructuring, and related contraction of our research and development and other activities, that we initiated at the end of 2011 in order to conserve resources and improve our financial position following the initial rejection of the application for marketing approval for Glybera in the European Union. Following the approval of Glybera in the European Union in October 2012 and additional investment received in the first quarter of 2012, we began to significantly expand our operations.

Comparison of the nine months ended September 30, 2012 and 2013


 
  NINE MONTHS ENDED SEPTEMBER 30,  
(€ in thousands)
  2012   2013   CHANGE  

Revenues:

                   

License revenues

    220     %
               

Collaboration revenues

        1,831      
               

Total revenues

        2,051      
               

Cost of goods sold

        (800 )    
               

Gross profit

        1,251      
               

Other income

    315     686     118  
               

Expenses:

                   

Research and development expenses

    (5,690 )   (9,856 )   73  

Selling, general and administrative expenses

    (4,438 )   (7,612 )   72  

Other losses, net

    (82 )   (269 )   228  
               

Operating result

    (9,895 )   (15,800 )   60  

Finance income

    16     48     200  

Finance expense

    (545 )   (4,676 )   758  
               

Net loss

    (10,424 )   (20,428 )   96  
                 

Revenues

License revenues of €0.2 million in the nine months ended September 30, 2013 related to the amortization of the upfront payment received from Chiesi in July 2013.

Collaboration revenues of €1.8 million in the nine months ended September 30, 2013 consisted mainly of reimbursements of covered expenses by Chiesi under our co-development agreement for hemophilia B,

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together with revenue from Institut Pasteur relating to our Sanfilippo B collaboration. We had no revenues in the nine months ended September 30, 2012.

Cost of Goods Sold

Cost of goods sold of €0.8 million in the nine months ended September 30, 2013 consisted of the recognition of a repayment obligation to the Dutch government with respect to a portion of a technical development loan. This repayment obligation was triggered by our entitlement to receive during the second quarter of 2013 a €2.0 million upfront payment from Chiesi in relation to our Glybera program. We had no cost of goods sold in the first nine months of 2012.

Other Income

Other income for the nine months ended September 30, 2013 was €0.69 million, a 118% increase from the €0.31 million recognized for the nine months ended September 30, 2012. This increase principally reflected an increase of €0.15 million in the amount of reimbursement of payroll taxes received from the Dutch government as a result of higher headcount in 2013, reflecting the lower staff numbers in the prior period following our strategic restructuring at the end of 2011. The remainder of the increase reflected the receipt of €0.23 million of grants to support research projects.

Research and Development Expenses

Research and development expenses for the nine months ended September 30, 2013 were €9.9 million, a 73% increase from the €5.7 million incurred for the nine months ended September 30, 2012. This increase reflected the expansion of our research and development activities to support the planned commercial launch of Glybera in the European Union as well as the further development of Glybera and our pipeline product candidates. Following our receipt of additional convertible loan and debt funding in the first nine months of 2013, we increased the level of research and development expenditures compared with the relatively low level of expenditure during 2012 attributable to our strategic restructuring at the end of 2011.

Glybera-related raw materials that cannot be used for commercial purposes are expensed; Glybera-related materials, including raw materials, work-in-progress and finished goods, that are expected to be used for commercial purposes are recorded as inventory on the balance sheet and are not accounted for within research and development expenses.

Selling, General and Administrative Expenses

Selling, general and administrative expenses for the nine months ended September 30, 2013 were €7.6 million, a 72% increase from the €4.4 million incurred for the nine months ended September 30, 2012. This increase resulted principally from our increased headcount in 2013 as we continued to ramp up our operations following our strategic restructuring at the end of 2011 and increased commercial, legal and other advisory fees.

Other losses—Net

Other losses—net for the nine months ended September 30, 2013 were a loss of €0.27 million, a 228% increase from the loss of €0.08 million for the nine months ended September 30, 2012, and related to foreign exchange impacts. This increase reflects changes in the exchange rate between the euro and the U.S. dollar.

Finance Income

Finance income for the nine months ended September 30, 2013 was €0.05 million, a 200% increase from the €0.01 million for the nine months ended September 30, 2012. This reflects our low average cash balances and low interest rates in both periods.

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Finance Expense

Finance expense for the nine months ended September 30, 2013 was €4.7 million, compared with €0.55 million for the nine months ended September 30, 2012. This increase primarily related to the revaluation of the embedded derivatives related to our convertible loans and the venture loan, which totaled €3.7 million during the nine months ended September 30, 2013.

Comparison of the years ended December 31, 2011 and 2012


 
  YEAR ENDED DECEMBER 31,  
(€ in thousands)
  2011   2012   CHANGE  
 
   
   
  %
 

Revenues:

         

License revenues

             

Collaboration revenues

             
               

Total revenues

             
               

Cost of goods sold

             
               

Gross loss

             
               

Other Income

    2,192     649     (70 )

Research and development expenses

    (15,500 )   (10,231 )   (34 )

Selling, general and administrative expenses

    (3,807 )   (4,564 )   20  

Other losses, net

    (26 )   (45 )   73  
               

Operating result

    17,141     14,191     (17 )

Finance income

    277     22     (92 )

Finance expense

    (436 )   (547 )   25  
               

Net loss

  (17,300 ) (14,716 )   (15 )
               

Other Income

Other income for the year ended December 31, 2012 was €0.6 million, a 70% decrease from the €2.2 million recognized for the year ended December 31, 2011. The higher amounts in 2011 reflected a grant in the amount of €1.0 million accounted for in that period from the European Union through our collaborator in connection with our AIP program, as well as €0.8 million from our collaborator Institut Pasteur related to the supply by us of material for use in our Sanfilippo B program. The reduction in the amount of Other income in 2012 reflects the variable nature of payments receivable under these arrangements.

Research and Development Expenses

Research and development expenses for 2012 were €10.2 million, a 34% decrease from the €15.5 million incurred for the year ended December 31, 2011. The decrease reflected the strategic restructuring and related reduction in our workforce we undertook at the end of 2011. Following the reduction in staff, we also reduced our overall level of activity. Furthermore, during the first half of 2012, we focused on our early-stage programs, which generally require less investment than more advanced programs.

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Selling, General and Administrative Expenses

Selling, general and administrative expenses for 2012 were €4.6 million, a 20% increase from the €3.8 million incurred for the year ended December 31, 2011. This increase reflected principally increased legal and other advisory costs incurred in 2012 in connection with our corporate reorganization, described above, and to a lesser extent expanded business development activities in 2012.

Other Losses—Net

Other losses—net were not material in either 2012 or 2011.

Finance Income

Finance income was nominal in 2012, compared with €0.3 million in 2011, reflecting the low average cash balances during 2012, when interest rates available on cash deposits were low.

Finance Expense

Finance expense remained relatively stable at €0.5 million in 2012 compared with €0.4 million in 2011, principally representing interest due on convertible loans in 2011, and the charge on the movement in the value of the derivative element of our convertible loans, which were converted on our restructuring in April 2012.

Liquidity and Capital Resources

In our early years we received funding and subsidized rent from the AMC, government grants, income for cGMP contract manufacturing of biologics for third parties, and small amounts of equity financing. Since our first institutional venture capital financing in 2006, we have funded our operations primarily through private and public placements of equity securities, and convertible and other debt securities, in the aggregate amount of €137.5 million ($179.9 million). During this period, we have also received total other income, consisting principally of government grants and subsidies, of €5.9 million, and total nonrefundable collaboration funding of €17.0 million, and $10.0 million (€7.5 million) in venture debt financing.

We had a net loss of €20.4 million in the first nine months of 2013, €14.7 million in full year 2012 and €17.3 million in full year 2011. As of September 30, 2013, we had an accumulated deficit of €138.0 million.

Cash flows

Our cash and cash equivalents as of September 30, 2013 were €31.4 million. The table below summarizes our consolidated cash flow data for the years ended December 31, 2011 and 2012 and each of the unaudited nine-month periods ended September 30, 2012 and 2013:


 
  YEAR ENDED
DECEMBER 31,
  NINE MONTHS ENDED
SEPTEMBER 30,
 
(€ in thousands)
  2011   2012   2012   2013  

Net cash (used in)/generated by operating activities

    (16,705 )   (11,277 )   (8,579 )   1,674  

Net cash used in investing activities

    (162 )   (832 )   (427 )   (4,179 )

Net cash generated from financing activities

    108     11,272     9,433     33,663  

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Net Cash (Used in)/Generated by Operating Activities

Net cash generated by operating activities was €1.7 million in the nine months ended September 30, 2013, a 120% increase from net cash used in operating activities of €8.6 million in the nine months ended September 30, 2012. The change reflected the receipt of the upfront payment under our collaboration agreements with Chiesi.

Net cash used in operating activities was €11.3 million in 2012, a 33% decrease from €16.7 million in 2011. The decrease reflected the reduction in net loss before corporate income tax for 2012 compared to 2011, which in turn was due to the strategic restructuring and related reduction in our workforce we undertook at the end of 2011. Following the reduction in staff we also reduced our overall activity. In 2012 our net loss before corporate income tax was €14.7 million, a decrease of €2.6 million compared to 2011. In addition, changes in overall composition of our working capital balance also resulted in an overall reduction in the cash used in operations.

Net Cash Used in Investing Activities

Net cash used in investing activities was €4.2 million in the nine months ended September 30, 2013, compared with net cash used in investing activities of €0.43 million in the nine months ended September 30, 2012. The increase reflected the capitalization of €2.1 million of Glybera development expenses beginning in March 2013.

Net cash used in investing activities was €0.8 million in 2012, an increase of 414% from €0.2 million in 2011. This increase was due to purchases of intangible assets and, to a lesser extent, purchases of property, plant and equipment.

Net Cash Generated from Financing Activities

Net cash generated from financing activities was €33.7 million in the nine months ended September 30, 2013, compared with net cash generated from financing activities of €9.4 million in the nine months ended September 30, 2012. The increase reflected the receipt of €12.0 million in funding from the issuances of convertible notes (all of which were fully converted in the period), $10.0 million in funding from a venture loan and the receipt of the €14.0 million equity investment from Chiesi during the nine months ended September 30, 2013.

Net cash generated from financing activities was €11.3 million in 2012, compared with €108,000 in 2011. The increase reflected our private placements of convertible notes and equity securities in 2012 in connection with and following our corporate reorganization.

Cash and Funding Sources

The table below summarizes our sources of financing for the years ended December 31, 2011 and 2012 and the nine months ended September 30, 2013.


(€ in thousands)
  EQUITY
CAPITAL(1)
  CONVERTIBLE
NOTES
  OTHER
DEBT
  TOTAL  

Nine months ended September 30, 2013

    14,278     11,999     7,492     33,769  

Year ended December 31, 2012

    9,774     1,498         11,272  

Year ended December 31, 2011

    108             108  
                   

Total

    24,160     13,497     7,492     45,149  
                   

(1)
Excludes shares issued upon conversion of convertible notes.

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Our sources of financing in the nine months ended September 30, 2013 were:

    the issuance and sale of 90,747 ordinary shares to our employees for gross proceeds of €0.3 million;

    the issuance and sale of €12.0 million of our convertible notes;

    a venture loan in the principal amount of $10.0 million from Hercules Technology Growth Capital, or Hercules, pursuant to a loan and security agreement dated June 14, 2013, or the Hercules Agreement; and

    the acquisition of 1,109,214 ordinary shares by Chiesi for €14.0 million.

As of September 30, 2013, we had debt of €7.3 million, which consisted solely of amounts outstanding under the Hercules Agreement.

Funding Requirements

We believe that the net proceeds of this offering, together with our existing cash and cash equivalents, will enable us to fund our operating expenses, including our debt repayment obligations as they become due, and capital expenditure requirements, including the build-out of our Lexington, Massachusetts facility, for at least the next 12 months. See "Use of Proceeds." We have based this estimate on assumptions that may prove to be incorrect, and we could use our capital resources earlier than we currently expect. Our future capital requirements will depend on many factors, including:

    the commercial success of Glybera, including the timing and amount of revenues generated, as well as our cost of goods sold;

    our collaboration agreements remaining in effect and our ability to obtain research and development funding and achieve milestones under these agreements;

    the progress and results of our current and planned clinical trials, including for Glybera, and those of our collaborators;

    the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for our additional product candidates;

    the number and development requirements of other product candidates that we pursue;

    the cost, timing and outcome of regulatory review of our product candidates, particularly for approval of Glybera in the United States;

    the cost and timing of future commercialization activities by us or our collaborators, including product manufacturing, marketing, sales and distribution, for Glybera and any of our product candidates for which we receive marketing approval in the future;

    the amount and timing of revenue, if any, we receive from commercial sales of any product candidates for which we receive marketing approval in the future;

    expenses in connection with our collaboration with 4D Molecular Therapeutics;

    the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property rights and defending any intellectual property-related claims;

    the extent to which we acquire or in-license other products or technologies; and

    the cost and progress of the build-out of our Lexington, Massachusetts manufacturing facility.

We have no committed sources of additional financing, other than our collaboration agreements with Chiesi. Until such time, if ever, as we can generate substantial product revenues from sales of Glybera by Chiesi or otherwise, we expect to finance our cash needs through a combination of equity offerings, debt financings, collaborations, strategic alliances and marketing, distribution and licensing arrangements. To the extent that we raise additional capital through the sale of equity or convertible debt securities, your ownership interest will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect your rights as an ordinary shareholder. We are subject to covenants under the Hercules Agreement, and may become subject to covenants under any future indebtedness, that could limit our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends,

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which could adversely impact our ability to conduct our business. In addition, our pledge of assets as collateral to secure our obligations under the Hercules Agreement may limit our ability to obtain debt financing. If we raise additional funds through collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams or product candidates or grant licenses on terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

For more information as to the risks associated with our future funding needs, see "Risk Factors—Risks Related to Our Financial Position and Need for Additional Capital".

Capital Expenditures

The following table sets forth our capital expenditures for the years ended December 31, 2011 and 2012, and for the nine months ended September 30, 2013 and 2012.


 
  YEAR ENDED
DECEMBER 31,
  NINE MONTHS
ENDED
SEPTEMBER 30,
 
(€ in thousands)
  2011   2012   2012   2013  

Investments in property, plant and equipment

    200     392     149     566  

Investments in intangible assets

    109     553     386     3,647  
                   

Total

    309     945     535     4,213  
                   

We are currently building out a 53,000 square foot leased manufacturing facility in Lexington, Massachusetts. We anticipate that the total construction costs will amount to approximately $16.4 million (€11.8 million), of which the landlord is obligated to pay $7.3 million (€5.5 million) in landlord improvements. In addition, we anticipate the total investment in property, plant and equipment to be approximately $6.0 million (€4.6 million). As of September 30, 2013, we had incurred expenses of $0.12 million (€0.09 million) and had contractual commitments of a further $0.2 million (€0.15 million). In addition, we provided a landlord deposit of $1.2 million (€0.92 million). We anticipate that we will have paid the full amount of these build-out costs by the end of the second quarter of 2014.

Since September 30, 2013, we have entered into additional construction commitments relating to the Lexington facility. The combined sum of these commitments amounted to $16.4 million before agreed reimbursements by the landlord, which was partially paid in the fourth quarter of 2013, with the remainder to be paid in 2014.

We also anticipate that we will incur additional capital expenditures related to our planned expansion of our facility in Amsterdam.

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Contractual Obligations and Commitments

The table below sets forth our contractual obligations and commercial commitments as of September 30, 2013 that are expected to have an impact on liquidity and cash flows in future periods.


 
  PAYMENTS DUE BY PERIOD  
(€ in thousands)
  LESS THAN
1 YEAR
  BETWEEN 1
AND 2 YEARS
  BETWEEN 2
AND 5 YEARS
  MORE THAN
5 YEARS
  TOTAL  

License maintenance obligations(1)(2)

    279     279     735     324     1,617  

Research and development related contractual obligations

    298                 298  

Debt obligations

    1,165     2,690     4,601         8,456  

Operating lease obligations

    542     542     678         1,762  

Finance lease obligations

    153     165     177         495  
                       

Total

    2,437     3,676     6,191     324     12,628  
                       

(1)
Annual license maintenance payments will be no longer payable following the expiration of the license payment obligations. Thereafter, we have a fully paid-up license.

(2)
Amounts are paid annually in advance; to the extent that we could terminate the agreement prior to the date of the next maintenance payment, these maintenance fees are not recognized within research commitments in the notes to the financial statements.

The table above does not include:

    Payments we may be obligated to make under our license or collaboration agreements, other than fixed periodic maintenance costs. Such additional payment obligations may be material. See "—Collaboration and License Agreements" and "Business—Intellectual Property—Licenses".

    Our obligations to repay the Dutch technical development loan described above.

    Our obligations under the collaboration and license agreement with 4D Molecular Therapeutics, entered into in January 2014, to fund research and development activities at a cost of approximately $3.0 million in aggregate over the next three years and approximately $200,000 of licenses fees during the first year.

    Payments in relation to the lease of the Lexington facility. These payments begin seven months after the landlord completed the required initial works to the building, which occurred on November 5, 2013. As of September 30, 2013, we considered the Lexington lease obligations a contingency and not yet a commitment as the landlord had remaining pre-existing obligations prior to the lease commitment. From November 5, 2013, we will account for these lease commitments as accruals under IFRS and will recognize the benefit of the seven month rent-free period over the duration of the lease.

    Payments in relation to the pre-construction commitments described above.

Hercules Loan and Security Agreement

We are party to a Loan and Security Agreement entered into with Hercules on June 13, 2013. Under the Loan and Security Agreement, we borrowed $10.0 million (€7.5 million) from Hercules, bearing interest at a variable rate of the greater of 11.85% or an amount equal to 11.85% plus the prime rate of interest minus 3.25%. We are required to pay only interest in monthly payments until October 2014. From October 2014, we will be required to make monthly payments of interest and principal in the amount of $387,000 (€295,872). The loan matures on October 1, 2016, when we will be required to make a final payment of $2.6 million (€2.1 million). The loan and security agreement also provides for payment of a maturity charge, the amount of which was reduced in exchange for the issuance to Hercules, on September 24, 2013, of 37,174 warrants, at an exercise price of €10.10 per share.

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We have pledged substantially all of our assets as collateral to the Hercules loan, by means of a first ranking right of pledge. The Loan and Security Agreement contains covenants that restrict our ability to, among other things, incur future indebtedness and obtain additional financing, to make investments in securities or in other companies, to transfer our assets, to perform certain corporate changes, to make loans to employees, officers and directors, and to make dividend payments and other distributions. Further, we are required to keep a minimum cash balance deposited in bank accounts in the United States, equivalent to the lesser of the outstanding balance of principal due and 50% of our worldwide cash reserves. The Loan and Security Agreement contains default provisions that include the occurrence of a material adverse effect, as defined therein, that would entitle Hercules to declare all principal, interest and other amounts owed by us immediately due and payable.

Off-Balance Sheet Arrangements

Over the period from October 1, 2000 through May 31, 2005, we received a grant called a "Technisch ontwikkelingskrediet," or technical development loan, from the Dutch government. We received grants totaling €3.6 million during the grant period. The grant amount bears interest of 5.7% per year and includes a repayment clause in the event we generate revenues from Glybera, during the period from January 1, 2008 through December 31, 2017, based upon a percentage of revenues which are derived from the sale of Glybera, if any. If future amounts received are not sufficient to repay the grant on or prior to December 31, 2017, or if there are no revenues generated from Glybera, the remaining balance will be forgiven. The amount of this contingent commitment as of September 30, 2013 totaled €5.4 million, comprising the original grant together with accrued interest, less an initial repayment made in the third quarter of 2013. We have not recorded any liability to repay amounts in respect of this contingent commitment. Further amounts may be recognized once revenues related to produce sales at Glybera commence.

As of the date of this prospectus, and during the periods presented in this prospectus, we did not have any other off-balance sheet arrangements.

Quantitative and Qualitative Disclosures about Market Risk

We are exposed to a variety of financial risks, including market risk (including currency risk, price risk and cash flow and fair value interest rate risk), credit risk and liquidity risk. Our overall risk management program focuses on preservation of capital and the unpredictability of financial markets and has sought to minimize potential adverse effects on our financial performance and position.

Market Risk

We are exposed to foreign exchange risk arising from various currency exposures, primarily with respect to the U.S. dollar, particularly as we expand our operations in the United States and build-out our manufacturing facility in Lexington, Massachusetts. We have not established any formal practice to manage the foreign exchange risk against our functional currency. As of September 30, 2013, we had no significant outstanding receivables or payables in currencies other than euros, other than our loan from Hercules, which was received and is repayable in U.S. dollars. Subsequent to September 30, 2013, we have incurred obligations in U.S. dollars in respect of our manufacturing facility in Lexington, Massachusetts, as described above. Foreign exchange rate movements had no material effect during the periods under review.

Our interest rate risk arises from short and long-term borrowings. As of December 31, 2012, we had no borrowings with variable rates and we were not exposed to cash flow interest rate risk. In June 2013, we entered into the Hercules Agreement under which our borrowings bear interest at a variable rate. Borrowings issued at fixed rates expose us to fair value interest rate risk.

As of December 31, 2012, we had neither significant long-term interest-bearing assets nor significant long-term interest bearing liabilities other than our convertible notes, which were subsequently converted

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into ordinary shares on July 26, 2013. As of September 30, 2013, the loans issued under the Hercules Agreement bore interest at the rate of the greater of 11.85% and an amount equal to 11.85% plus the prime rate of interest minus 3.25%.

Credit Risk

We have a limited group of material external counterparties, of which the most significant is Chiesi. Over the coming years, funding under our collaboration and co-development agreements with Chiesi, including milestone payments, collaboration revenues and reimbursable research expenses, remains critical for our product development programs and represents our principal credit risk.

Our cash and cash equivalents are invested primarily in savings and deposit accounts with original maturities of three months or less. Savings and deposit accounts generate a small amount of interest income. For banks and financial institutions, we accept only independently rated parties with a minimum rating of 'A-'.

Liquidity Risk

We believe that the net proceeds of this offering, together with our existing cash and cash equivalents and anticipated payments under our agreements with Chiesi will enable us to fund our operating expenses and capital expenditure requirements for at least the next 12 months. See "Use of Proceeds."

Internal Control Over Financial Reporting

In connection with the preparation and external audit of our consolidated financial statements as of and for the year ended December 31, 2012 and the review of our consolidated financial statements as of and for the nine months ended September 30, 2013, we and our auditors, an independent registered public accounting firm, noted three material weaknesses in our internal control over financial reporting. The material weaknesses identified were:

    a lack of accounting resources required to fulfill IFRS and SEC reporting requirements,

    a lack of comprehensive IFRS accounting policies and financial reporting procedures; and

    a lack of segregation of duties given the size of our finance and accounting team.

We have implemented and are continuing to implement various measures to address the material weaknesses identified; these measures are outlined below.

Neither we nor our independent registered public accounting firm undertook a comprehensive assessment of our internal control for purposes of identifying and reporting material weaknesses, significant deficiencies and control deficiencies in our internal control over financial reporting as we will be required to do once we become a public company. We believe it is possible that, had we performed a formal assessment of our internal control over financial reporting or had our independent registered public accounting firm performed an audit of our internal control over financial reporting, additional control deficiencies may have been identified.

We have begun the process of evaluating our internal control over financial reporting, although we may not complete our review until after this offering is completed. We have also taken several remedial actions to address the material weaknesses that have been identified. To this end, we have hired additional staff for the finance department who have external reporting and IFRS experience, and experience with establishing appropriate financial reporting policies. Moreover, we have engaged a team of external consultants to assist us to improve our corporate governance and internal control procedures and help us design and implement a structured control environment for complying with the Sarbanes-Oxley Act of 2002, and we have devoted significant efforts to remedy any deficiencies or control gaps identified in the process. We expect to complete the measures above as soon as practicable and we will continue to implement measures to remedy our internal control deficiencies in order to meet the deadline imposed under Section 404 of the Sarbanes-

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Oxley Act. However, the implementation of these measures may not fully address the existing material weaknesses in our internal control over financial reporting, and we cannot yet conclude that they have been fully remedied.

The process of designing and implementing an effective financial reporting system is a continuous effort that requires us to anticipate and react to changes in our business and the economic and regulatory environments and to expend significant resources to maintain a financial reporting system that is adequate to satisfy our reporting obligations. See "Risk Factors—Risks Related to this Offering and Ownership of our Ordinary Shares—If we fail to implement and maintain an effective system of internal control, we may be unable to accurately report our results of operations or prevent fraud or fail to meet our reporting obligations, and investor confidence and the market price of our ordinary shares may be materially and adversely affected."

Critical Accounting Policies and Significant Judgments and Estimates

Our management's discussion and analysis of our financial condition and results of operations is based on our consolidated financial statements, which we have prepared in accordance with IFRS as issued by the IASB. The preparation of these financial statements requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities and the disclosure of contingent assets and liabilities at the date of the financial statements, as well as the reported revenues and expenses during the reporting periods. Actual results may differ from these estimates under different assumptions or conditions.

Our significant accounting policies are more fully described in the notes to our consolidated financial statements appearing elsewhere in this prospectus. We believe that the following accounting policies involve the most significant judgments and estimates by management and are the most critical to aid you in fully understanding and evaluating our financial condition and results of operations.

Revenue Recognition

We have not generated any revenues from royalties or product sales for any periods covered by the financial statements included in this prospectus.

During 2013, we received upfront payments in connection with our Glybera commercialization agreement and hemophilia B co-development agreement, each with Chiesi. Revenues from such non-refundable, up-front payments are initially reported as deferred revenues on the consolidated balance sheet and are recognized in revenues on the income statement as earned over the period of the development, commercialization, collaboration or manufacturing obligation.

We also generate revenues from collaborative research and development arrangements. Such agreements may consist of multiple elements and provide for varying consideration terms, such as up-front, milestone and similar payments, which require significant analysis by management in order to determine the appropriate method of revenue recognition.

Where such arrangements can be divided into separate units of accounting (each unit constituting a separate earnings process), the arrangement consideration is allocated to the different units based on their relative fair values and recognized over the respective performance period. Where the arrangement cannot be divided into separate units, the individual deliverables are combined as a single unit of accounting and the total arrangement consideration is recognized over the estimated collaboration period. This analysis requires considerable estimates and judgments to be made by us, including estimates of the relative fair values of the various elements included in such agreements and the estimated length of the respective performance periods.

Non-refundable upfront payments received from Chiesi related to licenses and reimbursement of past development costs for Glybera and our hemophilia B program. We have concluded that the elements of the

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payments are linked in such a way that the commercial effect cannot be understood without reference to the series of transactions as a whole. Therefore the individual performance obligations have been treated as a single unit of accounting and the total arrangement consideration is recognized over the estimated life of the agreements under which the continuing performance obligations exist.

Research and Development Expenses

We recognize research expenses as incurred. We recognize expenses incurred on development projects as intangible assets as of the date that it can be established that it is probable that future economic benefits that are attributable to the asset will flow to us, considering the development projects' commercial and technological feasibility, generally when we receive regulatory approval for commercial sale, and when expenses can be measured reliably. Given the stage of the development of our products and product candidates, we did not capitalize any development expenditures prior to 2013. As noted above, we incurred significant expenses in the development of Glybera. We received marketing approval from the European Commission for Glybera for a subset of LPLD patients in October 2012. Because we did not have sufficient financial resources at that time to complete the development of Glybera, including the post-approval activities required by the EMA prior to commercial launch, however, we did not capitalize the development expenses related to Glybera during the year ended December 31, 2012. Following our receipt of an additional €10.0 million in convertible debt financing in the first quarter of 2013, we determined that we had sufficient financial resources to complete these post-approval activities, and accordingly began to capitalize the related development expenses from March 21, 2013. Glybera-related raw materials that cannot be used for commercial purposes are expensed; Glybera-related materials, including raw materials, work-in-progress and finished goods, that are expected to be used for commercial purposes are recorded as inventory on the balance sheet and are not accounted for within research and development expenses.

As of each balance sheet date, we estimate the level of service performed by our vendors or other counterparties and the associated costs incurred for the services performed. As part of the process of preparing our financial statements we are required to estimate our accrued expenses. This process involves reviewing quotations and contracts, identifying services that have been performed on our behalf, estimating the level of service performed and the associated costs incurred for the service when it has not yet been invoiced or we have not otherwise been notified of the actual costs. The majority of our service providers invoice us monthly in arrears for services performed or when contractual milestones are met. We make estimates of our accrued expenses as of each balance sheet date in our financial statements based on facts and circumstances known to us at that time. We periodically confirm the accuracy of our estimates with the service providers and make adjustments if necessary. The significant estimates in our accrued research and development expenses are related to fees paid to clinical research organizations, or CROs, in connection with research and development activities for which we have not yet been invoiced. We base our expenses related to CROs on our estimates of the services received and efforts expended pursuant to quotes and contracts with CROs that conduct research and development on our behalf.

The financial terms of these agreements are subject to negotiation, vary from contract to contract and may result in uneven payment flows. There may be instances in which payments made to vendors and other counterparties will exceed the level of services provided and result in a prepayment of the research and development expenses. In accruing service fees, we estimate the time period over which services will be performed and the level of effort to be expended in each period. If the actual timing of the performance of services or the level of effort varies from our estimate, we adjust the accrual or prepayment expense accordingly. Although we do not expect our estimates to be materially different from amounts actually incurred, our understanding of the status and timing of services performed relative to the actual status and timing of services performed may vary and could result in reporting amounts that are too high or too low in any particular period.

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Corporate and Other Taxes

We are subject to corporate taxes in the Netherlands and the United States. Significant judgment is required in determining the use of net operating loss carry forwards and taxation of upfront and milestone payments for corporate tax purposes. There are many transactions and calculations for which the ultimate tax determination is uncertain. Where the final tax outcome of these matters is different from the amounts that were initially recorded, such differences will impact the current and deferred corporate tax assets and liabilities in the period in which such determination is made.

We did not recognize any taxes or income during the periods covered by financial statements contained in this prospectus, since we are in a loss making position and have a history of losses. As of September 30, 2013, the total amount of tax losses carried forward was €121.5 million.

We have a history of tax losses, and therefore recognize deferred tax assets arising from unused tax losses or tax credits only to the extent that the relevant consolidated Dutch entity has sufficient taxable temporary differences or there is convincing other evidence that sufficient taxable profit will be available against which the unused tax losses or unused tax credits can be utilized by the consolidated Dutch entities. Management believes that sufficient convincing other evidence is not currently available and therefore we have not recorded a deferred tax asset in the financial statements contained in this prospectus. Tax losses in the Netherlands may be carried forward for nine years.

Impairments of Assets

Assets that are subject to amortization are reviewed for impairment whenever events or changes in circumstances indicate that the carrying amount may not be recoverable. In the nine months ended September 30, 2013 and the year ended December 31, 2012, we have reviewed the carrying amount of these assets and determined that no adjustments to carrying values were required.

In the year ended December 31, 2011, we recorded an impairment charge of €0.3 million in respect of the termination of a research license under which we had made an initial payment of €0.3 million.

We test assets that are not subject to amortization annually for impairment. For the purpose of assessing impairment, we group assets at the lowest levels for which there are separately identifiable cash flows (cash-generating units). We currently use all material assets in the development of our gene therapies. Therefore, our management regularly reviews all activities of our group as a single component and one cash-generating unit. Although we are not currently selling any products, our collaborator, Chiesi, is preparing the commercial launch of Glybera in the European Union. Our future revenues from product sales, if any, will depend on the success of Chiesi's commercialization efforts in the European Union and our success in obtaining marketing authorization for Glybera and any other product candidates in additional countries.

We have determined that no impairment was required to be recorded during the year ended December 31, 2012 or the first nine months of 2013. Based on our expectations of revenues and gross margin from anticipated sales of Glybera by Chiesi, we have determined that no impairment charge in respect of intangible assets relating to Glybera is necessary. These expectations are based principally on our estimate of the market size for Glybera and the gross margin that we expect to realize.

Compound Financial Instruments

We classify a financial instrument or its component parts on initial recognition as a financial liability, a financial asset or an equity instrument in accordance with the substance of the contractual arrangement and the definitions of a financial liability, a financial asset and an equity instrument. We have analyzed the convertible loans we issued in 2012 and 2013 and the venture debt financing received from Hercules in 2013, and concluded that both instruments were composed of a loan component and an embedded financial derivative component, which qualified as financing liabilities. We estimated the fair value of these

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liabilities using option pricing models and assumptions that are based on the individual characteristics of the instruments on the valuation date.

Share-Based Compensation

We issue share-based compensation awards, in the form of options to purchase ordinary shares, to certain of our employees, supervisory board members and consultants. We measure share-based compensation expense related to these awards by reference to the estimated fair value of the award at the date of grant. The total amount of the awards is expensed over the estimated vesting period. We have used the Black-Scholes option pricing model to determine the fair value of option awards, which requires the input of various assumptions that require management to apply judgment and make assumptions and estimates, including:

    the expected life of the option award, which we calculate using the simplified method as we have insufficient historical information regarding our share options to provide a basis for estimate;

    the expected volatility of the underlying ordinary shares, which we estimate based on the historical volatility of a peer group of comparable publicly traded companies with product candidates in similar stages of development; and

    historically, the fair value of our ordinary shares determined on the date of grant.

At each balance sheet date, we revise our estimates of the number of options that are expected to become exercisable. We recognize the impact of the revision of original estimates, if any, in the statement of comprehensive income and a corresponding adjustment to equity. We expect all vested options to be exercised over the remainder of their contractual life. We consider the expected life of the options to be in line with the average remaining term of the options post vesting.

Prior to our acquisition of the AMT business on April 5, 2012, AMT was listed on Euronext Amsterdam from June 2007 through April 2012. This period provided company-specific historical and implied volatility information. Since the de-listing of AMT in April 2012, we have not had the same level of company-specific historical and implied volatility information; therefore, we estimate the expected volatility based on the historical volatility of publicly traded peer companies with a similar focus on gene therapies, biological products or orphan diseases, including Oxford Biomedica plc, MolMed S.p.A., Transgene SA, Sarepta Therapeutics, Inc., Sangamo Biosciences Inc. and Synageva BioPharma Corp.

We account for share options as an expense in the statement of comprehensive income over the estimated vesting period, with a corresponding contribution to equity. See Note 10 to our audited consolidated financial statements included elsewhere in this prospectus for a discussion of the total expense recognized in the statement of comprehensive income for share options granted to employees, supervisory board members and consultants.

The following table summarizes, by grant date, the number of ordinary shares underlying share options granted from January 1, 2012 through the date of this prospectus, as well as the associated per share exercise price, the estimated fair value per ordinary share on the grant date, the retrospective estimated fair value per share on the grant date, and the estimated fair value per option as of the grant date:

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GRANT DATE
  NUMBER OF
ORDINARY SHARES
UNDERLYING
OPTIONS GRANTED
  EXERCISE
PRICE PER
ORDINARY
SHARE
  ESTIMATED
FAIR VALUE PER
ORDINARY SHARE
AT GRANT DATE
  RETROSPECTIVE
FAIR VALUE
PER ORDINARY
SHARE AS OF
GRANT DATE(1)
  ESTIMATED
FAIR VALUE
PER OPTION
AS OF
GRANT DATE
 

April 5, 2012

    1,366,304   3.07   3.07   3.07   2.05  

June 12, 2012

    15,000     3.07     3.07     3.07     2.05  

December 1, 2012

    140,652     3.07     3.07     4.85     3.35  

December 22, 2012

    84,391     3.07     3.07     5.10     3.60  

January 1, 2013

    112,000     5.00     5.00     5.45     3.40  

March 26, 2013

    14,065     5.00     5.00     7.65     5.30  

June 5/6, 2013

    28,000     10.10     10.10     12.60     8.15  

September 1, 2013

    140,652     10.10     13.30     N/A     8.85  

October 1, 2013

    6,751     3.07     13.40     N/A     12.35  

January 17, 2014

    609,744     0.05     10.37 (2)   N/A     10.32  

(1)
The fair value of our ordinary shares at the grant date was adjusted in connection with our retrospective fair value assessment for financial reporting purposes, as described below.

(2)
The Euro equivalent of the mid point of the price range set forth on the cover page of this prospectus.

Of the 2,301,588 options which have been granted under our equity incentive plans and in connection with our agreement with 4D Molecular Therapeutics, and remained outstanding as of the date of this prospectus, an aggregate of 478,217 options were granted to members of the management board. 1,507,443 options which have been granted and remained outstanding at January 24, 2014 will vest in full on or before the closing of this offering, which would result in the acceleration of any unrecognized expense related to these options. As of September 30, 2013, the unrecognized expense related to the options which have been granted and remained outstanding was €2.2 million.

The intrinsic value of all outstanding vested and unvested options as of the date of this prospectus was $23.2 million, based on an assumed public offering price of $14.00 per ordinary share (€10.37 per ordinary share), which is the midpoint of the price range set forth on the cover page of this prospectus, and was based on 2,301,588 ordinary shares issuable upon the exercise of options outstanding as of the date of this prospectus with a weighted average exercise price of €2.89 per share.

Determination of the Fair Value of Ordinary Shares on Grant Dates

We are a private company with no active public market for our ordinary shares. Therefore, we have periodically determined for financial reporting purposes the estimated per share fair value of our ordinary shares at various dates using contemporaneous valuations. We performed these contemporaneous valuations as of each of the grant dates identified above. In conducting the contemporaneous valuations, our management board and supervisory board considered all objective and subjective factors that we believed to be relevant for each valuation conducted, including their best estimate of our business condition, prospects and operating performance at each valuation date.

In connection with the preparation of our audited financial statements for 2012, our management board and supervisory board reconsidered the fair values as of each grant date through September 2013, and engaged an independent third party to conduct a retrospective fair value assessment as of each grant date, as described below, for financial reporting purposes. In light of management's retrospective assessment of the various grants, the estimated fair values and, accordingly, the related compensation expense, were adjusted as appropriate.

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There are significant judgments and estimates inherent in the determination of the fair value of our ordinary shares. These judgments and estimates include assumptions regarding our future operating performance, the time to completing an initial public offering or other liquidity event and the determinations of the appropriate valuation methods. If we had made different assumptions, our share-based compensation expense, net loss and net loss per ordinary share could have been significantly different.

Our management board and supervisory board consider numerous objective and subjective factors to determine their best estimate of the fair value of the ordinary shares as of each grant date, including the following:

    the progress of our research and development programs;

    achievement of enterprise milestones, including the entering into of collaboration and license agreements;

    contemporaneous issuances and valuations of our ordinary shares;

    our historical and forecasted performance and operating results;

    our need for future financing to fund operations;

    the likelihood of our achieving a discrete liquidity event, such as a sale of our company or an initial public offering, given prevailing market conditions;

    the dilutive effect of employee incentive instruments, our convertible loan and warrants; and

    external market and economic conditions impacting our industry.

In determining the estimated fair values of our ordinary shares as of each award grant date, three generally accepted approaches were considered: income approach, market approach and cost approach. Based on our stage of development and information available, we have determined that the income approach is the most appropriate method. When applicable, we have also applied the market approach by employing recent sales of company shares as a method to estimate our aggregate enterprise value. In addition, we have taken into consideration the guidance prescribed by the American Institute of Certified Public Accounts, or AICPA, Audit and Accounting Practice Aid, Valuation of Privately-Held-Company Equity Securities Issued as Compensation.

Discounted cash flow, or DCF, an income approach to determining the fair value of the ordinary shares, which we estimated as of each award grant date, is an estimate of the present value of the future monetary benefits expected to flow to the owners of a business. It requires a projection of the cash flows that the business is expected to generate. These cash flows are converted to present value by means of discounting, using a rate of return that accounts for the time value of money and the appropriate degree of risks inherent in the business. The discount rate in the DCF analysis is based upon a weighted average cost of capital, or WACC, calculated at each valuation date. The WACC is a method that market participants commonly use to price securities and is derived by using the capital asset pricing model and inputs such as the risk-free rate, beta coefficient, which is a measure of the sensitivity of a share price to movements in the overall securities market, equity risk premiums and the size of the company. We analyzed our financial and operating projections, including revenues, operating expenses, working capital investments and capital expenditures, to form the basis for our DCF valuation.

In applying the Black-Scholes option model, we applied a discount for lack of marketability, or DLOM, to reflect the increased risk arising from the inability to readily sell the ordinary shares underlying the options granted. Under this method, we considered the cost of the put option, which can hedge the price change before the privately held ordinary shares can be sold, as the basis to determine the DLOM. The cost of the put option was the only factor we considered and applied in the discount. The put option analysis reflects the potential loss from marketability over the expected time to liquidity and is a commonly applied approach to estimate this discount.

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We have also considered prior arm's length sales of our equity securities in order to estimate our business enterprise value. Considerations factored into the analysis include the type and amount of equity sold, the relationship of the parties involved, the timing compared to the ordinary share valuation date and the financial condition and structure of a company at the time of the sale.

In the retrospective valuation described above, three key valuation inflection points were identified during the period from April 2012 through December 2013:

    On July 20, 2012, the CHMP issued a positive recommendation for the approval of our marketing authorization application for Glybera.

    On October 31, 2012, the European Commission formally approved Glybera for a subset of LPLD patients.

    On April 29, 2013, we signed an agreement with Chiesi for the commercialization of Glybera in the European Union and other specified countries.

We believe that each of these events had a significant positive effect on the fair value of our ordinary shares, and served as reference points for the determination of fair value at each grant date. In particular, developments between October 2012 and April 2013 reduced both execution and financing risks facing our business. For grants made between these value inflection points and between April and September 2013, we interpolated the key valuation assumptions, including the probability of success of our individual development programs and the weighted average cost of capital as of such dates.

Share Option Grants on April 5, 2012

AMT shares were previously listed on Euronext Amsterdam. On the five business days immediately prior to February 17, 2012, the date on which we announced our proposed acquisition of the entire business and assets of AMT, the average closing price of the shares of AMT on Euronext Amsterdam was €3.07 per AMT share. Given that uniQure had no other business of its own, and that the consideration for purchase of the business and assets of AMT was a one-for-one share issuance in respect of each AMT share then in issue, we believed this represented the fair value of our ordinary shares as of this date. In addition, on April 5, 2012, we raised €6.0 million through the issuance of new shares to an existing shareholder at a price per ordinary share of €3.07.

All AMT options outstanding at the time we acquired the assets and business of AMT were terminated. In order to retain and provide incentives for our employees following this corporate reorganization, we granted options to purchase an aggregate of 1,366,304 ordinary shares on April 5, 2012, with an exercise price of €3.07 per share. Our management board and supervisory board determined that €3.07 represented the fair value per ordinary shares as of the grant date based on the average closing price of AMT shares on Euronext Amsterdam on the five days immediately prior to the announcement of the acquisition of the business and assets of AMT by uniQure and the concurrent equity investment transaction.

Share Option Grants on June 12, 2012

On April 19, 2012, the EMA announced that, following a request from the European Commission in January 2012, it had re-evaluated Glybera in a restricted group of patients with severe or multiple pancreatitis attacks. The EMA maintained its previous recommendation that Glybera should not be granted marketing authorization at that time.

On April 18, 2012, we raised €1.0 million through the issuance of new shares to an existing shareholder at a price of €3.07 per ordinary share. Our management board and supervisory board determined that, although we had raised sufficient new capital in our financing transaction in April 2012 to continue as a going concern, we did not have enough capital at that time to progress the development and commercialization of Glybera. Therefore, the issuance price for the April 2012 equity financing was unchanged from the issuance price used in the April equity financing. Accordingly, our management board

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and supervisory board determined that €3.07 remained the estimated fair value of our ordinary shares at that date based on this third party equity financing transaction.

On June 12, 2012, we granted options to purchase an aggregate of 15,000 ordinary shares at an exercise price of €3.07 per share. Our management board and supervisory board determined that there had been no meaningful change in our financial position or performance between April 18, 2012 and this grant date to warrant a change in the estimated fair value of our ordinary shares.

Share Option Grants on December 1, 2012

On July 20, 2012, the CHMP recommended approval of Glybera for the restricted population of LPLD patients with severe or multiple pancreatitis attacks, subject to additional post-marketing studies for efficacy. We view this as the first of three key value inflection points at which we observed a significant change in our company and per share value. Although there was still significant uncertainty about Glybera's formal approval in the European Union and our ability to proceed, we believe that this marked an increase in our company value.

On October 31, 2012, the second value inflection point, the European Commission formally approved the marketing authorization for Glybera under exceptional circumstances. This removed further uncertainty around formal approval of Glybera.

Notwithstanding the positive regulatory developments in the European Union for Glybera, during 2012 and the first nine months of 2013, our management board and supervisory board considered that any increase in the value of our company following the approval of Glybera was partially offset by the substantial increase in financial risk, including uncertainty as to whether we would be able to continue as a going concern. Accordingly, to calculate our company valuation at each value inflection point, we performed an analysis, revising the value drivers to account for the changes in probability of success of our pipeline product candidates in light of the EU regulatory developments surrounding Glybera, changes in the WACC to reflect changes in financing risk and in the probability of success, our cash burn, and the discounting effect of cash flows.

We used these outcomes to estimate the fair value of option grants on December 1, 2012; December 22, 2012; January 1, 2013; March 26, 2013 and June 5/6, 2013 using the Black-Scholes option pricing model. Use of this valuation methodology requires that we make assumptions as to the value of the underlying asset, the exercise price, the expected volatility of share price returns, which is estimated based on the observed average of the daily share price returns of selected guideline companies measured over a historic period equal to the expected term of our share options and the risk free interest rate for a period that approximates the expected term of our share options and our expected dividend yield.

On December 1, 2012, we granted options to purchase an aggregate of 140,652 ordinary shares with an exercise price of €3.07 per share, which our management board and supervisory board contemporaneously determined to be the fair value of our ordinary shares as of such date.

Our management board and supervisory board subsequently commissioned a retrospective valuation of these ordinary shares, considering our financial risk, and arrived at an estimated fair value per share of €4.85. We relied on the DCF method to perform the retrospective valuation as of December 1, 2012. Our key assumptions included probabilities of success of 65 to 85% and a WACC of 21%. We applied a DLOM of 20%. Based on an estimated value per ordinary share of €4.85, this resulted in the fair value per option of €3.30 to €3.40. The key assumptions we used to arrive at the estimated value per option included an estimated volatility of 70%, an expected life of 5.5 to 6.3 years, and a risk-free rate of 0.6% to 0.7% based on the yield to maturity of German sovereign debt, for a term equal to the expected life as measured on the grant date. This increase from the prior valuation performed in June 2012 primarily related to the European Commission's formal approval of the marketing authorization for Glybera and the resulting

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increased probability of success of our Glybera program. For financial reporting purposes, this value has been applied retrospectively to our December 1, 2012 option grants.

Share Option Grants on December 22, 2012

On December 22, 2012, we granted options to purchase an aggregate of 84,391 ordinary shares with an exercise price of €3.07 per share, which our management board and supervisory board contemporaneously determined to be the fair value of our ordinary shares as of such date.

Our management board and supervisory board subsequently commissioned a retrospective valuation of these ordinary shares, considering our financial risk, and arrived at an estimated fair value per share of €5.10. We relied on the DCF method to perform the retrospective valuation as of December 22, 2012. Key assumptions were unchanged relative to the December 1, 2012 valuation date, including probabilities of success of 65 to 85% and a WACC of 21%. We applied a DLOM of 15%. Based on estimated value per ordinary share of €5.10, this resulted in the fair value per option of €3.55 to €3.65. The key assumptions we used to arrive at this estimated fair value per option included an estimated volatility of 70%, an expected life of 5.5-6.3 years, and a risk-free rate of 0.5% to 0.7% based on the yield to maturity of German sovereign debt, for a term equal to the expected life as measured on the grant date. This increase from the prior valuation primarily reflected the increased probability of success of our Glybera program and additional funding received during December 2012. For financial reporting purposes, this value has been applied retrospectively to our December 22, 2012 option grants.

Share Option Grants on January 1, 2013

On January 1, 2013, we granted options to purchase an aggregate of 112,000 ordinary shares with an exercise price of €5.00 per share, which our management board and supervisory board contemporaneously determined to be the fair value of our ordinary shares as of such date.

Our management board and supervisory board subsequently commissioned a retrospective valuation of these ordinary shares, considering our financial risk, and arrived at an estimated fair value per share of €5.45. We relied on the DCF method to perform the retrospective valuation as of January 1, 2013. Key assumptions were unchanged relative to the December 22, 2012 valuation date, including probabilities of success of 65 to 85% and a WACC of 21%. We applied a DLOM of 15%. Based on an estimated value per ordinary share of €5.45, this resulted in the fair value per option of €3.35 to €3.50. The key assumptions we used to arrive at the estimated fair value per option included an estimated volatility of 70%, an expected life of 5.5 to 6.3 years, and a risk-free rate of 0.4% to 0.6% based on the yield to maturity of German sovereign debt, for a term equal to the expected life as measured on the grant date. This increase from the previous valuation primarily reflected the progress we had made by that date in identifying a potential collaborator for the commercialization of Glybera. For financial reporting purposes, this value has been applied retrospectively to our January 1, 2013 option grants.

Share Option Grants on March 26, 2013

On March 26, 2013, we granted options to purchase an aggregate of 14,065 ordinary shares with an exercise price of €5.00 per share, which our management board and supervisory board contemporaneously determined to be the fair value of our ordinary shares as of such date.

Our management board and supervisory board subsequently commissioned a retrospective valuation of these ordinary shares, considering our financial risk, and arrived at an estimated fair value per share of €7.65. We relied on the DCF method to perform the retrospective valuation as of March 26, 2013. Key assumptions included increased probabilities of success of 70 to 90% due to technical progress achieved and a WACC of 18.9% due to decreased financing risk since the January 1, 2013 valuation date. We applied a DLOM of 15%. Based on estimated value per ordinary share of €7.65, this resulted in the fair value per option of €5.20 to €5.40. The key assumptions we used to arrive at the estimated fair value per option included an

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estimated volatility of 70%, an expected life of 5.5 to 6.3 years, and a risk-free rate of 0.5% to 0.6% based on the yield to maturity of German sovereign debt, for a term equal to the expected life as measured on the grant date. This increase in the fair value of our ordinary shares primarily reflected additional financing received since the prior valuation, which provided us with the funds necessary to continue the development of Glybera. For financial reporting purposes, this value has been applied retrospectively to our March 26, 2013 option grants.

Share Option Grants on June 5/6, 2013

On April 29, 2013, the third value inflection point, we entered into an agreement with Chiesi with respect to the commercialization of Glybera in the European Union and selected other countries. This agreement was subject to the satisfaction by us of specified conditions precedent. The Chiesi transaction allowed us to update the estimate of the present value of our expected future cash flows based on the value of the transaction.

On June 5, 2013 and June 6, 2013, we granted options to purchase an aggregate of 28,000 ordinary shares with an exercise price of €10.10 per share, which our management board and supervisory board contemporaneously determined to be the fair value of our ordinary shares as of such date.

Our management board and supervisory board subsequently commissioned a retrospective valuation of these ordinary shares, considering our financial risk, and arrived at an estimated fair value per share of €12.60. We primarily relied on the expected transaction price of the ordinary shares subsequently acquired by Chiesi pursuant to the conditional agreements entered into in April 2013, of €12.60 per share to perform the retrospective valuation as of June 5/6, 2013. Additionally, we performed a DCF as of June 2013. Key assumptions included probabilities of success of 70 to 90% and a WACC of 16.0%. We applied a DLOM of 15%. The probabilities of success remained unchanged relative the prior valuation date, while the WACC was lowered to reflect a further decrease in financing risk given the additional funding provided by Chiesi. Based on estimated value per ordinary share of €12.60, this resulted in the fair value per option of €8.00 to €8.35. The key assumptions we used to arrive at the estimated fair value per option included an estimated volatility of 70%, an expected life of 5.5 to 6.3 years, and a risk-free rate of 0.7% to 0.8% based on the yield to maturity of German sovereign debt, for a term equal to the expected life as measured on the grant date. This increase in the fair value of the ordinary shares was primarily due to the announcement that we would be entering into collaboration agreements with Chiesi, including the issuance to Chiesi of 8.75% of our share capital. For financial reporting purposes, this value has been applied retrospectively to our June 5/6, 2013 option grants.

Share Option Grants on September 1, 2013

On September 1, 2013, we granted options to purchase an aggregate of 140,652 ordinary shares with an exercise price of €10.10 per share.

Our management board and supervisory board contemporaneously commissioned a valuation of the ordinary shares, and arrived at an estimated fair value per share of €13.30 as of the grant date. We performed a DCF as of September 1, 2013. Key assumptions included probabilities of success of approximately 70 to 90% and a WACC of 16.0%. We applied a DLOM of 10%. The probabilities of success remained unchanged relative to the prior valuation date. Based on estimated value per ordinary share of €13.30, this resulted in the fair value per option of €8.70 to €9.05. The key assumptions we used to arrive at the estimated fair value per option included an estimated volatility of 70%, an expected life of 5.5 to 6.3 years, and a risk-free rate of 1.0% to 1.2% based on the yield to maturity of German sovereign debt, for a term equal to the expected life as measured on the grant date. This increase in the fair value of the ordinary shares was primarily due to passage of time, such that positive operating cash flows come nearer.

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Share Options Grant on October 1, 2013

On October 1, 2013, we granted options to purchase an aggregate of 6,751 ordinary shares at an exercise price of €3.07 per share. Our management board and supervisory board contemporaneously commissioned a valuation of the ordinary shares, and arrived at an estimated fair value per share of €13.40 as of the grant date. We performed a DCF as of October 1, 2013. Key assumptions included probabilities of success of approximately 70% to 90% and a WACC of 16.0%. We applied a DLOM of 10%. The probabilities of success remained unchanged relative to the prior valuation date. Based on an estimated value per ordinary share of €13.40, this resulted in the fair value per option of €11.25 to €11.40. The key assumptions we used to arrive at the estimated fair value per option of each tranche of the grant included an estimated expected volatility of 70%, an expected life of 5.5 to 6.3 years, and a risk-free rate of 0.9% to 1.0% based on the yield to maturity of German sovereign debt, for a term equal to the expected life as measured on the grant date. This increase in the fair value of the ordinary shares from €3.07 to €13.40 was primarily due to passage of time, such that positive operating cash flows come nearer.

The grant was originally discussed with the participant in June 2012, but the option agreement was only concluded on October 1, 2013. As a result, the option is granted with an exercise price of €3.07 and other terms as originally proposed in June 2012. To reflect the start of the service commencement period as of April 5, 2012, related option expenses for the period April 5, 2012 to October 1, 2013 were recorded based on an estimated grant date fair value of the options. An adjustment to these estimated expenses was recorded as of October 1, 2013 to reflect the fair value of the granted options as determined at the formal grant date, October 1, 2013.

Share Options Grant on January 17, 2014

On January 17, 2014, we granted options to purchase an aggregate of 609,744 ordinary shares at an exercise price of €0.05 per share. These options were granted in connection with the collaboration and license agreement we entered into on that date with 4D Molecular Therapeutics, and were granted to two consultants who will be providing services to us in connection with that agreement. The options vest in three tranches, on October 1, 2014, January 31, 2015, and January 31, 2016. Our management board and supervisory board determined that the fair value of the ordinary shares as of the grant date was €10.37, the midpoint of the price range set forth on the front cover of this prospectus. The key assumptions we used to arrive at the estimated fair value per option of each tranche of the grant included an expected volatility of 70%, an expected average life of 1.6 years, and a risk-free rate of 0.1% based on the yield to maturity of German sovereign debt, for a term equal to the expected life as measured on the grant date.

Recent Accounting Pronouncements

There are no IFRS standards as issued by the IASB or interpretations issued by the IFRS interpretations committee (e.g. IFRS 10, 11, 12, 13 and IAS 19R) that are effective for the first time for the financial year beginning on or after January 1, 2013 that had or are expected to have a material impact on our financial position.

JOBS Act Exemptions

On April 5, 2012, the Jumpstart Our Business Startups, or JOBS, Act was signed into law. The JOBS Act contains provisions that, among other things, reduce certain reporting requirements for an "emerging growth company." As an emerging growth company, we are electing to take advantage of the following exemptions:

    including the use of two years of audited financial statements rather than three years;

    not providing an auditor attestation report on our system of internal controls over financial reporting;

    not providing all of the compensation disclosure that may be required of non-emerging growth public companies under the U.S. Dodd-Frank Wall Street Reform and Consumer Protection Act; and

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    not complying with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding mandatory audit firm rotation or a supplement to the auditor's report providing additional information about the audit and the financial statements (auditor discussion and analysis).

The JOBS Act permits an "emerging growth company" such as us to take advantage of an extended transition period to comply with new or revised accounting standards applicable to public companies. We are irrevocably electing not to avail ourselves of this extended transition period for complying with new or revised accounting standards and, therefore, we will be subject to the same new or revised accounting standards as other public companies that are not "emerging growth companies."

These exemptions will apply for a period of five years following the completion of our IPO or until we no longer meet the requirements of being an "emerging growth company," whichever is earlier. We would cease to be an emerging growth company if we have more than $1.0 billion in annual revenue, have more than $700 million in market value of our ordinary shares held by non-affiliates or issue more than $1.0 billion of non-convertible debt over a three-year period.

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BUSINESS

Overview

We are a leader in the field of gene therapy and have developed the first and currently the only gene therapy product to receive regulatory approval in the European Union. Gene therapy offers the prospect of long-term and potentially curative benefit to patients with genetic or acquired diseases by directing the expression of a therapeutic protein or restoring the expression of a missing protein through a single administration. Our first product, Glybera, was approved by the European Commission in October 2012 under exceptional circumstances for the treatment of a subset of patients with LPLD, a potentially life-threatening, orphan metabolic disease. We expect to launch Glybera commercially in selected European countries in the first half of 2014 through our collaboration with Chiesi, which we entered into in April 2013. We retain full commercial rights to Glybera in the United States. In August and December 2013, we met with the FDA to discuss the regulatory pathway for Glybera in the United States and we plan to file an IND with the FDA for Glybera in the first half of 2014.

We are developing a pipeline of additional AAV-based gene therapies through multiple collaborations that are designed to accelerate the development and commercialization of these programs. We develop our gene therapies using our innovative, modular technology platform, including our proprietary, cost-effective manufacturing process. Our pipeline includes product candidates targeting diseases for which either the efficacy of existing treatments is limited or the administration regimen is burdensome, such as hemophilia B, as well as diseases for which there are currently no treatments, such as Sanfilippo B syndrome. We initially intend to focus on orphan diseases but believe we will also be able to leverage our technology to develop gene therapies targeting chronic and degenerative diseases that affect larger populations. Through our gene delivery system know-how, our proprietary manufacturing process, the state-of-the-art facility we are building out and equipping in the United States, and our experience in developing and obtaining regulatory approval for Glybera in the European Union, we believe we will be able to develop and commercialize additional gene therapies more efficiently than our competitors.

Our gene therapy approach seeks to treat the causes of genetic diseases by enabling patients to effectively express a missing or deficient protein. To accomplish this, Glybera and our product candidates are designed to deliver a transgene through a delivery system called a vector. Our approach is designed to be modular, in that it may allow us to develop, manufacture and seek regulatory approval for multiple gene therapies generally using the same principal components. The key components of our gene therapy approach are:

    the therapeutic gene cassettes we design or in-license from academic research institutions and biotechnology and pharmaceutical companies, including our collaborators;

    an AAV-based vector delivery system with a demonstrated safety profile that selectively targets relevant tissues;

    administration technologies designed to optimize the introduction of our gene therapy vectors into the patient's body; and

    our scalable, proprietary manufacturing process.

Glybera is indicated for the treatment of adult patients diagnosed with familial LPLD confirmed by genetic testing and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. LPLD results in hyper-chylomicronemia, or dramatic and potentially life-threatening increases in the level of large fat-carrying particles, called chylomicrons, in the blood after eating. In many cases, LPLD and the associated elevated levels of chylomicrons can cause acute and potentially life-threatening inflammation of the pancreas, known as pancreatitis, thus leading to frequent hospitalizations. Recurrent pancreatitis can lead to chronic abdominal pain, pancreatic insufficiency, which is an inability to properly digest food due to a lack of digestive enzymes made by the pancreas, and diabetes.

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Prior to Glybera, there has been no approved therapy for the treatment of LPLD. Patients with this rare condition are required to adhere to a strict low-fat diet and to abstain from alcohol. These restrictions, as well as frequent hospitalizations and the constant fear of encountering pancreatitis attacks, have a significant negative impact on the daily activity level of LPLD patients and on their quality of life.

In addition to Glybera, our development pipeline includes our internal program for hemophilia B, two collaborator-sponsored programs for monogenic diseases, one collaborator-sponsored program for a chronic degenerative disease and several programs in early preclinical development. The most advanced of these pipeline programs are the following:

Internal Program: AMT-060 for Hemophilia B.    In collaboration with Chiesi, we are developing AMT-060 for the treatment of hemophilia B, which is a severe orphan blood clotting disorder. AMT-060 consists of an AAV5 vector carrying a therapeutic hFIX gene cassette that we have exclusively licensed from St. Jude. We plan to file an IND and an IMPD to initiate a Phase I/II dose escalation clinical trial of this product candidate in the second half of 2014 in 13 to 16 patients. St. Jude is currently conducting a Phase I/II clinical trial in this indication with a gene therapy consisting of an AAV8 vector carrying the same hFIX gene that we are using in AMT-060. We describe these as both Phase I and Phase II clinical trials because their goals are not merely to evaluate the therapy's safety but also to obtain a preliminary determination of efficacy.

Collaborator-Sponsored Programs.    We are also collaborating with third parties that are sponsoring early-stage clinical trials of gene therapy product candidates to which we hold certain rights. We believe that this approach enables us to cost-effectively obtain access to preclinical and early-stage clinical results without expending significant resources of our own. These programs utilize either clinical materials that we have manufactured as part of our collaborations or gene cassettes that we have licensed. We generally have the rights to the data generated in these collaborator-sponsored clinical development programs, but do not control their design or timing. If we decide to progress any of these programs internally, we may need to develop or in-license additional technology. The most advanced of these programs are the following:

    AMT-021 for Acute Intermittent Porphyria.  We and our collaborator Digna Biotech are developing AMT-021 as a gene therapy for AIP, a severe liver disorder. AMT-021 consists of an AAV5 vector carrying a therapeutic PBGD gene that we exclusively license from Applied Medical Research Center of the University of Navarra in Spain, or CIMA. Digna Biotech is currently conducting a Phase I clinical trial of AMT-021 in eight patients in Spain. We have manufactured the gene therapy being used in this clinical trial. We understand from Digna Biotech that data are expected in the second half of 2014. Under an agreement with Digna Biotech, we have an exclusive right to use all preclinical and Phase I clinical trial data from this program.

    AMT-110 for Sanfilippo B Syndrome.  We and our collaborator Institut Pasteur are developing AMT-110 as a gene therapy for Sanfilippo B syndrome, a potentially fatal lysosomal storage disease that results in serious brain degeneration in children. This gene therapy consists of an AAV5 vector carrying a therapeutic NaGLU gene. Institut Pasteur is currently conducting a Phase I/II clinical trial of AMT-110 in four patients in France. We have manufactured the gene therapy being used in this clinical trial. We have an agreement in principle with Institut Pasteur to acquire the clinical results and commercial rights under this program following completion of this Phase I/II clinical trial, and are currently in negotiations with Institut Pasteur regarding the terms of a definitive agreement in this regard. We understand from Institut Pasteur that data are expected in the first half of 2015.

    AAV2/GDNF for Parkinson's Disease.  We and our collaborator UCSF are developing a gene therapy for Parkinson's disease, a progressive neurodegenerative disorder affecting motor skills, speech and other neurological functions and resulting in progressive neurologic dysfunction and death. UCSF is collaborating with the NIH to conduct a Phase I clinical trial of a gene therapy in this indication that consists of an AAV2 vector manufactured by a third party using a mammalian cell-based process, carrying a therapeutic gene we have exclusively licensed in the gene therapy field from Amgen that

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      expresses GDNF. The NIH is funding and sponsoring the clinical trial. We have rights to the clinical data from this trial. Based on the results of the UCSF study, we may decide to develop an AAV2-based gene therapy containing the GDNF gene manufactured with our insect cell-based manufacturing process.

We operate a cGMP-manufacturing facility at our headquarters in Amsterdam, the Netherlands, which the EMA has approved for clinical and commercial-grade production. We have also begun the build-out of a 53,000 square-foot manufacturing facility in Lexington, Massachusetts, in the United States, which we believe will be the world's most advanced dedicated facility for the production of AAV-based gene therapies.

Gene Therapy Background

Genes are the specific areas of DNA that provide the blueprint used by the body's cellular machinery to make proteins, which are enzymes or other large molecules in the cells of the body that serve a functional purpose. Each gene consists of a specific sequence that encodes for the production of specific proteins. This protein production process in the cell is called gene expression.

A mutation, or defect, in a specific gene can result in the inability or reduced ability to express a protein, or the reduced functionality of a protein. For example, when the gene associated with the production of a protein required for blood clotting is missing or mutated in hemophilia B patients, sufficient blood clotting will not occur, resulting in continued internal or external bleeding after even minor trauma or surgery. Introducing a copy of the proper gene into the cell would restore the presence and natural function of the blood clotting factor, which would prevent bleeding.

A large number of serious diseases result from a defect in a single gene. For many of these monogenic diseases, there is currently no cure or therapy. In other cases, existing therapies involve burdensome administration or frequent readministration, and may provide limited efficacy. For example, in the case of hemophilia B, most patients must receive frequent intravenous administration of plasma-derived or recombinant human Factor IX, currently two to three times per week, which often does not completely prevent bleeding. Millions of patients rely on recurrent medical care to help manage their life-long chronic ailments, often at significant cost and, depending upon the disease, with little chance of sustained success.

More than 30 years ago, scientists began exploring the concept of gene therapy as an approach to treating disease. The goal of gene therapy is to treat the underlying genetic cause of disease by introducing a functional gene to replace or supplement the activity of a missing or mutated gene. Gene therapy approaches include in vivo therapies, in which the functional gene is introduced directly into the patient's body, and ex vivo therapies, in which a patient's cells are removed, genetically modified and then transplanted back into the patient.

To enable delivery of the functional gene into the cells where it can produce the required protein, researchers use a vector that can enter, or transduce, the cell without harming it. Researchers generally consider vector systems derived from viruses to be more efficient in entering the target cells than non-viral vector systems. In addition, to target the vector to the tissues for the relevant disease, researchers using AAV-based vectors utilize different variants, or serotypes, of AAV to selectively target particular tissues. The vectors are designed to include DNA promoters, which are additional DNA sequences that allow for tissue-specific expression of the required protein.

We believe that most research and development efforts in gene therapy have focused on monogenic diseases, which include many hereditary diseases. Although these diseases are severe, their cause is generally better understood and less complex than diseases that involve more than one dysfunctional or missing gene. There are also opportunities to apply gene therapy in diseases caused by more complex pathology in which one particular protein plays a crucial role in the causation of the disease. In such indications, such as some liver diseases, disorders of the central nervous system and cardiovascular diseases, it may be possible to halt or eradicate the disease with a gene therapy that promotes the natural

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production or function of the relevant protein. Gene therapy also has the potential to neutralize faulty genes, referred to as gene silencing, and to switch genes on or off.

We believe that as scientific understanding of the genetic causes of disease expands and as genetic sequencing becomes more cost-efficient and routine, the practice of medicine will increasingly turn to gene therapy as an approach to treating, and potentially preventing, disease, with resulting longer-term cost benefits to the health care system.

Historical Challenges Faced By Gene Therapy

Gene therapy has historically confronted a number of significant challenges, including the following:

    Poor Safety Profile.  Early gene therapies raised significant safety concerns. For example, some ex vivo gene therapy approaches use lentiviral or retroviral vectors that can integrate at relatively high frequency into parts of the genome in a manner that increases the risk of cancer. In addition, an early in vivo gene therapy approach using an adenovirus vector triggered a strong innate immune response in a patient that resulted in multiple-organ failure and death. These high-profile safety issues resulted in negative public perceptions of the safety of gene therapy generally.

    Limited Efficacy.  Early gene therapy manufacturing processes produced a large proportion of empty vectors, or viral packages that did not include the therapeutic gene of interest. In addition, because patients' immune systems respond to proteins in the vector shell, the large proportion of empty vectors generated counterproductive immune responses. Limited long-term expression of the delivered genes in target cells also made it difficult to achieve meaningful clinical efficacy in either the short- or long-term. These problems reflected the fact that early researchers had not identified the AAV serotypes, optimized genes or DNA promoters that could target the appropriate tissues and produce levels of gene expression necessary to demonstrate clinical efficacy. Earlier approaches utilizing AAV vectors also typically involved the packaging of single-stranded DNA into delivery vectors. Because the required starting point for the transcription of a gene is double-stranded DNA, this single-stranded approach required the cellular machinery to make a second copy of the DNA, which added an additional step in the process and reduced expression levels.

    Difficulties in Administration and Tissue-Specific Targeting.  The efficacy of some earlier gene therapies was limited by difficulties in administering the vector to the patient's body in a manner that resulted in effective delivery of the therapeutic transgene into the desired target tissue or organ. For example, researchers have historically been challenged in administering gene therapies targeting CNS indications due to the difficulties presented by the blood-brain barrier. Only recently have scientists begun to optimize the gene therapy administration process through the use of advanced technologies for local administration to muscle cells and neurons.

    Lack of Cost-Effective and Consistent Manufacturing.  Until recently, AAV-based vectors could not be manufactured at commercial scale on a cost-effective, reliable and reproducible basis. Difficulties in increasing production levels to commercial scale were particularly challenging in manufacturing processes that utilized mammalian cells. These mammalian cell processes typically use adherent cells, which are cells that only grow on a surface. As a result, production of larger quantities of vector required large surfaces, which is more challenging and less economical than manufacturing processes that use cells that can be grown in a suspension culture.

We believe these factors have contributed to the failure to develop approved gene therapy products in the past. Glybera is the only approved gene therapy in the European Union and no gene therapy has been approved to date in North America.

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Our Gene Therapy Approach

Overview

We believe that our modular technology platform addresses many of the historical challenges of gene therapy. The key components of our gene therapy approach are the following:

    therapeutic gene cassettes;

    AAV-based vector delivery system;

    administration technologies; and

    our scalable, proprietary manufacturing process.

We expect that our modular approach will allow us to use the same building blocks to efficiently develop, manufacture and seek regulatory approval for multiple new gene therapies. In some cases, we believe that the disease-specific gene cassette will be the only component we need to change to target a new disease in a particular tissue. As a result, we may be able to reduce the overall preclinical and potentially clinical development activities required to obtain regulatory approval, and to significantly reduce the overall development risk, time and cost.

Therapeutic Gene Cassettes

We design our gene therapies to deliver into the body's cells a transgene that encodes, or provides the blueprint for the expression of, a therapeutic protein. The transgene is carried in a gene cassette together with DNA promoters that direct expression in specific tissues. We either develop the gene cassettes we use or in-license them, often as part of our collaborations with academic research institutions and biotechnology and pharmaceutical companies. In-licensing gene cassettes provides us access to key intellectual property and allows us to build upon our collaborators' scientific expertise and financial investment, as well as their preclinical and, in some cases, clinical development efforts.

Our AAV-based Vector Delivery System

We deliver the gene cassette to the target tissue using an engineered, non-replicating viral vector delivery system based on AAV. We have based Glybera and all of our current product candidates on our AAV-based vector technologies, which we believe address many of the safety and efficacy challenges that hindered earlier gene therapy approaches.

Demonstrated Safety Profile.    AAV is one of several viruses commonly used as a vector in gene therapy. A significant proportion of people have already been exposed to AAV in the normal course of their lives. AAV-based vectors cause only a mild immune response, including innate responses immediately following treatment. Regulatory agencies in the United States and European Union have extensive experience reviewing AAV-based vectors. In preclinical research and more than 80 gene therapy clinical studies conducted by us or third parties, AAV-based vectors have demonstrated a good safety profile.

Unlike retrovirus and lentivirus vectors, which are other vectors commonly used in gene therapies, AAV vectors integrate into the host genome only at low frequency, which substantially reduces the risk of adverse effects, including cancer. As a further safety measure, we engineer our AAV vectors without any components required for the virus to replicate and infect additional cells. We also believe the purification step in our manufacturing process enables us to optimize the purity of our vector material, which reduces the risk of side effects.

Improved Gene Expression.    For a gene therapy to be effective, it must provide lasting therapeutic gene expression in the target tissue. AAV-based vectors have shown persistent effects in animal experiments and in clinical studies. AAV-based vectors have also demonstrated sustained expression in target tissue in non-human primates for more than five years. St. Jude has reported expression in target tissue in humans

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for more than three years after a single treatment in its ongoing Phase I/II clinical trial of a gene therapy for the treatment of hemophilia B.

We use different serotypes of AAV to selectively target particular tissues. We use AAV1 in Glybera, for example, because we believe it is particularly suited to targeting myocytes, a type of cell found in muscle tissue. We have based most of our pipeline projects on AAV5, which we believe has a strong tropism for both hepatocytes, a type of cell found in the liver, and neurons, a type of cell found in the central nervous system. We hold an exclusive license to three patents owned by the NIH for the development and sale of AAV5-based therapeutic products to be delivered to the brain or liver for the treatment of human diseases originating in the brain or liver, excluding arthritis related diseases, and a non-exclusive license to those patents for the development and sale of AAV5-based therapeutic products to treat other human diseases. In addition, we are using AAV2 as a vector for gene therapies that are delivered to the brain.

In the case of diseases for which relatively modest levels of gene expression may result in therapeutic benefit, we expect that we will be able to achieve adequate levels of expression using existing, naturally derived AAV serotypes. In the case of diseases for which higher levels of gene expression may be required for therapeutic benefit, however, we may need access to more potent vectors than are currently available. To complement our internal development efforts in this regard, in January 2014 we entered into a collaboration and license agreement with 4D, a recently formed, private biotechnology company with a team that we believe is a leader in AAV vector discovery and optimization. 4D uses directed evolution techniques, which involve an iterative selection process in which researchers screen libraries of mutant AAV variants to identify those with optimal properties for achieving higher levels of gene expression.

Under our collaboration and license agreement with 4D, we have an exclusive license to 4D's existing and certain future know-how and other intellectual property for the delivery of AAV vectors to CNS or liver cells for the diagnosis, treatment, palliation or prevention of all diseases or medical conditions. Under this collaboration, the 4D team, including Dr. David Schaffer, 4D's co-founder and Professor of Chemical and Biomolecular Engineering at the University of California, Berkeley, has agreed to establish a laboratory, which we have agreed to fund, to identify product candidates for clinical development.

Administration Technologies

We and our collaborators are developing expertise in utilizing a variety of technologies to administer the vector to the body in order to optimize delivery of our gene therapies into the tissues or organs relevant to the indication we are targeting. These include intramuscular injection of AAV1 vectors that deliver a transgene into muscle cells for Glybera, intravenous infusion of AAV5 vectors that deliver a transgene to liver cells for our hemophilia B program, and intracranial administration of AAV5 and AAV2 vectors for delivery of a transgene to cells within the brain for Sanfilippo B and Parkinson's disease, respectively. In the case of diseases of the CNS, in particular, we believe that the effectiveness of gene therapy will depend upon both the choice of vector and the mode of administration of the vector. For example, our collaborator UCSF is currently conducting a Phase I clinical trial of a gene therapy for Parkinson's disease using MRI guided convection-enhanced delivery to the brain. Convection-enhanced delivery involves placement of one or more catheters directly into the brain to provide distribution of the therapeutic agent to a confined region, such as the putamen, in order to provide adequate drug concentrations directly to the relevant tissue. We believe that this may represent a significant improvement over administration methods used in prior clinical trials of gene therapies targeting the brain. In other CNS indications, widespread delivery of a transgene is preferable. In preclinical animal models, we have shown widespread distribution of AAV5 in the brain when administered via the cerebral spinal fluid.

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Scalable, Proprietary Manufacturing

We produce our AAV-based gene therapies in our own facility with our proprietary manufacturing process, which uses insect cells and baculoviruses, a common family of viruses found in invertebrates. Our insect cell-based manufacturing process, which uses cells that can be grown in a suspension culture, is designed to produce higher yields of vectors more cost-effectively and efficiently than the mammalian cell-based approaches that many of our competitors utilize. We non-exclusively license from the NIH the use of baculoviruses and insect cells in the production of AAV-based vectors, and have augmented this licensed technology with patented improvements to the replication process designed to allow us to produce gene therapies at commercial scale. The key steps in our proprietary manufacturing process are the following:

    We use a gene cassette containing the therapeutic transgene together with the appropriate promoter and other DNA components required for replication and packaging by the AAV vector.

    We insert the gene cassette into the genome of a baculovirus, which we use as an engineering tool in our manufacturing process to generate the AAV particles that are ultimately used for the therapeutic intervention.

    We then infect insect cells derived from Spodoptera frugiperda, the caterpillar stage of the fall army worm moth, with the baculovirus containing the gene cassette.

    At the same time, we infect these cells with two additional baculoviruses containing the elements needed for the proteins of the shell, or capsid, of the AAV vector, and the replication proteins required to create multiple copies of the gene cassette that are subsequently packaged into the AAV capsids. The replication proteins we use incorporate our patented modifications to increase the efficiency of production, and in particular to effect an increase in the proportion of particles containing the therapeutic gene cassette, rather than empty vectors, and to reduce impurities. Our patented modifications also make it possible to efficiently package the equivalent of double-stranded, or self-complementary, DNA into the capsids, which results in increased protein expression levels from the transgene compared with single-stranded DNA.

    We incubate the cells infected with the three different baculoviruses for three days. During this time, the cells produce large numbers of the AAV vector particles containing the gene cassette.

    After three days, we harvest the cells and treat them with a solution known as a lysis buffer to burst the insect cells, which releases the AAV vectors.

    We then purify, concentrate and filter the AAV vectors to yield a pure, high-grade AAV vector suitable for use in therapeutic interventions.

We have begun commercial-scale production of Glybera and expect that once the build-out of our Lexington, Massachusetts facility is complete, our manufacturing process and facilities will enable us to produce Glybera and many other gene therapies cost-effectively at commercial scale.

Our Strategy

Our strategic goal is to transform the paradigm of care for many severe and chronic diseases by moving from the short-term management of symptoms to potentially curative resolution of the disease through sustained therapeutic gene expression in target tissues. We are building on the capabilities that have enabled us to obtain the first regulatory approval of a gene therapy in the European Union to address a range of diseases for which we believe we can reach the market with a gene therapy ahead of our competitors. We seek to achieve our goal by pursuing the following key objectives:

    Maximize the value of Glybera.  We are working with our collaborator Chiesi to commercially launch Glybera in the European Union in the first half of 2014. We and Chiesi also plan to seek additional marketing approvals for Glybera in countries outside the European Union that are covered by this collaboration. We have agreed to manufacture and supply to Chiesi its commercial requirements of Glybera. We are working with Chiesi to establish a gene therapy pricing and business model for Glybera that is designed to capture the significant value we believe Glybera delivers to patients and

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      the healthcare system. We believe that our collaboration with Chiesi will enable us to efficiently access markets in which Chiesi has a commercial presence. We are also applying our experience in obtaining EMA approval of Glybera to our development strategy in the United States. We met with the FDA in August and December 2013 to discuss the regulatory pathway for Glybera and we plan to file an IND with the FDA for Glybera in the first half of 2014. If we receive regulatory approval from the FDA, we currently plan to market Glybera in the United States ourselves. Outside the United States and the Chiesi territory, we intend to determine on a case by case basis whether to pursue regulatory approval and commercialize Glybera on our own or to do so through partnerships with regional and national biotechnology or pharmaceutical companies.

    Exploit the potential of our gene therapy platform to develop AAV-based gene therapies for additional orphan monogenic diseases and selected chronic and degenerative diseases.  We believe that gene therapy is well-suited as an approach for the treatment of monogenic diseases as only a single genetic defect needs to be addressed. We are initially focusing on orphan monogenic diseases that affect small patient populations because we expect to be able to complete clinical trials with relatively small numbers of patients and take advantage of the specialized regulatory approval processes for these rare conditions that exist in some countries. As a result, we anticipate that these programs may be more cost-effective to complete and have shorter timelines than are customary for other diseases and conditions. In addition to our programs in monogenic diseases, we plan to develop gene therapies for chronic and degenerative diseases that result from the body's inability to produce a necessary protein or enzyme and that affect larger populations, such as Parkinson's disease.

    Leverage our competitive strengths to retain our position as a leading gene therapy company and to establish additional collaborations.  We believe our experience and expertise in gene therapy research and development and our proprietary manufacturing capabilities make us an attractive collaborator for academic research institutions and biotechnology and pharmaceutical companies seeking to advance their programs into larger, late-stage clinical trials that require commercial-scale manufacturing. We believe that these collaborations will enable us to gain access to early clinical programs and related data, as well as promising transgenes and other intellectual property, with limited financial investment by us. We also believe that we can be a consolidator of gene therapy assets by entering into license and other arrangements with these types of entities.

    Continue to invest in our technology platform and expand our modular capabilities.  We are continuously innovating, building and expanding our vector delivery and manufacturing technologies to further capitalize on the potential of gene therapy. We are currently focusing on developing:

    next-generation AAV vectors with the potential for increased gene expression through improved cell-specific delivery and efficient release of DNA in the cell nucleus;

    methods to allow successful re-administration in cases in which a one-time treatment may not be sufficient; and

    methods for the successful control of gene expression following gene transfer, including the ability to terminate expression if needed.

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Product and Development Pipeline

In addition to Glybera, our development pipeline includes our internal program for hemophilia B, two collaborator-sponsored programs for monogenic diseases, one collaborator-sponsored program for a chronic degenerative disease and several programs in early preclinical development. The following chart provides summary information on the most advanced of these programs:

CHART


(1)
hFIX, GDNF and PBGD transgenes have been exclusively licensed to uniQure.

(2)
The trial commenced in May 2013; gene therapy was produced using mammalian-cell based process.

Internal Program: Glybera

Overview

Glybera is a gene therapy that is designed to restore the LPL enzyme activity required by tissues of the body to clear, or process, fat-carrying chylomicron particles that are formed in the intestine and transported via the lymphatic system to the blood after a fat-containing meal. The product consists of an engineered copy of the human LPL gene packaged with a tissue-specific promoter in a non-replicating AAV1 vector, which has a particular tropism for muscle cells. In order to improve activity, we use a naturally occurring variant of the LPL gene that has higher enzyme activity than the normal version of the gene that encodes the protein. We produce Glybera using our insect cell-based manufacturing process. Clinicians administer Glybera in a one-time series of up to 60 intramuscular injections in the legs. The patient is administered spinal anesthesia or deep sedation during the procedure. In addition, an immunosuppressive regimen is recommended from three days prior to and for 12 weeks following Glybera administration.

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LPLD Disease and Market Background

LPLD is a serious, debilitating disease caused by mutations in the LPL gene, resulting in significantly diminished or absent activity of the LPL protein and, as a consequence, severe hypertriglyceridemia. Severe hypertriglyceridemia results in hyper-chylomicronemia, or dramatic and potentially life-threatening increases in the level of fat-carrying particles, called chylomicrons, in the blood after eating. LPLD patients suffer from a wide range of serious disease manifestations. A prominent manifestation of the disease is acute and recurrent pancreatitis, which often leads to recurrent admission to hospitals and intensive care units, or ICUs. Chronic pancreatitis may also lead to pancreatic insufficiency that may result in decreased or absent production of digestive enzymes, increased risk of glucose intolerance and diabetes mellitus. In addition, the chronic dysregulation in lipid metabolism may lead to an increased risk of cardiovascular events. The most severe cases of acute pancreatitis are associated with an increased risk of death. In daily life, LPLD patients experience recurrent and chronic abdominal pain, eruptive xanthomas, or depositions of yellowish cholesterol-rich material in the skin, and neurological manifestations, which include headache, itching, tingling and burning sensations.

Women with LPLD experience additional complications. During pregnancy, natural increases in triglycerides may increase the risk of pancreatitis, which can put both the mother and the unborn child at considerable risk. Extreme dietary fat restriction to less than two grams per day during the second and third trimester with close monitoring of plasma triglyceride concentration may be required. Breastfeeding may not be possible beyond the first few days since the breast milk is unlikely to be nutritionally complete. The likelihood of gestational diabetes is increased in LPLD mothers. Furthermore, oral birth control and hormone replacement therapy are not advised since estrogen can cause dramatic increases in plasma triglycerides, which may lead to pancreatitis.

Prior to Glybera, there was no approved therapy for the treatment of LPLD. Clinicians advise LPLD patients to adhere to a strict diet restricting fat to less than 20% of daily calorie intake and to abstain from alcohol. Compliance with this dietary regimen is very difficult. Even with good compliance, the regimen is often ineffective in reducing hyper-chylomicronemia. LPLD patients therefore remain at increased risk for potentially lethal pancreatitis. These restrictions, as well as the need for frequent hospitalizations and the constant fear of encountering pancreatitis attacks, have a significant negative impact on the daily activity level of LPLD patients and on their quality of life.

LPLD is a rare disease. The medical literature generally states that the prevalence of LPLD is approximately one person per million people. However, we believe that this number was not based on an epidemiological study, but rather was simply an estimate based on a non-systematic review of individual published case reports of patients with the disease. Historically, physicians have not routinely tested patients for LPLD as there was no reason to do so in light of the absence of any treatment options. In market research that we commissioned from IMS Health, an international health information firm, key opinion leader physicians in the United States generally were of the view that LPLD may be significantly under-diagnosed.

We commissioned a third party study conducted in 2011 in Germany and the Netherlands of an experimental LPLD diagnostic test for LPLD. This unpublished study involved 314 patients with severe hypertriglyceridemia at 15 lipid centers. In this study, eight of the patients tested had at least one known pathogenic mutation of the LPLD gene and a clinical manifestation of LPLD.

The number of likely LPLD patients as a percentage of the total patients in this study (8/314) was, therefore, 2.55%. In a 1982 study by Brunzell and Bierman published in Medical Clinics of North America, the authors estimated that there were approximately 180 persons per million in the United States with severe hypertriglyceridemia. On this basis, there might be up to 4.6 persons with LPLD per million people (180 × 2.55%). Because of the small number of LPLD patients in the diagnostic study described above and the absence of other evidence our estimate is preliminary, and we plan to conduct additional studies to establish a more precise figure. Based on an article by Tremblay et al. published in the Journal of

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Lipidology in 2011, we further estimate that approximately 50% of persons with LPLD experience severe or multiple pancreatitis attacks.

Glybera Regulatory Status

In October 2012, the European Commission granted marketing authorization for Glybera under exceptional circumstances as a treatment for adult patients diagnosed with familial LPLD confirmed by genetic testing, detectable levels of LPL protein, and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The EMA ultimately assessed the combined quality, safety and efficacy data sets collected in the period from 2005 to 2011 using a totality of evidence approach. On this basis, the EMA considered clinical benefit to be sufficiently established to allow for positive benefit-risk estimation in an exceptional circumstance setting. Marketing authorization under exceptional circumstances in the European Union is available for products for which the target indications are so rare that comprehensive data on efficacy and safety cannot reasonably be expected to be available prior to commercial launch. In the European Union, we have been granted orphan drug exclusivity for Glybera for treatment of LPLD until October 2022, subject to the conditions applicable to orphan drug exclusivity. The FDA has also granted orphan drug designation to Glybera for treatment of LPLD.

The link among the missing LPL enzyme activity, measurable metabolic lipid dysregulation and the actual disease manifestations of LPLD is not fully understood. There is an association between higher than normal plasma triglyceride levels, impaired clearance of chylomicrons following a meal and pancreatitis. Our earlier clinical trials of Glybera aimed to demonstrate a relevant and sustainable reduction in plasma triglycerides. As the clinical development program progressed over the following years, however, we began studying the level of newly formed chylomicrons after a meal as a relevant biological marker of LPL activity.

Within the EMA, the Committee for Human Medicinal Products, or CHMP, assesses drugs for human use. For gene and cell therapy drugs, the CHMP coordinates its assessment with the EMA's Committee for Advanced Therapies, or CAT, which is primarily responsible for the scientific evaluation of gene and cell therapies. The CAT provides a draft opinion to the CHMP on the quality, safety and efficacy of gene and cell therapies that are submitted for approval.

We initially submitted a marketing authorization application to the EMA in December 2009 and finally received marketing authorization in October 2012. During the review process, we answered, to the CHMP's and CAT's satisfaction, all of their questions regarding the safety of the vector and the manufacturing process, which had historically been matters of key concern for gene therapies. Nevertheless, in their initial decision in June 2011, both the CAT and the CHMP determined that the benefit-risk balance was negative for the treatment of all patients with LPLD. We requested a reexamination, and in October 2011, the CAT gave a positive opinion for the treatment of the subset of patients with LPLD suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The CHMP, however, determined that there were not enough data points to show efficacy in a sufficient number of patients over a sufficiently long time period, and again recommended against approval at that time.

In January 2012, the European Commission recommended that the CHMP reassess its decision, requesting a further review for the proposed use of Glybera only in patients with severe or multiple pancreatitis attacks. In April 2012, the CHMP recommended against approval, but this recommendation was considered void for procedural reasons, and the CHMP then reassessed Glybera again for the proposed restricted population. In June 2012 the CAT gave a positive opinion and in July 2012 the CHMP recommended approval for the restricted population of adult patients diagnosed with familial LPLD confirmed by genetic testing, with detectable levels of LPL protein, and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions, subject to specified conditions, including additional post-marketing studies for efficacy. The CHMP recommendation was made by the majority of its members, with 17 members voting in favor and 15 dissenting. The European Commission granted this approval in October 2012.

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Pursuant to the European Commission's decision to approve Glybera under exceptional circumstances, Glybera must be administered only under strict medical supervision. In addition, we must undertake an additional post-approval clinical trial and establish a patient registry, described below.

Post-EU Approval Program for Glybera

Post-Approval Clinical Trial.    We currently plan to enroll 12 patients with LPLD, along with eight healthy volunteers, in our planned post-approval clinical trial of Glybera. LPLD patients will receive a fixed dose of Glybera of 1x1012 genome copies per kilogram of body weight, which is a measure of the number of copies of the gene administered to the patient based on the patient's weight, in a single series of intramuscular injections. We are currently discussing with the EMA an amendment to the protocol pursuant to which only half of the LPLD patients will also receive an immunosuppressant regimen for a period beginning three days and ending 12 weeks after Glybera administration. We expect that this will allow us to evaluate the adequacy of the immunosuppressant regimen. We anticipate that the trial will be conducted as a multicenter trial including sites in the United States, which we expect will enable us to enroll all patients during the first six to twelve months and to complete the study towards the end of 2016, including a two-year follow-up period. We will collect data on a broad range of clinically meaningful endpoints in this open label, single arm post-approval study, in which the current primary objective is to investigate the effect of Glybera on chylomicron metabolism after a meal in LPLD patients over a two year period. We also intend to investigate:

    the clinical response of Glybera in LPLD patients using a range of parameters, including the incidence and severity of pancreatitis attacks, general LPLD disease manifestations and quality of life scales; and

    chylomicron metabolism after a meal in healthy volunteers.

The EMA has approved the protocol for this clinical trial. We currently anticipate that we will commence this clinical trial in the second half of 2014. We will seek to amend the protocol for this post-approval trial to address the requirements of the FDA, as described below.

Planned LPLD Registry.    Another condition of the EMA approval of Glybera under exceptional circumstances is that we maintain a registry of LPLD patients. The objectives of the LPLD registry are to:

    collect, analyze and present available clinical safety and efficacy information in LPLD patients treated with Glybera over a 15-year period; and

    to collect natural history information in LPLD patients not treated with Glybera.

We intend to collect data during the course of treatment and at approximately annual intervals during the first two years post-treatment and every two to three years thereafter. The objectives will be to assess the:

    long-term safety of Glybera;

    long-term clinical response to Glybera; and

    epidemiology of LPLD and the demographics of LPLD patients.

The EMA has reviewed and approved the protocol for this patient registry. We anticipate that we will commence the patient registry in the first half of 2014. We are required to implement this registry prior to the commercial sale of Glybera.

We are also currently in the process of collecting additional long-term follow-up information in patients previously treated with Glybera, as an extension of the case note review described below, in order to further substantiate the data that we initially submitted to the EMA and that we intend to include in the data package we expect to submit to the FDA.

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Planned U.S. Program for Glybera

We met with the FDA in August and December 2013 to discuss the regulatory pathway in the United States for Glybera. In contrast with the European Union, the United States does not have a process to approve marketing of a drug under exceptional circumstances. In our meetings, the FDA advised that it would require data in addition to what we had submitted to obtain marketing approval for Glybera in the European Union. The FDA advised that severe hypertriglyceridemia is currently considered a hallmark of LPLD, and agreed that changes in chylomicron metabolism following a meal may provide data to support the bioactivity of Glybera. However, the FDA also advised that changes in chylomicron metabolism following a meal alone would not be adequate for obtaining marketing approval in the United States at this stage, since it is not yet sufficiently understood how this biological effect translates into clinical meaningfulness. The FDA recommended that we identify the clinical manifestations of LPLD for which Glybera might have the best prospects for demonstrating a meaningful impact in designing an adequate and appropriately controlled trial.

We plan discuss the details of the EU post-approval trial and patient registry with the FDA, and if applicable to seek to amend the protocols for the post-approval trial and patient registry so that they also could serve as a clinical program with a design that addresses the FDA's requirements. We also plan to file an IND with the FDA for Glybera in the first half of 2014 so that we can include U.S. LPLD patients in the post-approval trial and registry. We believe the patient registry will provide valuable data for the FDA to consider as part of the totality of our U.S. regulatory submissions. Our current expectation, subject to satisfactory completion of regulatory discussions with the FDA, is to have sufficient data from a further clinical trial of Glybera and the patient registry to file a BLA for Glybera with the FDA in 2017.

Glybera Commercialization Plan

We expect to launch Glybera commercially through our collaboration with Chiesi in selected countries in the European Union in the first half of 2014. We and Chiesi are working together through a joint commercialization committee to, among other things, plan a market roll-out strategy in the territory covered by the agreement, including developing a business model for the commercialization of a therapy administered in a one-time intervention. We and Chiesi are building new models for product pricing and reimbursement, expanding key opinion leader relationships, identifying centers of excellence, and developing physician and patient education and patient access programs.

Pricing and Reimbursement in the European Union.    To obtain payment coverage for Glybera from the relevant pricing and reimbursement agencies in countries in the European Union, Chiesi must generally submit price and reimbursement dossiers to the relevant bodies in each country. Chiesi is in discussions with these bodies in several countries, and expects to begin commercial sales during the first half of 2014. We expect that reference prices in the larger countries in the European Union will provide a basis for pricing discussions in other countries in the European Union. Pricing and reimbursement decisions are made on a country-by-country basis in the European Union and no country is under the obligation to follow another's pricing; however, prices in one country can influence the price level in other countries.

In developing our pricing strategy for Glybera we have commissioned third party research studies by Simon Kucher & Partners, a global consulting firm specializing in strategy, marketing, pricing and sales, on the pricing framework and are developing business models for gene therapies and orphan drugs in the markets we are targeting. In developing our pricing strategy, we and Chiesi considered current orphan disease treatments. We believe that Chiesi will seek a price for Glybera in the European Union reflecting the anticipated multi-year benefit of a one-time administration therapy and the unmet medical need of LPLD patients. We also believe that Glybera's effect in reducing pancreatitis attacks will result in a reduction of related hospitalizations and ICU stays, with attendant cost savings to the health care system. Based on the disease and therapy profiles, we believe that a one-time, up-front pricing model may be more in line with current analysis in pricing and reimbursement than an annuity model, which would provide for recurring

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periodic payments over a patient's lifetime. We therefore currently consider that a one-time price per patient treatment with Glybera to be the likely pricing model.

As an example of the pricing and reimbursement process, in Germany, the largest EU market, commercial sales of Glybera in the out-patient setting could begin immediately after submitting the price and reimbursement dossier to the Gemeinsamer Bundesausschuss, or G-BA, even if the competent pricing and reimbursement bodies have not completed the benefit assessment and a price has not been agreed at that time. The G-BA decides on early benefit assessment of innovative pharmaceuticals. A different final price may take effect following the final price assessment, which may take up to 12 months following the initial sales of Glybera, and sales made thereafter would be made at that final price.

A further option for market access and sales of Glybera in Germany would be within the in-patient setting via a process known as Neue Untersuchungs-und Behandlungsmethoden, or NUB. Each hospital must separately apply for pricing and reimbursement levels for technologies that have recently been introduced in Germany. Such approvals can take significant time.

Commercial Preparation and Roll-Out.    Chiesi plans to identify centers of excellence in each of the five largest EU markets—France, Germany, Italy, Spain and the United Kingdom—where Glybera will be administered. Chiesi is developing a strategy to facilitate patient referrals to these centers, in part through broader educational efforts and outreach to relevant medical practitioners throughout the European Union. As part of this effort, we have established a publications library of clinical and non-clinical materials regarding Glybera and materials for key opinion leaders, as well as materials regarding LPLD and gene therapy generally.

If we obtain marketing approval for Glybera in the United States, we currently plan to commercialize Glybera ourselves. We have begun preliminary preparations for a potential launch in the United States, including commissioning a third party pricing and reimbursement study, and have conducted two market research studies directed at key opinion leaders. We have also initiated the development of a diagnostic referral program, engaged in key opinion leader and patient identification efforts and begun networking with key patient organizations in the United States.

Glybera Clinical Development to Date

Our clinical development program for Glybera to date has consisted of three non-controlled, prospective, open-label clinical trials in which we administered Glybera to a total of 27 LPLD patients. In addition, we carried out a retrospective case note review of 17 of the 27 patients to determine the impact of Glybera treatment on the frequency and severity of pancreatitis events. Our clinical development program for Glybera included trials with our AMT-011 product candidate, which was produced using our insect cell-based manufacturing process, as well as AMT-010, a predecessor product candidate produced using a mammalian cell-based manufacturing process.

Overall Results of Clinical Program

In recommending approval of Glybera for a subset of LPLD patients under exceptional circumstances in July 2012, the CHMP recognized that, given the combination of the rarity of the disease and the varying levels of genetic penetration in LPLD patients, we were unable to provide comprehensive data on efficacy and safety under normal conditions of use prior to approval. The CHMP further noted the lack of consistency of the data on clinical benefit. Using a totality of the evidence approach, the CHMP assessed the quality, efficacy and safety of Glybera by combining the information from the different trials with individual patient profiles. On this basis, the following combined results assessed across the three clinical trials and the case

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note review from our clinical development program for Glybera provided the basis for the CHMP's positive recommendation to approve Glybera under exceptional circumstances:

    In one clinical trial, we observed a clear indication of a consistent and significant biological effect of Glybera on chylomicron metabolism after a meal, with significant improvement in chylomicron metabolism in all five patients seen at week 14 and all three patients seen at week 52 after a single treatment.

    In the clinical case note review involving a total of 17 patients, we observed a reduction in pancreatitis events and severity of attacks in nine of the 12 patients who had a history of pancreatitis. Although these observations were made in a small number of patients for varying pre-treatment observation periods, and subject to statistical limitations, they suggested that Glybera leads to a clinically relevant reduction of pancreatitis risk in nine of 12 patients with severe or multiple pancreatitis attacks. This was supported by the reduction in the total number of hospital admissions and ICU stays.

    On the basis of the clinical program and the case note review, a positive benefit/risk was considered shown in the subset of patients defined by the restricted indication proposed for Glybera in adult patients diagnosed with LPLD and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The indication was restricted to patients with detectable levels of LPL protein.

    A link between LPL expression, sustained improvement of chylomicron metabolism after a meal, both at 14 and 52 weeks following treatment, and a reduced risk of pancreatitis attacks was observed in two subjects who suffered from multiple recurrent pancreatitis and abdominal pain events before treatment. These findings, although highly limited by the limited number of observations, suggested a correlation between biochemical and clinical data in these two individual subjects. Sustained improvement in chylomicron metabolism after a meal in a third subject 52 weeks following treatment was also noted. Further, the data on LPL enzyme expression and function in injected and non-injected muscles, along with other relevant clinical and preclinical data, provided indications of functional expression.

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The following table provides key information about the clinical program that we have carried out to date for Glybera:


Summary of Glybera Clinical Development Program


STUDY:
  NO. OF
PATIENTS
  OBJECTIVES   DURATION OF
FOLLOW-UP
Retrospective Analysis:              

Case Note Review
AMT-011-03

   
17
 

Effect on frequency and severity of pancreatitis in patients treated with Glybera in prior clinical trials

 

Retrospective case note review of patients through 2010

 
Clinical Trials:              

Phase II/III trial
AMT-011-02

   
5
  Primary:

Effect on fasting triglyceride levels at 12 weeks

   
          Secondary:

Effect on chylomicron metabolism at
14 and 52 weeks

  1 year
         

LPL activity at 3 months

   
         

Safety

   

Phase II/III trial

   
14
 

Safety

 

5 years

AMT-011-01        

Effect on triglyceride levels at 12 weeks

   
         

LPL activity in the muscle at 6 months

   

Phase I/II trial

   
8
 

Safety

 

5 years

AMT-010-01        

Effect on fasting triglyceride levels at 12 weeks

   

Efficacy.    We did not achieve statistically significant data for the primary efficacy endpoints in the clinical trials described above.

Safety.    In our clinical development program, Glybera demonstrated an acceptable overall safety profile. There were a total of 48 serious adverse events in these three clinical trials, only two of which were determined to be related to Glybera, a pulmonary embolism and fever. The most frequent adverse events were reactions associated with the injection procedure. These reactions were transient and mild to moderate. Further, immune responses to either the vector or the transgene were mild and there was no clinical evidence of long-term effects on muscle function, although muscle function was not formally tested. The shedding data illustrated that the vector was gradually eliminated from various bodily fluids with only low concentrations detected beyond 12 weeks following treatment.

AMT-011-03: Case Note Review

From January 2011 to March 2011, we conducted a review of hospital admission and discharge records for 17 patients previously treated with Glybera in clinical studies AMT-011-01 and AMT-011-02, in order to determine the frequency and severity of reported acute abdominal pancreatitis episodes. These data included:

    historic acute abdominal pain events;

    the development of chronic pancreatitis; and

    the development of pancreatic insufficiency.

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In addition, we collected additional information regarding past medical history and prior hospital admissions of the patients. The median analysis period pre- and post-treatment was 2.9 years. An extension of the 11-03 study (clincal study 11-05) to increase the case note review period up to 5 years is ongoing and we expect to complete this extension study in the first half of 2014.

We presented the data from individual patients as subject profiles to a panel of independent medical experts with expertise in the assessment and treatment of LPLD subjects and pancreatitis. This panel evaluated these data using the Revised Atlanta Diagnostic Criteria, which are international consensus criteria commonly used to classify acute abdominal pain events as either "definite acute pancreatitis," "probable acute pancreatitis," "abdominal pain" or "other." The panel evaluated the number, frequency, and severity of episodes of pancreatitis and then the extent of LPLD disease progression. The panel identified 77 events in subjects treated with Glybera that conformed to the Revised Atlanta Diagnostic Criteria for pancreatitis. Using retrospective control data, the analysis of pancreatitis events indicated that the frequency of acute abdominal events and pancreatitis in LPLD subjects decreased after the treatment with Glybera, but the data in isolation were not considered sufficiently strong to support a claim of a clinically relevant reduction in pancreatitis risk.

For this reason, in its assessment of the data from the AMT-011-03 case note review, the CHMP requested that data also be presented in the form of individual patient profiles in the 12 patients with the most severe manifestations of the disease, multiple recurrent pancreatitis and abdominal pain events, before treatment. The profiles indicated a reduction in pancreatitis events and severity of attacks in nine of these 12 patients, suggesting that Glybera leads to a clinically relevant reduction of pancreatitis risk in patients with severe or multiple pancreatitis attacks. This was supported by the reduction in hospital admissions and ICU stays.

Phase II/III Clinical Trial (AMT-011-02)

We initiated our second Phase II/III clinical trial of Glybera in Quebec, Canada in the first quarter of 2009. We describe this as both a Phase II and Phase III clinical trial because it was designed to support, if successful, an application for marketing approval of Glybera. We utilized our insect cell-based manufacturing process to manufacture the Glybera used in this trial. The primary objective of the study was to achieve a 40% reduction of mean fasting triglyceride levels at 12 weeks. In addition, a secondary objective of the study was to understand the effect of Glybera on chylomicron metabolism and to evaluate and validate the use of a radiolabeled tracer to measure the appearance and removal of newly formed chylomicrons after eating as a relevant biological marker. We treated five patients. Per the inclusion criteria, all trial participants:

    suffered from LPLD as confirmed by genetic testing;

    were on a low-fat diet;

    had LPL activity 20% or less of normal levels;

    had LPL mass at least 5% above normal;

    had triglyceride levels of more than 10 millimoles per liter, or mmol/L, which is the level indicating increased risk of pancreatitis; and

    had a history of pancreatitis.

Prior to the clinical trial, subjects participated in an observational study to establish baseline data.

Each patient received one intramuscular dose of 1 × 1012 genetic components per kilogram of body weight, or gc/kg, which is the measure of the number of copies of the gene administered to the patient based on his weight, as well as an immunosuppressant course of treatment to prevent immune responses to Glybera interfering with efficacy results.

The key results were as follows:

    only one of five patients demonstrated a fasting triglyceride level of less than 10 mmol/L;

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    in the five patients measured at 14 weeks, metabolism of chylomicrons newly formed after eating improved over baseline, with a reduction of an average of 79% at six hours after eating and an average of 93% at 24 hours after eating, compared with baseline; and

    in the three patients measured at 52 weeks, improvements in metabolism of chylomicrons newly formed after eating as compared with baseline persisted, with a reduction of an average of 50% at six hours after eating and an average of 68% at 24 hours after eating, compared with baseline.

The graph below depicts the appearance and removal of newly formed chylomicrons in the blood over a 24-hour period after a standardized meal, through use of a radiolabeled tracer. Patients were observed prior to treatment with Glybera, and at 14 weeks and 52 weeks following treatment. In LPLD patients only very limited and slow metabolism of chylomicrons occurs during a 24-hour period. The top line in the graph represents the pretreatment condition and depicts mean levels of newly formed chylomicrons in the five patients prior to treatment with Glybera. We observed a consistent and significant improvement in the appearance and removal of newly formed chylomicrons from the blood in all five patients measured at week 14 after treatment, represented by the bottom line in the graph, and all three patients measured at week 52 after treatment, represented by the middle line in the graph. We believe that the improvement in newly formed chylomicron metabolism reflects an increase in LPL activity post treatment with Glybera.


Appearance and Removal of Newly Formed Chylomicrons Post-Meal

CHART


(1)
Depiction of mean levels of newly formed chylomicrons using a radiolabeled tracer measured by tritium activity (in centimorgans). Participants consumed a standardized meal containing tritium-marked particles, which were measured in newly formed chylomicrons in the 24-hour period after the meal.

In addition, in muscle biopsies in three out of five patients, a one-time administration of Glybera led to sustained expression of the LPL gene and biological activity of the protein in muscle. The muscle biopsy data obtained post-intervention, together with the chylomicron data, suggest that Glybera resulted in enzymatically active LPL expression in these patients, and that this restored LPL activity was able to exert an effect on lipid metabolism despite plasma triglyceride levels typically returning to baseline by this time point.

Phase II/III Clinical Trial (AMT-011-01)

Our first Phase II/III clinical trial of Glybera was a dose escalation trial, which we initiated in Québec, Canada, in the third quarter of 2007. We utilized our insect cell-based manufacturing process to produce the Glybera used in this clinical trial.

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We treated a total of 14 LPLD patients under the same principal inclusion criteria as in our 2009 Phase II/III clinical trial described above. Prior to the clinical trial, subjects participated in an observational study to establish baseline data. We divided patients into three cohorts for treatment with a single-dose intramuscular injection. One cohort of two patients and one cohort of four patients each received an intermediate dose of 3 × 1011 gc/kg, and the third cohort of eight patients received a lower dose of 1 × 1012 gc/kg. The second higher-dose cohort and the third cohort were also given an immunosuppressant course of treatment to prevent immune responses to Glybera interfering with efficacy results, based on our observations in our Phase I/II clinical trial. We established the cohort without this course of immunosuppressant as a bridge from the results of our Phase I/II clinical trial.

The key results relating to the primary endpoints were as follows:

    seven of the 14 patients, or 50%, reached the primary efficacy endpoint of a 40% reduction in median triglyceride levels during the period three to 12 weeks after treatment, including five of the eight patients, or 62.5%, in the highest dosing cohort; and

The results relating to the secondary endpoints were as follows:

    four patients met the secondary efficacy endpoint of a median fasting plasma triglyceride level of less than or equal to 10 mmol/L between three and 12 weeks post-treatment; and

    initial reductions in plasma triglyceride levels were statistically significant, but at 26 weeks post-treatment plasma triglyceride levels had returned to baseline.

In addition, we observed the following:

    lipid uptake in muscle cells was evident in biopsies in all seven participants from whom biopsies were obtained; and

    evidence supporting changes in lipoprotein distribution, which supported the rationale for the subsequent trial.

Phase I/II Clinical Trial (AMT-010-01)

Our initial Phase I/II clinical trial of Glybera was a dose escalation trial that we conducted at the Academic Medical Center, University of Amsterdam, Netherlands, in 2005. Unlike our later trials, in which we used Glybera that we produced with our insect cell-based manufacturing process, in this trial we used Glybera that we produced in a mammalian cell-based manufacturing process. We treated eight LPLD patients under the same inclusion criteria as in our 2009 Phase II/III clinical trial described above, except that we did not require a history of pancreatitis. Prior to the clinical trial, subjects participated in an observational study during which they maintained a low-fat diet in order to establish baseline triglyceride levels.

The key result relating to the primary endpoint was as follows:

    at 12 weeks after treatment, all patients showed a reduction in median triglyceride levels from baseline, and for three of them the reduction was greater than 40%.

The results relating to the secondary endpoints were:

    muscle biopsies 10 to 36 weeks after treatment in seven of the eight trial participants suggested that administration of Glybera led to long-term biological activity and expression of protein in the injected muscle; and

    we observed an immune response to AAV and determined that we should administer an immunosuppressant regimen in future trials.

From the point 12 weeks post-treatment to the long-term follow-up period at two to three years post-treatment, median triglyceride levels increased to around or above baseline, which we initially interpreted as a potential indication of transient efficacy.

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Internal Program: AMT-060 for Hemophilia B

Hemophilia B Disease and Market Background

Hemophilia B is a serious rare inherited disease in males characterized by insufficient blood clotting. The condition can lead to repeated and sometimes life-threatening episodes of external and internal bleeding following accidental trauma or medical interventions. The episodes can cause long-term damage, for example to the joints, and can be fatal if they occur in the brain. The deficient blood clotting results from the lack of functional human Factor IX, or hFIX, a blood clotting factor, as a result of mutations in the relevant gene. The presence of hFIX at greater than 1% of normal levels has a therapeutic effect in promoting clotting. The current standard of care for hemophilia B is prophylactic or on-demand protein replacement therapy, in which frequent intravenous administrations of plasma-derived or recombinant hFIX are required to stop or prevent bleeding. Protein replacement therapy is expensive, often costing approximately $220,000 to $340,000 per patient per year in the United States. Such therapy is also burdensome and does not completely prevent bleeding.

Hemophilia B affects approximately 20 to 25 persons per million males globally, and 28 persons per million males in the United States, according to the World Federation of Hemophilia. Approximately 60% of individuals with the disease have severe hemophilia, according to the National Hemophilia Foundation, characterized by functional hFIX levels that are less than 1% of normal; 15% of the hemophilia population have moderately severe disease, with 1 to 5% of normal levels; and the remainder have mild disease, with 5 to 50% of normal levels. Based on these estimates we believe that the approximately 60 to 70% of the worldwide patient population with severe to moderate disease would be eligible for treatment with gene therapy.

Overview of AMT-060

The goal of our AMT-060 program is to develop a gene therapy for hemophilia B that restores blood clotting on a long-term and potentially curative basis through the delivery of the functional gene for hFIX into the patient's liver cells. In collaboration with Chiesi, we are developing AMT-060 as a gene therapy consisting of an AAV5 vector carrying an hFIX gene that we have exclusively licensed from St. Jude, in which we have altered the codons to maximize expression, together with the insertion of a liver-specific promoter, LP1. We produce this vector with our insect cell-based manufacturing process. We are designing this therapy for systemic administration through intravenous infusion in a single treatment. We are currently preparing for a Phase I/II clinical trial with this product candidate, which we expect to commence in the second half of 2014. Our collaborator St. Jude is currently conducting a Phase I/II clinical trial in this indication with a gene therapy consisting of an AAV8 vector carrying the same therapeutic gene and produced in a third party mammalian cell-based manufacturing process. We have entered into a co-development agreement with Chiesi for the development and commercialization of AMT-060 in the European Union and other specified countries.

Planned Phase I/II Clinical Trials

We are currently planning to initiate a Phase I/II clinical trial of our AMT-060 product candidate in the second half of 2014 under our co-development agreement with Chiesi. We intend to file an IND and IMPD in order to initiate clinical development of AMT-060 and anticipate that the trial sites will be in Europe. We are designing this clinical trial as a multicenter, open label, prospective, interventional, single dose, dose escalation study to investigate the safety and tolerability of AMT-060 in patients with severe hemophilia B. We currently expect to recruit 13 to 16 male patients between the ages of 18 and 35 with severe, genetically confirmed hemophilia B. The primary objective of this clinical trial will be to assess the safety of systemic administration and determine the maximum tolerated doses. We expect that the secondary objectives will include:

    determining the appropriate dose required to achieve delivery of the transgene resulting in stable expression of hFIX at or above 3% of normal;

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    assessing the immune response to the hFIX transgene and to the AAV5 capsid proteins, as well as viral shedding; and

    assessing the need for concomitant hFIX treatment.

The draft protocol calls for initial patient follow-up to last for six months as part of the trial. We then plan to follow patients for safety and therapeutic response at intervals of 24 weeks for three years. We expect data from this clinical trial to be available in the second half of 2015.

Preclinical Program with AMT-060

We are currently conducting a number of preclinical safety and toxicology studies to support our development program for AMT-060, including studies in mice and non-human primates to measure pharmacokinetics, toxicity, shedding patterns, persistence in semen and risk of germline transmission, and carcinogenicity. We expect to complete these safety and toxicology studies by the end of 2013. We need to successfully complete these preclinical studies in order to file for regulatory clearance to initiate our planned Phase I/II clinical trial of AMT-060.

The principal results of our preclinical tests to date are as follows:

    In wild-type mice, intravenous administration of AMT-060 resulted in dose-dependent levels of hFIX levels in plasma. hFIX levels amounted to up to 11% of those in normal human plasma four weeks after infusion, indicating that AMT-060 produced in our insect-cell manufacturing process is biologically active.

    In Rhesus monkeys dosed at one dose level with a single treatment of AMT-060 by intravenous infusion, hFIX levels peaked to 7% to 16% of normal human levels one week after infusion, and stabilized at 5% to 10% of normal human levels two weeks after infusion until sacrifice at 12 weeks after dosing. These kinetics are in accordance with those we and others observed in previous studies, indicating that intravenous administration of AMT-060 produced in our insect cell-based manufacturing process results in a level of hFIX in plasma that is similar to that produced using AAV5 and AAV8 vectors produced in mammalian cells.

    Cynomolgus monkeys dosed at four dose levels with a single treatment of AMT-060 by intravenous infusion showed a linear dose response in relation to hFIX levels. At the top dose, expression levels plateaued at 7%, although the data showed significant variability among subjects. Monitoring over the six months following dosing demonstrated the treatment was well tolerated and safe.

    In mice studies, post-mortem tests showed homogeneous delivery of the vector DNA and transgene expression in the liver. We observed no signs of adverse reactions. Infusion was associated with slight and transient effects in plasma chemistry shortly after dosing, such as a brief increase of liver enzyme activity levels, consistent with the infusion of a viral protein. Necropsy revealed no significant macroscopic or microscopic abnormalities. Overall, administration of AMT-060 in mice resulted in therapeutically relevant hFIX levels and was well tolerated.

Phase I/II Clinical Trial of AAV8-based hFIX Gene Therapy by St. Jude

St. Jude is conducting a Phase I/II open label, dose escalation clinical trial of an hFIX gene therapy in adults with severe hemophilia B. The St. Jude gene therapy consists of the same therapeutic gene cassette we have exclusively licensed, delivered in an AAV8 vector. St. Jude produced the vector in human embryonic kidney cells. The principal investigators of the trial reported interim data from the trial in the New England Journal of Medicine, the NEJM, in December 2011. The information in this prospectus about this Phase I/II clinical trial is derived from the NEJM article. We understand from St. Jude that the final data from this clinical trial are expected to be released in the second half of 2015.

This dose escalation trial initially enrolled six male adults suffering from severe hemophilia B, with three dose cohorts of two patients each. The gene therapy was administered in a single dose by infusion into a

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peripheral vein. St. Jude followed the participants for six to 16 months after treatment by way of twice weekly clinical evaluations.

The interim data indicated that the administration of the St. Jude gene therapy did not result in acute or long-lasting toxicity in patients with severe hemophilia B. Further, the interim data indicated the following:

    the high dose cohort achieved a stable expression of hFIX at or above 3% of the normal levels while the low and intermediate cohorts did not;

    St. Jude did not detect any neutralizing antibodies and the immune response was consistent with a primary immune response to AAV8; and

    St Jude's did not detect T-cell, or white blood cell, mediated immune responses to hFIX.

St. Jude observed AAV-mediated expression of hFIX at 2% to 11% of normal levels in all patients. Four of the six patients discontinued prophylactic hFIX protein replacement therapy and remained free of bleeding even during activities that had previously led to hemorrhaging. Of the two participants who received the highest dose, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood, and the other had a slight increase in liver-enzyme levels, the cause of which was less clear. St. Jude administered a short course of glucocorticoid therapy to those two patients to reduce liver inflammation in an effort to maintain hFIX levels in the range of 3% to 11% of normal values.

Patients experienced a total of three adverse events. Two patients developed anemia after treatment and a third patient had a transient period of below-normal heart rate. No serious adverse events were reported.

We understand from public presentations by the principal investigators for this trial that two additional patients at the highest dose level in this clinical trial have now also demonstrated such long-term expression.

We believe that these interim results constitute proof of concept of the use of this therapeutic gene in treating hemophilia B, which may reduce the risks involved in the development of AMT-060.

Collaborator-Sponsored Programs

We are also collaborating with third parties that are sponsoring early-stage clinical trials of gene therapy product candidates to which we hold specified rights. We believe that this approach enables us to cost-effectively obtain access to preclinical and early-stage clinical results without expending significant resources of our own. As described below, some of these programs utilize clinical materials that we have manufactured as part of our collaborations or gene cassettes that we have licensed. We generally have the rights to the data generated in these collaborator-sponsored clinical development programs, but do not control their design or timing. If we decide to progress any of these programs internally, we may need to develop or in-license additional technology. The most advanced of these programs are the following:

Acute Intermittent Porphyria

AIP Disease and Market Background

AIP is a rare metabolic liver disorder resulting from mutations in the PBGD gene. This gene encodes for the enzyme porphobilinogen deaminase, a liver protein necessary for the production of heme, which is a component of hemoglobin and other blood proteins. Insufficient activity of this protein leads to an accumulation of toxic metabolites, resulting in a wide variety of serious clinical problems, including acute, severe abdominal pain, muscular weakness and an array of neurologic manifestations, including psychiatric episodes, seizures and coma. In the majority of cases, precipitating factors, such as hormonal fluctuations, infections, drugs and dietary changes, trigger attacks. Long-term consequences may include irreversible nerve damage, liver cancer and kidney failure. Patients with AIP experience regular hospitalizations and extremely poor quality of life. Acute attacks can be life-threatening. Current therapies include intravenous

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administration of heme and carbohydrate loading, which aim to treat the symptoms only and do not prevent attacks. In some cases, AIP patients require liver transplants.

Overview of AMT-021

We and our collaborator Digna Biotech are developing AMT-021 as a gene therapy to provide long-term normalization of the PBGD protein in order to prevent acute AIP attacks and their complications. The AMT-021 gene cassette contains the PBGD gene, which we exclusively license from CIMA, in which we have altered the codons to maximize expression, together with Alb-hAAT, a liver-specific promoter. We package this gene cassette in our AAV5 vector, which we believe has a tropism for liver cells. We produce AMT-021 using our insect cell-based manufacturing process. AMT-021 is administered through a single intravenous infusion to a peripheral vein. We are a member of the AIPGENE consortium in Europe, through which Digna Biotech, a consortium member, is currently conducting a Phase I clinical trial of AMT-021.

Phase I Clinical Trial Sponsored by Digna Biotech

Digna Biotech commenced a multicenter, open label, prospective, interventional, single dose, dose escalation Phase I clinical trial in December 2012 to investigate the safety and tolerability of AMT-021 in eight patients with severe AIP. Digna Biotech is conducting this clinical trial at two sites in Spain. There are four dosing cohorts in the trial, with two patients per cohort. All patients have been dosed. Digna Biotech will monitor all patients for one year following treatment. Digna Biotech has also completed a prospective pre-treatment observational study of the eight patients enrolled in this clinical trial to assess the evolution of disease-related clinical and laboratory parameters over time and to characterize aspects of disease management, such as AIP-related hospitalization.

The primary objective of this Phase I clinical trial is to assess the safety of systemic administration and to determine the maximum tolerated dose of AMT-021. Secondary objectives include measuring urinary levels of toxic metabolites to determine whether these metabolites can be used as a biomarker of potential treatment effect.

Digna has advised us that through November 30, 2013, there was one serious adverse event in this trial that was determined by the investigator not to be treatment-related. Digna further reported that there were no treatment-related adverse events or liver events related to AMT-021. Digna does not plan to report clinical outcomes data from this Phase I clinical trial until the second half of 2014. However, to date, Digna has not observed a reduction in the urinary levels of toxic metabolites in trial participants that might have served as a surrogate marker for efficacy. We believe that this result may suggest that a relatively high level of transgene expression will be required for a gene therapy to provide a clinical benefit in this indication. This contrasts with an indication such as hemophilia, in which the near or total absence of a protein in the patient means that a relatively low level of gene expression may result in a clinical benefit. In light of the absence of dose-limiting toxicities in the ongoing Phase I clinical trial, upon receipt of the clinical outcomes data, we plan to consider continuing the trial at higher dose levels or initiating a new clinical trial with a new vector that we are developing that may provide increased potency. Under our consortium agreement with Digna Biotech and the other consortium members, following completion of this Phase I trial we have an exclusive right to use all data related to the program.

Preclinical Program

In preclinical tests by Digna Biotech, AMT-021 resulted in normalization of the PBGD protein in a mouse model of AIP. AMT-021 completely prevented the occurrence of AIP-related attacks and significantly ameliorated the neuropathy that develops in untreated mice. In these preclinical tests, AMT-021 also demonstrated a good safety profile. Key findings from these mouse studies include long-term therapeutic efficacy indicated by:

    the metabolic correction of the hepatic PBGD enzyme activity;

    improvement of motor coordination;

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    clearance of AMT-021 from the blood and urine, but not the liver, by 30 days after administration; and

    expression of PBGD in the liver for more than one year.

In addition, in normal non-human primates treated with AMT-021, PBGD enzymatic activity increased by a factor of two in males and by a factor of between three and five in females compared with endogenous levels.

AMT-110 for Sanfilippo B Syndrome

Sanfilippo B Syndrome Disease and Market Background

Sanfilippo B syndrome, or mucopolysaccharidosis type III (MPSIII), is a rare lysosomal storage disease, or LSD, that results in serious brain degeneration in children, and is generally fatal. In this condition, a defect in the a-N-acetylglucosaminidase, or NaGLU, gene results in the accumulation of partially degraded oligosaccharides, or carbohydrates, of heparan sulfate, which are molecules that regulate various developmental processes. NaGlu is necessary for the degradation of heparan sulphate. The clinical manifestations are mainly neurological, with early symptoms observed during the first five years of life, leading to progressive deterioration of cognitive abilities. Affected children require specialist care between ages two and six and progressively develop profound mental retardation with severe muscle problems. Death occurs at the median age of 15. No treatment for Sanfilippo B is currently available.

Overview of AMT-110

We and our collaborator Institut Pasteur are developing AMT-110 as a gene therapy for Sanfilippo B syndrome. The gene cassette contains the NaGLU gene and is packaged in an AAV5 vector, which we believe has a tropism for neurons. We produce AMT-110 using our insect cell-based manufacturing process.

We believe that if the results of this clinical trial are positive, it will constitute proof of concept of the administration to the brain of a gene therapy for lysomal storage diseases.

Phase I/II Clinical Trial with AMT-110 Sponsored by Institut Pasteur

Our collaborator Institut Pasteur commenced a Phase I/II open label trial of intra-cerebral administration of AMT-110 for the treatment of children with Sanfilippo B syndrome in October 2013. We understand from Institut Pasteur that final data are expected in the first half of 2015. This Phase I/II clinical trial is being conducted in Paris, France, and is scheduled to run over an eight- to 12-month period, with a follow-up period of one year for each patient. Pursuant to our collaboration agreement with Institut Pasteur, we have manufactured the clinical material that Institut Pasteur is using in this trial.

The protocol for this single-dose Phase I/II clinical trial calls for the inclusion of four Sanfilippo B syndrome patients between the ages of 18 months and five years with NaGLU levels less than 10% of those found in the general population. Patients will receive an immunosuppressant course of treatment prior to administration of the therapy, to prevent an immune response to either the AAV vector capsid or the expressed protein. The primary objective is to evaluate the clinical, radiological and biological safety of the proposed treatment. The secondary objective is to collect data to define exploratory tests that could inform further clinical studies.

We have an agreement in principle with Institut Pasteur to acquire the clinical results and commercial rights under this program following completion of this Phase I/II clinical trial, and are currently in negotiations with Institut Pasteur regarding the terms of a definitive agreement in this regard.

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Preclinical Development of AMT-110 by Institut Pasteur

Institut Pasteur has conducted preclinical animal tests of AMT-110. Key findings of these studies include the following:

    rodents displayed no signs of toxicity at seven days, three months or six months after treatment despite administration of up to 37 times the level of dosage required for human patients;

    biodistribution studies in rodents indicated no differences between those following an immunosuppressant treatment course and those that were not, and shedding from major organs over time; and

    biodistribution studies in canine subjects indicated that the vector was absent in major organs approximately four months after administration.

AAV2/GDNF for Parkinson's Disease

Disease and Market Background

Parkinson's disease is a progressive neurodegenerative disorder that affects motor skills, speech and other neurological functions. The symptoms of Parkinson's disease result from degeneration and death of nerve cells in the putamen, a part of the brain that produces dopamine, which is a chemical that sends messages in the brain to coordinate and control muscular action and movements, and other neuro-transmitters. Progressive loss of nigral dopaminergic neurons, the pathological hallmark of Parkinson's disease, results in progressive neurologic dysfunction and death. There is currently no cure for Parkinson's disease. Medications or surgery can provide symptomatic relief, but they do not affect the degenerative process. In addition, the efficacy of these therapies declines over time, and they can result in significant side effects and co-morbidities, such as depression and a movement disorder called dyskinesias. The most widely used treatment is L-dopa in various forms, which is converted to dopamine in the central nervous system.

GDNF stimulates the production of dopamine in the putamen and prevents further degeneration of dopaminergic neurons in preclinical models. A series of preclinical and clinical studies by third parties involving the infusion of GDNF protein into the brain have shown potential benefit in treating Parkinson's disease. Results from these early clinical trials underscore the need for a clinical approach that can accurately introduce appropriate levels of GDNF to the intended sites in the brain where the dopaminergic neurons and their terminals reside.

Overview of AAV2/GDNF

We and our collaborator UCSF are developing a gene therapy for Parkinson's disease. As described below, UCSF is collaborating with the NIH to conduct a clinical trial of a gene therapy consisting of an AAV2 vector carrying the GDNF gene we have exclusively licensed in the gene therapy field from Amgen, manufactured by a third party using a mammalian cell-based process. If we progress our AMT-090 program, we would transition this product candidate to our insect cell-based manufacturing process.

Phase I Clinical Trial Sponsored by the NIH

Our collaborator UCSF is working with the NIH to conduct a Phase I clinical trial of a gene therapy for Parkinson's disease consisting of an AAV2-based vector carrying the GDNF gene we have exclusively licensed, produced in a third party mammalian cell-based manufacturing process. This trial is sponsored and funded by the NIH and will involve 24 patients. The aim of this clinical trial is to introduce the GDNF gene to provide a consistent supply of GDNF to the relevant areas of the brain. In this clinical trial, the NIH is using convection enhanced delivery with the goal of achieving more precisely targeted administration than the methods used in early approaches, which may result in improved efficacy. Convection-enhanced delivery involves MRI-guided placement of one or more catheters directly into the brain to provide distribution of the therapeutic agent to a larger volume of the brain tissue, provide higher drug concentrations directly to the tissue and to use molecules that do not normally cross the blood-brain barrier. We have the right to acquire all of UCSF's data from this clinical trial.

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Potential Additional Pipeline Programs

We are also conducting early-stage discovery and preclinical research, often in collaboration with academic research institutions, into a number of other potential applications of our technologies. Our principal near-term research focus is on diseases originating in the liver and the CNS. We believe that the liver is a promising target for gene therapies because we can both target liver-specific diseases and also use the liver to secrete proteins into the blood to have a systemic patient benefit. We believe that the CNS is also an attractive target organ for gene therapy as monogenic diseases that affect the brain are often poorly served by existing treatments, such as enzyme replacement therapies, which are not able to cross the blood-brain barrier following administration into the blood. Moreover, continual direct administration of proteins into the brain is practically difficult. Our AAV5-based vectors have a particular tropism for both the liver and CNS. We also plan to develop other AAV serotypes as appropriate to target specific indications.

We choose potential additional indications to develop independently or in conjunction with a collaborator, by applying the following criteria:

    we seek indications in which gene delivery would be expected to result in gene expression in the substantial proportion of cells of a target organ or tissue such that the symptoms of the underlying disease would be expected to be addressed;

    we seek indications in which a locally secreted protein would be expected to have systemic clinical benefit (in effect, the target organ is used as a protein factory) which may not necessarily require expression in a substantial proportion of the cells of the target organ or tissue;

    we seek indications for which relatively low restored protein expression levels as compared to normal would be expected to have therapeutic benefit;

    we target diseases that have sufficient prevalence to allow clinical development to be possible and for there to either be a viable commercial market in the indication or the indication provides proof of concept for related diseases;

    we look to select indications for which there is a robust and available animal model for preclinical testing;

    we seek indications in which the disease is sufficiently well-characterized such that it is reasonable to expect that if effective delivery of the relevant transgene is achieved, clinical efficacy should result; and

    we prioritize indications for which markers of biological activity are available that may permit assessment of benefit in early clinical studies.

Based on these criteria, we have prioritized approximately ten indications for preclinical development. We may seek to advance these programs independently or alternatively with collaborators who are already working in the relevant disease area and who may have already conducted preclinical or clinical studies.

Our current preclinical research and discovery programs include those described below:

Liver Application:

    Hemophilia A. Hemophilia A is an X-linked recessive genetic bleeding disorder. The disease results from the production of dysfunctional factor VIII protein or by production of an insufficient amount of factor VIII. Hemophilia A patients suffer from spontaneous bleeding into the large joints and soft tissue, and are at risk of intracranial hemorrhage. Even a modest 1% increase of the protein levels can markedly reduce spontaneous bleedings. We are developing an AAV5-based vector carrying the human factor VIII gene. The challenge for factor VIII development is in packaging the relevant gene, which is larger than the packaging capacity of the AAV vector. We believe we have successfully overcome this challenge by packaging the two different and complementary ends of a factor VIII DNA strand into different vectors for delivery to the cells of interest, where they recombine into a complete expression cassette. We have shown proof of concept by tail vein injection of AAV5-factor VIII in

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      mice, which resulted in delivery of the transgene to liver cells and production of active factor VIII by the liver.

In addition, we are seeking to develop next-generation vectors with increased potency to target liver indications in which high relative percentage increases in the secretion of a protein above the disease state would be required for therapeutic benefit. One approach we are using is directed evolution, which involves a vector selection process in which libraries of mutant variants are screened for optimal properties.

CNS Applications:

    Lysosomal storage diseases. As noted above, we believe that if the results of Institut Pasteur's Phase I/II clinical trial in Sanfilippo B syndrome are positive, it will constitute proof of concept of the administration of a gene therapy for lysosomal storage diseases to the brain. In such event, we believe that we may be able to apply this approach to develop gene therapies with the goal of addressing a number of the more than 30 lysosomal storage diseases that have CNS-specific disease manifestations and for which no treatment is currently available. We are conducting preclinical research to advance the application of our technologies in this area. For example, we have shown in preclinical models widespread distribution of AAV5 in the brain when administered via the cerebral spinal fluid.

    Applications of GDNF. We are using our academic relationships to test proof of concept of the GDNF gene that we have exclusively licensed in the field of gene therapy in animals to extend the use of this potent neurotrophic factor, including potentially for the treatment of multiple systems atrophy, amyotrophic lateral sclerosis and hearing loss.

We also have ongoing research programs in the areas of gene expression control, re-administration protocols and nuclear targeting, to further increase expression levels and safety margin. We are also conducting research into potential applications of our technology in transcription silencing, also called post transcriptional gene silencing, which is a biological process in which RNA molecules inhibit gene expression, typically by causing the destruction of specific miRNA molecules.

Intellectual Property

Introduction

We strive to protect the proprietary technologies that we believe are important to our business, including seeking and maintaining patent protection in the United States, Europe and other countries for novel components of gene therapies, the chemistries and processes for manufacturing these gene therapies, the use of these components in gene therapies, and other inventions and related technology that are important to our business, such as those relating to our technology platform. We also rely on trade secrets and careful monitoring of our proprietary information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

Our success will depend significantly on our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business, defend and enforce our patents, maintain our licenses to use intellectual property owned by third parties, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and other proprietary rights of third parties. We also rely on know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen, and maintain our proprietary position in the field of AAV-based gene therapies.

We also are heavily dependent on the patented or proprietary technology of third parties to develop and commercialize our products. We must obtain licenses from such third parties on commercially reasonable terms, or our business could be harmed, possibly materially. For example, we license from third parties essential parts of the therapeutic gene cassette used in Glybera and our other gene therapies, as well as the

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principal AAV vectors we use and key elements of our manufacturing process. We anticipate that we will require additional licenses in the future.

Because most patent applications throughout the world are confidential for 18 months after the earliest claimed priority date, and since the publication of discoveries in the scientific and patent literature often lags behind actual discoveries, we cannot be certain that we were the first to invent or file applications for the inventions covered by our pending patent applications. Moreover, we may have to participate in post-grant proceedings in the patent offices of the United States or foreign jurisdictions, such as oppositions, reexaminations or interferences, in which the patentability or priority of our inventions are challenged. Such proceedings could result in substantial cost, even if the eventual outcome is favorable to us.

Our intellectual property portfolio consists of owned and in-licensed patents, licenses, trademarks, trade secrets and other intellectual property rights.

Patent Portfolio

Our gene therapy programs are protected by patents and patent applications directed to various aspects of our technology. For example, our gene therapy programs are protected by patents and patent applications with composition-of-matter or method of use claims that cover the therapeutic gene, the promoter, the viral vector capsid or other specific parts of these technologies. We also seek protection of core aspects of our manufacturing process, particularly regarding our baculovirus expression system for AAV vectors in insect cells. In addition, we have filed manufacturing patent applications with claims directed to alternative compositions-of-matter and manufacturing processes to seek better protection from competitors.

Our principal operations are currently in Europe and we are in the process of building out a new manufacturing facility in the United States. We file the initial patent applications for our commercially important technologies in both Europe and the United States. For the same technologies, we typically file international patent applications under the Patent Cooperation Treaty, or PCT, within a year. We also may seek, usually on a case-by-case basis, local patent protection in Canada, Australia, Japan, China, India, Israel, South Africa, New Zealand, South Korea and Eurasia, as well as South American jurisdictions such as Brazil and Mexico.

As of the date of this prospectus, our patent portfolio includes the following patent families:

    13 patent families that we own;

    8 patent families that we exclusively in-license; and

    6 patent families that we non-exclusively in-license.

The geographic breakdown of our owned patent portfolio is as follows:

    2 issued U.S. patents;

    2 granted European Patent Office patents;

    1 pending PCT patent application;

    7 pending U.S. patent applications;

    8 pending European Patent Office patent applications; and

    57 pending patent applications in other jurisdictions.

The patent portfolios for our manufacturing platform and most advanced programs are summarized below.

NIH Patents

Our manufacturing patent families contain issued patents in the United States, Europe and other territories, as well as numerous pending patent applications.

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We have non-exclusively in-licensed from the NIH a patent family relating to the insect cell-based manufacturing of AAV-based vectors. The patents in this family include two issued patents in the United States and one issued patent in Europe, as well as issued patents in other jurisdictions. The standard 20-year term for patents in this family will expire in 2022. This patent family relates to technology used in Glybera and all of our development programs.

We also in-license from the NIH two patent families relating to AAV5-based vectors. These patents are licensed exclusively for AAV5-based therapeutic products to be delivered to the brain or liver for the treatment of human diseases originating in the brain or liver, excluding arthritis-related diseases, and non-exclusively for AAV5-based therapeutic products to treat any human disease in any manner not covered by the exclusive license. The patents in the first family include two issued patents in the United States, one issued patent in Europe and two issued patents in Japan, as well as issued patents and a pending application in other jurisdictions. The standard 20-year term for patents in this family will expire in 2019. This patent family relates to technology used in our AIP, hemophilia B and Sanfilippo B programs. The second family includes one issued U.S. patent with a standard 20-year term that will expire in 2020. This patent family relates to technology used in our Sanfilippo B program. See "Risk Factors—Risks Related to Our Intellectual Property—Our intellectual property licenses with third parties may be subject to disagreements over contract interpretation, which could narrow the scope of our rights to the relevant intellectual property or technology or increase our financial or other obligations to our licensors."

Other Manufacturing Patents

We own a patent family directed to improved AAV vectors that are stably expressed in insect cells. The family includes an issued patent in the United States and pending applications in the United States, Europe, Japan and other jurisdictions. The standard 20-year term for patents in this family will expire in 2027. This patent family relates to technology used in Glybera and all of our development programs.

We also in-license a patent family related to aspects of the AAV insect cell production technology from Protein Sciences Corporation. This family includes issued patents in the United States, Europe and elsewhere. This license is exclusive in respect of the products we develop with the use of this patent family for LPLD, hemophilia B and AIP, and we may add additional products to the license on an exclusive basis except in certain specified circumstances. The standard 20-year term for patents in this family will expire in 2019. This patent family relates to technology used in Glybera and all of our development programs.

We non-exclusively in-license a family of patents relating to methods for intramuscular administration of AAV vectors from Asklêpios Biopharmaceutical, Inc., or AskBio. This family includes issued patents in Europe, Japan and other jurisdictions, and a pending application in the United States. The standard 20-year term for patents in this family will expire in 2016. This patent family relates to technology used in Glybera.

We own a method of manufacturing patent family relating to a second-generation manufacturing method used in our AIP, hemophilia B and Parkinson's disease programs. This patent family contains pending applications in the United States, Europe, Japan and other jurisdictions, and issued patents in several jurisdictions. The standard 20-year term for patents in this family will expire in 2028.

We also own a PCT application that relates to a proprietary baculovirus filtration process. The standard 20-year term for patents in this family, if issued, will expire in 2032. This patent family relates to technology used in Glybera and all of our development programs.

Glybera

We co-own with University of British Columbia, or UBC, a patent family relating to the lipoprotein lipase variant LPL-S447X transgene used in Glybera, including issued patents in Europe and Japan. The standard 20-year term for patents in this family will expire in 2020. UBC exclusively licensed its patent rights to Xenon, which has granted us the sublicense described below.

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We exclusively in-license from Aventis Pharma S.A., or Aventis, a patent family co-owned by UBC and Aventis that relates to the use of AAV-LPL vectors for LPL-deficiency, including issued patents in Europe and other jurisdictions and two pending U.S. patent applications. The standard 20-year term for patents in this family will expire in 2015.

We own a family of patents relating to a VP1 vector capsid modification, which relates to the production of AAV vectors in insect cells and to AAV vectors with an altered ratio of viral capsid proteins that provides improved infectivity of the viral particles. This patent family includes issued patents in the United States, Europe and elsewhere, as well as pending applications in Europe, Japan and other jurisdictions. The standard 20-year term for patents in this family will expire in 2026.

We non-exclusively in-license a patent family from the Salk Institute that relates to a genetic promoter that enhances the expression of LPL-S447X delivered to the target tissues. This family includes four issued patents in the United States that have standard 20-year terms that will expire in 2017, and issued patents in Europe and other jurisdictions that have standard 20-year terms that will expire in 2018.

We non-exclusively in-license a patent family relating to the AAV1 capsid from AmpliPhi Biosciences, Inc. (formerly Targeted Genetics Corporation), or AmpliPhi. This family includes three issued patents in the United States, and one each in Europe and Japan, as well as issued patents elsewhere and a pending application in the United States. The standard 20-year term for patents in this family will expire in 2019. The University of Pennsylvania exclusively licensed its patent rights to AmpliPhi, which has granted us the sublicense described below.

Other Programs

Hemophilia B.    Our patent portfolio covering our hemophilia B program includes an exclusively in-licensed patent family from St. Jude relating to a specific promoter and a codon optimized hFIX transgene. This patent family includes two issued patents in the United States and one in Europe. The U.S. patent rights will expire in 2028 and the European patents will expire in 2025.

AIP.    Our patent portfolio covering our AIP program includes a patent family co-owned with Proyecto de Biomedicina Cima S.L. and exclusively licensed to us. This family relates to the codon optimized PBGD transgene and its use for the treatment of AIP. This family includes pending applications in the United States, Europe, Japan and elsewhere. The standard 20-year term for patents in this family will expire in 2029.

Parkinson's disease.    For our Parkinson's disease program, we have in-licensed a patent family and corresponding know-how relating to the GDNF transgene from Amgen for the field of gene therapy. The license is exclusive and expires on a country-by-country basis on the later of 10 years following launch of the relevant product or of expiration of the last-to-expire licensed patent in the applicable country, after which the license will become non-exclusive for that given country. This patent family includes two issued patents in the United States, one of which will expire in 2015 and one in 2017.

Licenses

We have obtained exclusive or non-exclusive rights from third parties under a range of patents and other technology that we use in our product and development programs, as described below. Our agreements with these third parties generally grant us a license to make, use, sell, offer to sell and import products covered by the licensed patent rights in exchange for our payment of some combination of an upfront amount, annual fees, royalties, a portion of amounts we receive from our licensees and payments upon the achievement of specified development, regulatory or commercial milestones. Some of the agreements specify the extent of the efforts we must use to develop and commercialize licensed products. The agreements generally expire upon expiration of the last-to-expire valid claim of the licensed patents. Each licensor may terminate the applicable agreement if we materially breach our obligations and fail to cure the breach within a specified cure period, in addition to other termination rights in some cases.

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Technology Used for Multiple Programs

We are exploiting technology from the third party sources described below in more than one of our programs.

National Institutes of Health—AAV production.    In 2007, we entered into a license agreement with the NIH, which we amended in 2009 and 2013. Under the license agreement, the NIH has granted us a non-exclusive license to patents relating to production of AAV vectors, to make, use, sell, offer to sell and import specified plasmids, which are small DNA molecules that are physically separate from, and can replicate independently of, chromosomal DNA within a cell, or other materials, which we refer to as AAV products. We may only grant sublicenses under this agreement with the NIH's consent, which may not be unreasonably withheld. We are exploiting this technology for our Glybera program and our programs for hemophilia B, AIP, and Sanfilippo B syndrome, and Parkinson's disease.

Payment obligations to the NIH under this license agreement include a one-time upfront payment of $12,000, which we have paid; a low single-digit percentage royalty on the sale of AAV products by us or on our behalf; a maximum sub-teen double-digit percentage of sublicensing income; potential additional development milestone fees for the initiation of each clinical trial, which would total in the aggregate $255,000 for one Phase I, Phase II and Phase III trial; potential regulatory milestone fees totaling $750,000 for the first marketing approvals in specified countries or jurisdictions; and an annual maintenance fee of $15,000 creditable against royalties. We do not have to pay royalties or milestone fees under this agreement if we have to pay royalties or milestone fees under our 2011 agreement with the NIH, described below, for the same product. In connection with entering into our relationship with Chiesi and obtaining the NIH's consent to sublicense our rights under this agreement to Chiesi, we also paid the NIH a total of $328,684 in amendment and sublicense payments. Under the license agreement, we have agreed to meet benchmarks in our development efforts, including as to development events, clinical trials and marketing approval, within specified timeframes.

The NIH may terminate this agreement in specified circumstances relating to our insolvency or bankruptcy. We may terminate this agreement for any reason, in any territory, subject to a specified notice period.

National Institutes of Health—AAV5.    In 2011, we entered into another license agreement with the NIH, which superseded a prior 2007 agreement and which we amended in 2013. Under this agreement, the NIH granted us an exclusive, worldwide license to patents relating to AAV5 for use in therapeutic products to be delivered to the brain or liver for treatment of human diseases originating in the brain or liver, but excluding arthritis-related diseases, and a non-exclusive, worldwide license to patents relating to AAV5 for all other diseases, in each case to make, use, sell, offer to sell and import products within the scope of the specified patent claims. We refer to the products licensed under this agreement as AAV5 products. We may grant sublicenses under this agreement only with the NIH's consent, which may not be unreasonably withheld. We are currently exploiting this technology for our programs on hemophilia B, AIP, and Sanfilippo B syndrome. See "Risk Factors—Our intellectual property licenses with third parties may be subject to disagreements over contract interpretation, which could narrow the scope of our rights to the relevant intellectual property or technology or increase our financial or other obligations to our licensors."

We have agreed to pay the NIH an initial payment of $140,000, which we have paid, an amendment royalty fee of $500,000, of which $250,000 would be payable upon a sublicense of the corresponding rights, which we have paid in full, royalties equal to a low single-digit percentage of net sales of AAV5 products, if any, by or on behalf of us or our sublicensees; a single to subteen double-digit percentage of sublicensing income; potential additional development milestone fees for the initiation of each clinical trial, which would total in the aggregate $267,500 for one Phase I, Phase II and Phase III trial; total potential regulatory milestone fees of $1,731,000 for the first marketing approvals in specified countries or jurisdictions; and an annual maintenance fee of $15,000 creditable against royalties. In connection with entering into our relationship with Chiesi and obtaining the NIH's consent to sublicense our rights under this agreement to Chiesi, we paid the NIH a total of $716,567 in amendment and sublicense payments. If an AAV5 product

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is also covered by our 2007 agreement with the NIH, our obligation to pay royalties on net sales and our obligation to pay milestone fees only apply under this 2011 agreement and not the 2007 agreement. We have agreed to meet benchmarks in our development efforts, including as to development events, clinical trials and marketing approval, within specified timeframes.

The NIH may terminate this agreement in specified circumstances relating to our insolvency or bankruptcy. We may terminate this agreement for any reason, in any country or territory, subject to a specified notice period.

Protein Sciences.    In 2007, we entered into a license agreement with Protein Sciences Corporation, or PSC, which we amended in 2012. Under the license agreement, PSC granted us a worldwide license, with a right to sublicense, to specified claims of a patent relating to an insect cell line, to research, develop, manufacture, import, market, and to offer for sale and sell certain products using a recombinant AAV vector developed using PSC's technology. The license is exclusive with respect to LPLD, hemophilia B and AIP, and we are exploiting this technology for those programs. We are licensed to use this technology for products listed in the agreement and we may add additional products to the agreement on an exclusive basis except in certain specified circumstances.

Payments obligations under the PSC agreement include a one-time upfront payment of $50,000, which we have paid, payments of $50,000 for each additional product added to the license agreement, and an annual maintenance fee of $50,000 for each product up to an annual maximum of $150,000 and limited by an overall specified life-time maximum of $500,000 for each product. We are not required to pay maintenance fees on products we no longer wish to develop. In addition, we must pay PSC an annual fee of $50,000 while any product is being sold or is subject to a license, partnership or funding relationship with another party, but for no more than 10 years after the first commercial sale of the product. We have no royalty payment obligations under the agreement.

The agreement will remain in effect as long as we remain current with our payments or until we or PSC exercise our rights to terminate it. PSC may terminate the agreement in circumstances relating to our insolvency or bankruptcy. We may terminate the agreement for convenience subject to a specified notice period.

Technology Used for Specific Programs

    Glybera

We are exploiting technology from the following third party sources in our Glybera program.

Academic Medical Center at the University of Amsterdam.    In 2006, we entered into an agreement with the Academic Medical Center at the University of Amsterdam, or AMC, and certain other parties, through which AMC invested in our predecessor company. Under this agreement, AMC assigned patent rights to us relating to LPLD and certain other indications.

We have agreed to pay AMC royalties equal to a low single-digit percentage of net sales, if any, of gene therapies to treat LPLD or certain other indications sold by us or our sublicensees that are covered by the assigned patent.

We have agreed to use commercially reasonable and diligent efforts to obtain marketing approvals for, and to commercialize, gene therapies to treat LPLD and certain other indications. If we decide to cease developing and commercializing a product to treat LPLD or certain other indications in each of Europe, the United States and Canada, we must re-assign to AMC the patent rights related to that product upon AMC's request.

Xenon Genetics, Inc.    In 2001, we entered into a sublicense agreement with Xenon Genetics, Inc., or Xenon, which we subsequently amended. Under the sublicense agreement, Xenon has granted us an exclusive, worldwide sublicense to patents and related technology relating to a truncated form of the LPL

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protein, to use, manufacture, distribute and sell products using the licensed patents or technology. We may only grant sublicenses under this agreement with consent of Xenon and its licensor UBC.

Payment obligations under the agreement include an initial sublicense fee of Canadian dollars C$75,000 and a one-time upfront payment to Xenon in the total amount of C$600,000, both of which we have paid, payment of certain past and future patent costs, a mid-single-digit percentage royalty on net sales, if any, of licensed products sold by us or our affiliates while covered by a valid patent claim, a low single-digit percentage royalty in countries where no patent protection covers the products, a double-digit percentage share of the royalties paid to us by Chiesi and an equal or slightly higher share of royalties paid to us by other sublicensees in other specified circumstances. The share of the royalty we receive from Chiesi and any other sublicensee that we have agreed to pay to Xenon decreases to a mid-single digit percentage after patent coverage expires, and the obligation terminates 10 years after the first commercial sale of the product. We have also agreed to pay Xenon development milestone fees totaling a maximum of C$350,000, plus an additional maximum of C$200,000 per additional product for a different indication upon our achievement of specified development milestones, as well as fees upon our achievement of specified regulatory milestones totaling a maximum of C$400,000 plus an additional maximum of C$400,000 per additional product for a different indication; or, if higher, a double-digit percentage share of any non-royalty fees we receive from a sublicensee.

The agreement will remain in effect until we or Xenon exercise our rights to terminate it. Either party may terminate the agreement in circumstances relating to the other party's insolvency or bankruptcy.

Aventis.    In 2006, we entered into a license agreement with Aventis Pharma, S.A., or Aventis, which we amended in 2013. Under the license agreement, Aventis has granted us an exclusive license, with a right to sublicense, to patents owned by Aventis and co-owned by Aventis and UBC, to develop, use, make, sell and offer to sell gene therapies containing a recombinant virus with an LPL gene.

Under the agreement, we made a one-time upfront payment to Aventis of €10,000 and agreed to pay Aventis a high single-digit to sub-teen double-digit royalty as a percentage of our net sales of licensed products, or if sales are made by a commercialization partner, a low single-digit as a percentage of net sales royalty, or, if higher, a high single-digit to sub-teen double-digit royalty as a percentage of royalties we receive from such commercialization partner plus an equivalent percentage of the price we invoice the commercialization partner for the licensed products less our cost of goods sold, subject to a floor of a low single-digit percentage of net sales by Chiesi or another commercialization partner. We have also agreed to pay Aventis a one-time milestone fee of €50,000 upon our achievement of a specified regulatory milestone and €75,000 upon our achievement of a specified commercial milestone.

In conjunction with amending the agreement in 2013, we have agreed to provide Aventis with a right of first negotiation regarding a specified product candidate to treat AIP if, at the time we complete Phase I/II clinical trials of the product candidate or within a specified period thereafter, we contemplate entering into a partnership for the co-development and commercialization of the product candidate.

The agreement will remain in effect until the expiration of the protection provided by the licensed patents, or until we or Aventis exercise our rights to terminate it. Aventis may terminate the agreement in circumstances relating to our bankruptcy.

Asklêpios Biopharmaceutical.    In 2010, we entered into a license agreement with AskBio under which AskBio granted us a non-exclusive, worldwide license, with a right to sublicense, to patents relating to administration of an AAV vector to muscle tissue for use in treatment of LPLD with Glybera or other products that contain an AAV vector having an AAV genetic construct encoding an LPL gene variant, to research, develop, make, use, sell, offer for sale, and import the products to treat LPLD.

We made a one-time upfront payment to AskBio of $50,000 and have agreed to pay AskBio annual maintenance fees of $50,000 during the term of the license.

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The agreement will remain in effect on a country-by-country basis until the earlier of June 5, 2016 or the expiration of the last to expire of the valid claims in the licensed patents. We may terminate the agreement for convenience at any time subject to a specified notice period.

Salk Institute for Biological Studies.    In 2008, we entered into a license agreement with the Salk Institute for Biological Studies, or Salk, which we amended in 2013. Under the license agreement, Salk has granted us a non-exclusive license to specified biological materials and patents relating to a DNA promoter, to research, develop, make, use, import, offer for sale, and sell products using their technology for gene therapy. We have a right to enter into sublicenses under this agreement, subject to prior written consent by Salk, which may not be unreasonably withheld, and to other conditions.

Payment obligations under the agreements include an upfront payment of $35,000 in 2008 and $5,000 in 2013 in connection with an amendment and consent to sublicense to Chiesi, both of which we have paid, as well as annual maintenance fees of $30,000, a royalty equal to a low single-digit percentage of net sales, if any, of licensed products sold by us, or, if higher, by Chiesi, and payments of a low single-digit percentage of all execution fees, maintenance fees, milestone fees and other non-royalty payments received by us from Chiesi or any other sublicensee.

The agreement will remain in effect on a country-by-country basis until the latest of 15 years from the effective date, the date of expiration of the last to expire licensed patent or the abandonment of the last remaining licensed patent application.

AmpliPhi Biosciences.    In 2006, we entered into a license agreement with AmpliPhi (formerly Targeted Genetics Corporation), which we amended in 2013. Under the license agreement, AmpliPhi has granted us a non-exclusive, worldwide sublicense to patents exclusively licensed by AmpliPhi from the University of Pennsylvania, or Penn, relating to AAV1, to make, develop, use, sell, offer to sell and import products using the patent rights to treat LPLD type 1, which includes the Glybera patient population, and LPLD type 5 by in vivo gene therapy. We may only grant sublicenses under this agreement with the consent of AmpliPhi and Penn, which may not be unreasonably withheld.

We have to date paid to AmpliPhi a one-time up-front payment of $1,750,000. We have agreed to pay AmpliPhi annual fees of $100,000, a total of $4,950,000 in development and regulatory milestone payments, which we have paid, and a royalty equal to a low single-digit percentage of net sales, if any, of licensed products sold by us or Chiesi.

Either party may terminate the agreement in circumstances relating to the other party's insolvency or bankruptcy. We may terminate the agreement for convenience at any time subject to a specified notice period.

If the agreement is terminated by us due to AmpliPhi's insolvency, bankruptcy or material uncured breach, or if AmpliPhi's license agreement with Penn is terminated, our license from AmpliPhi may be assigned to Penn. The assignment must be made on our request but is at Penn's discretion, which Penn may not unreasonably withhold, provided that the agreement specifies that Penn's obligations are consistent with its current obligations and provided that we assume all AmpliPhi's obligations.

    Hemophilia B

St. Jude Children's Research Hospital.    In 2008, we entered into a license agreement with St. Jude, which we amended in 2012. Under the license agreement, St. Jude has granted us an exclusive license, with a right to sublicense, to patent rights relating to expression of hFIX in gene therapy vectors, to make, import, distribute, use and commercialize products containing hFIX covered by a valid patent claim in the field of gene therapy for treatment or prophylaxis of hemophilia B. In addition, we have a first right of negotiation regarding any patent applications that are filed by St. Jude for any improvements to the patent rights licensed to us.

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We have agreed to pay St. Jude a royalty equal to a low single-digit percentage of net sales, if any, by us or our sublicensees of products covered by the licensed patent rights, and a portion of certain amounts we receive from sublicensees ranging from a mid-single digit to a mid-teen double-digit percentage of such amounts. We have also agreed to pay St. Jude one-time milestone fees totaling $6,500,000 upon the achievement of specified development and regulatory milestones, and an annual maintenance fee of $10,000 creditable against royalties and milestones in the same year. We have agreed to use commercially reasonable efforts to diligently develop and commercialize products licensed under this agreement.

The agreement will remain in effect until no further payment is due relating to any licensed product under this agreement or either we or St. Jude exercise our rights to terminate it. St. Jude may terminate the agreement in specified circumstances relating to our insolvency. We may terminate the agreement for convenience at any time subject to a specified notice period.

    AIP

Digna Biotech.    In 2010, we entered into a license agreement with Digna Biotech, S.L, or Digna Biotech, Fundación para la Investigación Médica Applicada, or FIMA, the members of a collaborative research consortium known as UTE CIMA, and Proyecto de Biomedicina CIMA S.L., or Proyecto, which superseded several prior agreements amongst such parties. We refer to Digna Biotech, FIMA, UTE CIMA and Proyecto collectively as the CIMA Parties. Under the license agreement, Proyecto granted us an exclusive, worldwide license, with a right to sublicense, under its interest in patent rights we jointly own with Proyecto relating to PBGD gene therapy to use, develop, make, have made and commercialize products using the licensed patent rights. In addition, UTE CIMA granted us a non-exclusive, worldwide license, with the right to grant sublicenses, under certain patent rights, know-how and materials required for the use, development, manufacture or commercialization of products covered by our exclusive license from Proyecto in the gene therapy field.

We have agreed to pay Digna Biotech royalties equal to a mid-single digit percentage of net sales, if any, by us or our affiliates of licensed products covered by our exclusive license and a sub-teen double-digit percentage share of net revenues we receive from our sublicensees. Digna Biotech is responsible for apportioning the amounts we pay Digna Biotech amongst the CIMA Parties.

Under the agreement we have to use commercially reasonable efforts to further develop, manufacture and commercialize licensed products as soon as reasonably practicable.

The agreement will remain in effect until our payment obligations expire or we or another party exercise our rights to terminate it. A party may terminate the agreement in circumstances relating to another party's insolvency or bankruptcy or if our agreement under which Digna Biotech is conducting a Phase I clinical trial of AMT-021 terminates. We may terminate this agreement for convenience, subject to a specified notice period. If Digna Biotech terminates the license agreement for breach or insolvency, we or Digna Biotech terminate the license agreement because our other agreement with Digna Biotech terminates other than for breach or insolvency of Digna Biotech or if we terminate the license agreement for convenience, the CIMA Parties will have the exclusive right to use the patent rights we jointly own with Proyecto that were exclusively licensed to us to further develop and commercialize licensed products for the treatment or prevention of AIP without financial obligations to us.

    Parkinson's disease

Amgen.    In 2010, we entered into a license agreement with Amgen, Inc. which superseded a prior 2008 agreement. Under the license agreement, Amgen granted us an exclusive, worldwide license, with a right to sublicense, to patents and know-how relating to GDNF to research, develop, make, use, offer for sale, sell, import, export and otherwise exploit gene therapies capable of delivering GDNF, the gene encoding GDNF, or any fragment of GDNF that has specified functional activity, which we refer to as GDNF products. The license exclusivity, and our obligation to make the revenue sharing payments described below, with respect

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to a given GDNF product in a given country expires on the later of expiration of the last-to-expire licensed patent in such country that covers such GDNF product and the tenth anniversary of the first commercial sale of such GDNF product in such country. Thereafter the license would become non-exclusive with respect to that GDNF product in that country.

We have agreed to pay Amgen revenue sharing payments equal to a sub-teen double-digit percentage of net revenues, if any, that we receive from our sales of GDNF products, from granting sublicenses under the intellectual property licensed from Amgen or from granting licenses under certain of our intellectual property rights. Upon receipt of the first marketing approval anywhere in the world for the first GDNF product we have also agreed to pay Amgen a one-time milestone fee of the greater of $10 million or a sub-teen double digit percentage of any milestone payments we receive from third parties with respect to receiving such approval.

We agreed to use reasonably diligent efforts to develop at least one GDNF product and seek to obtain regulatory approvals for this GDNF product in the United States and the European Union, and to commercialize it.

We granted Amgen an option to negotiate an exclusive license from us to research, develop, make, use, offer for sale, sell and otherwise exploit GDNF products in the United States, Mexico and Canada. Amgen may exercise the option within a specified period following completion of the first Phase II clinical trial of the first GDNF product we develop. If Amgen exercises the option but we and Amgen do not execute a definitive agreement to grant these rights to Amgen within a specified period of time, we retain these rights but may not grant development or commercialization rights to a third party in these North American countries on financial terms less favorable to us than those last offered by Amgen.

The agreement will remain in effect until either we or Amgen exercise our rights to terminate it. We may terminate the agreement for convenience at any time subject to a specified notice period. If we terminate the agreement for convenience, or if Amgen terminates the agreement due to our uncured material breach, rights to GDNF products will revert to Amgen. As part of such reversion, if Amgen requests, we have agreed to grant Amgen an exclusive, worldwide license under our relevant intellectual property rights so that Amgen can research, develop, make, use, offer for sale, sell and otherwise exploit GDNF products, subject to a specified revenue sharing and a one-time regulatory milestone payment from Amgen to us.

UCSF.    In 2012, we entered into a data license agreement with the University of California in San Francisco, or UCSF, related to UCSF's rights to the clinical trial data from a Phase I/II clinical trial, sponsored by the NIH, and that UCSF is conducting, of a product candidate consisting of an AAV2 vector carrying the GDNF gene, and to certain related preclinical data and know-how. Under the data license agreement, UCSF granted us a non-exclusive license, with a right to sublicense, to research, develop, make, use, offer for sale, sell and otherwise exploit pharmaceutical products containing or consisting of an AAV2 genetic construct encoding GDNF, or any fragment of GDNF that has specified functional activity, for the therapeutic, palliative and prophylactic treatment of Parkinson's disease in humans. During the term of the data license agreement, UCSF has agreed not to grant to any other for-profit entity any of the rights granted to us thereunder, except under specified circumstances involving a breach of our diligence obligations described below.

Payment obligations under the agreement include a one-time, up-front payment of $300,000, which we have paid, a royalty equal to a low single-digit percentage of our net sales, if any, of products that are identified or developed through material use of the data licensed from UCSF, or identified products, as well as third party license fees with the percentage due to UCSF ranging from a low double-digit percentage for earlier-granted sublicenses to a low single-digit percentage for later-granted sublicenses. Our obligation to pay UCSF earned royalties with respect to a given country begins on the first commercial sale of an identified product in such country, and our obligation to pay earned royalties and third-party license fees

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expires on the tenth anniversary of such first commercial sale, after which the data license will become perpetual, non-exclusive, fully paid-up, and royalty-free in such country.

The UCSF agreement also contains certain other obligations we have agreed to complete by specified dates, including obligations to deliver to UCSF by June 12, 2014 specified materials for UCSF to complete a non-clinical study of an AAV2 vector carrying the GDNF gene, to demonstrate equivalent product release specifications of our vector to the vector used in the ongoing NIH-sponsored Phase I clinical trial, to pursue a bridging study using our AAV2 vector carrying a GDNF gene, and to use commercially reasonable efforts to proceed, either directly or through a third party licensee, to develop, seek to obtain regulatory approval for and market at least one identified product in the United States and the European Union.

If we materially fail to comply with any of the diligence obligations described above and do not cure such failure within specified cure periods, UCSF may at its option either terminate the data license agreement or be freed from its covenant not to grant to any other for-profit entity any of the rights granted to us thereunder.

The data license agreement will remain in effect until all of our payment obligations to UCSF have ended in all countries, unless either we or UCSF exercise our rights to terminate it earlier. UCSF may terminate the agreement in specified circumstances relating to our bankruptcy. We may terminate the agreement for convenience at any time subject to a specified notice period.

Trade Secrets

In addition to patents and licenses, we rely on trade secrets and know-how to develop and maintain our competitive position. For example, significant aspects of the process by which we manufacture Glybera and our gene therapies are based on unpatented trade secrets and know-how. We seek to protect our proprietary technology and processes and obtain and maintain ownership of certain technologies, in part, through confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and commercial partners. We also seek to preserve the integrity and confidentiality of our data, trade secrets and know-how by maintaining physical security of our premises and physical and electronic security of our information technology systems.

Trademarks

uniQure and Glybera are registered trademarks in various jurisdictions including the United States and the European Union. We intend to seek trade mark protection for other product candidates as and when appropriate.

Strategic Collaboration: Chiesi

In April 2013, we entered into two agreements with Chiesi. One is an agreement for the commercialization of Glybera for LPLD and the second is an agreement for the co-development and commercialization of our hemophilia B program. To date, under these two collaborations we have received €17.0 million in upfront payments aggregate non-equity funding, as well as a €14.0 million investment in our ordinary shares. Additionally, the agreements provide us with research funding for further development of our hemophilia B product candidate, the potential for commercial milestone payments of up to €42.0 million for Glybera for LPLD, and payments for commercial quantities of Glybera we supply to Chiesi. We summarize the key terms of these two agreements below.

Glybera for LPLD

Overview.    In April 2013, we entered into an agreement with Chiesi to commercialize Glybera for LPLD in the following countries, which we refer to as the Chiesi Glybera territory:

    the then current 27 member states of the European Union plus Iceland, Liechtenstein and Norway;

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    Albania, Andorra, Bosnia, Croatia, Macedonia, Monaco, Montenegro, Republic of San Marino, Serbia (including Kosovo), Switzerland and Vatican City; and

    Algeria, Brazil, China, Egypt, Mexico, Morocco, Pakistan, Russia and ex-Soviet countries (Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Tajikistan, Turkmenistan, Ukraine and Uzbekistan), Tunisia and Turkey.

In all other countries of the world, including the United States and Japan, we retain all product rights to Glybera for LPLD.

Under the terms of the agreement, we received a €2.0 million upfront payment in recognition of our past expenditures developing the product. In addition, we are eligible to earn up to €42.0 million in commercial milestone payments. We will receive payment for individual quantities of the product we manufacture and supply under the agreement, payable partly upon order and partly following delivery of such product quantities, and amounting to the greater of (1) 40% of the average net sales price of the product and (2) the fully loaded cost of goods plus 20% mark-up for each patient dose sold.

Under the agreement, we appointed Chiesi as our distributor with the exclusive right to commercialize, itself or through affiliates, or, with our written consent, other sub-distributors, Glybera for LPLD in the Chiesi Glybera territory. The appointment includes an exclusive license grant to our trademark "Glybera" in the Chiesi Glybera territory for the purposes of the agreement, as well as a license to certain intellectual property rights controlled by us. Chiesi is generally required to commercialize the product exclusively under the "Glybera" name.

Under the terms of the agreement, Chiesi does not have the right to carry out any research or development with respect to Glybera or to manufacture Glybera or have Glybera manufactured, except for certain exceptions, such as our failure to supply the product to them. During the term of the agreement, we are required to manufacture and supply, and Chiesi is required to purchase from us all of its requirements for Glybera for commercialization under the agreement.

Commercialization Obligations.    Chiesi has the sole right and responsibility to commercialize Glybera in the Chiesi Glybera territory at its expense using no less than commercially reasonable efforts, including compliance with an agreed marketing plan and budget and the allocation of an agreed minimum workforce to the commercialization of the product. Chiesi will also be responsible for conducting price and reimbursement submissions to the relevant reimbursement bodies. We and Chiesi have allocated between us responsibilities for the filing, holding and maintenance associated with marketing authorizations for Glybera in the various countries and jurisdictions covered by our agreement, as well as associated costs.

Governance.    Our collaboration with Chiesi is guided by a joint steering committee and a joint commercialization committee. Subject to limitations specified in the agreement, if the applicable governance committee is not able to make a decision by consensus and the parties are not able to resolve the issue through escalation to the superior committee or, in some cases, specified senior executives of the parties, then:

    we have final decision-making authority with respect to all matters related to research or development in relation to Glybera, with reasonable input from Chiesi taking into account territory-specific matters;

    Chiesi has final decision-making authority with respect to all matters related to commercialization of Glybera in the Chiesi Glybera territory, with reasonable input from us taking into account our global product strategy;

    on regulatory matters with respect to Glybera we generally will jointly work with Chiesi towards a regulatory strategy for Glybera in the countries of the Chiesi Glybera territory that are not member states of the European Union; and

    any other matter will be decided by binding arbitration.

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Exclusivity Restrictions.    During the term of the agreement, we may not offer for sale, sell, license or otherwise commercialize Glybera in the Chiesi Glybera territory other than in compliance with the terms of the agreement. Moreover, to the fullest extent consistent with applicable laws, each of Chiesi and we may not, directly or indirectly, develop, manufacture or commercialize in the Chiesi Glybera territory any gene therapy-based product for the treatment of LPLD, other than Glybera in accordance with the terms of the agreement.

Term and Termination.    Our agreement with Chiesi will remain in force, on a country-by-country basis, until the latest of:

    12 years from the first commercial sale of Glybera in the relevant country;

    expiry of any regulatory exclusivity granted by any marketing authorization or any other regulatory approval in the relevant country; or

    expiry of the last valid claim of specified patent rights covering Glybera in the relevant country.

Unless terminated by a party with three months written notice to the other party prior to the end of the initial or any subsequent term, the agreement will automatically renew for successive five year terms. Chiesi has the right to terminate the agreement in its entirety in case of our failure to supply Glybera for a period of at least nine months, provided such failure to supply is not caused by a force majeure event and other pre-conditions for termination are met. Either party may also terminate the agreement in its entirety in the event of a material breach by the other party, in the event the other party becomes subject to specified bankruptcy, insolvency or similar circumstances, or if the other party or any of its affiliates or, as the case may be, sub-distributors challenges the validity of any trademark to which rights are granted under the agreement. We may terminate the agreement in its entirety if Chiesi or any of its affiliates or sub-distributors challenges the validity, enforceability, patentability or scope of any valid claim included in any of the patents covering Glybera. We may also terminate this agreement in its entirety or with respect to particular countries if Chiesi fails to meet certain commercialization requirements and such failure is not caused by a force majeure event or our failure to supply. After termination in certain circumstances, we will have continuing supply obligations.

Hemophilia B (AMT-060)

Overview.    In April 2013, we entered into a co-development and license agreement with Chiesi in respect of our hemophilia B gene therapy program in the following countries, which we refer to as the Chiesi hemophilia B territory:

    the then current 27 member states of the European Union plus Iceland, Liechtenstein and Norway; and

    Albania, Algeria, Andorra, Bosnia, Brazil, Croatia, Egypt, Macedonia, Mexico, Monaco, Montenegro, Morocco, Pakistan, Republic of San Marino, Russia and ex-Soviet countries (Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Tajikistan, Turkmenistan, Ukraine and Uzbekistan), Serbia (including Kosovo), Switzerland, Tunisia, Turkey, and Vatican City.

In all other countries of the world, including the United States, China and Japan, we retain all product rights to our hemophilia B program.

Under the terms of the agreement, we received a €15.0 million upfront payment. In addition, we will share equally with Chiesi specified development costs attributable to the program according to a defined development plan and budget, including costs associated with preclinical and clinical studies as well as development and regulatory milestone payments associated with existing in-license agreements. We will receive payments from Chiesi for commercial quantities of our hemophilia B product candidate we manufacture and supply to them, if we receive regulatory approval for such product candidate. We estimate that the amount we would retain, net of cost of goods sold, including third party royalties and related amounts, will be between 25% and 35% of the revenues from sales of such product by Chiesi, varying by

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country of sale. We and Chiesi have agreed to negotiate a separate supply and distribution agreement in respect of the potential commercialization of our hemophilia B product candidate prior to dosing the first patient in any pivotal study. We are not entitled to any milestone payments under this co-development agreement.

Under the agreement, we granted to Chiesi and its affiliates an exclusive license, for the Chiesi hemophilia B territory, to co-develop, together with us, and exclusively commercialize a gene therapy for the treatment of hemophilia B in humans that includes an AAV5 vector containing a functional copy of the codon-optimized hFIX gene or part thereof under the control of a liver-specific promoter. Chiesi granted to us the right to use relevant data related to such product and generated under this development program in connection with development and regulatory activities conducted by us or on our behalf outside of the Chiesi hemophilia B territory.

Research Obligations.    We and Chiesi must use commercially reasonable efforts to conduct the activities assigned to each of us under the agreed development plan and budget. Specifically, we are responsible for all activities to develop the product in the Chiesi hemophilia B territory, including all clinical development activities required to obtain marketing authorization in the Chiesi hemophilia B territory, with particular emphasis on France, Germany, Italy, Spain and the United Kingdom, and must provide supplies of the product as necessary for the activities under the development plan and budget. We are also obligated to provide commercial supply of the product to Chiesi pursuant to a supply and distribution agreement, which we shall negotiate as noted above. Chiesi is responsible for all launch and pre-launch activities for the product in the territory, including regulatory filings and approvals, interaction with regulatory authorities, key opinion leader development, market research and pricing and reimbursement studies.

Governance.    Our collaboration with Chiesi is initially guided by at least a joint steering committee and a joint development committee. Subject to limitations specified in the agreement, if the applicable governance committee is not able to make a decision by consensus and the parties are not able to resolve the issue through escalation to the superior committee or, in some cases, specified senior executives of the parties, then:

    we will generally have final decision-making authority with respect to all research and development activities with respect to the product, with reasonable input from Chiesi taking into account territory-specific matters;

    Chiesi will generally have final decision-making authority with respect to all commercialization activities with respect to the product in the territory, with reasonable input from us taking into account our global product strategy; and

    certain items specifically identified in the agreement will require a unanimous decision of both parties.

With respect to regulatory matters, we and Chiesi will jointly work towards a regulatory strategy for the licensed product in the Chiesi hemophilia B territory, with an understanding that Chiesi will have the final decision right on the regulatory strategy for the product in the territory, and will support our global regulatory strategy for the licensed product unless such support leads to a material increase in costs or time to market for Chiesi. Any other matter will be decided by binding arbitration.

Exclusivity Restrictions.    During the term of the agreement neither party may, directly or indirectly, undertake the development, manufacture or commercialization anywhere in the Chiesi hemophilia B territory of any gene therapy for hemophilia B in humans other than the licensed product.

Term and Termination.    Our agreement with Chiesi will remain in force, on a country-by-country basis, until the latest of:

    12 years from the first commercial sale of the licensed product in the relevant country;

    expiry of any regulatory exclusivity granted by any marketing authorization or any other regulatory approval in the relevant country; or

    expiry of the last valid claim of the licensed patents covering the licensed product in the relevant country.

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Unless terminated by a party with three months written notice prior to the end of the initial or any subsequent term, the agreement will automatically renew for successive five-year terms. Chiesi may terminate the agreement for convenience upon six months' prior notice to us at any time during the term following the first six months of the agreement. Chiesi also has the right to terminate the agreement in its entirety in case of our failure to supply the licensed product for a period of at least nine months, provided such failure to supply is not caused by a force majeure event. The agreement may also be terminated in its entirety by either party in the event of a material breach by the other party, or if the other party or any of its affiliates or third party contractors challenges the validity, enforceability, patentability or scope of any claim included in any licensed patent.

Strategic Collaboration: 4D Molecular Therapeutics

In January 2014, we entered into a collaboration and license agreement with 4D for the discovery and optimization of next-generation AAV vectors. Under this agreement, 4D has granted us an exclusive, worldwide license, with the right to grant sublicenses, to 4D's existing and certain future know-how and other intellectual property, including certain patent rights 4D has exclusively licensed from the Regents of the University of California, to develop, make, use and sell certain AAV vectors and products containing such AAV vectors and gene constructs, for delivery of such gene constructs to CNS or liver cells for the diagnosis, treatment, palliation or prevention of any disease or medical condition. Under this collaboration, the 4D team, including Dr. David Schaffer, 4D's co-founder and Professor of Chemical and Biomolecular Engineering at the University of California, Berkeley, has agreed to establish a laboratory to identify next generation AAV vectors. In addition, in connection with our entry into this collaboration, Dr. Schaffer will join our Supervisory Board.

We have agreed to fund a three-year research collaboration, which can be extended at our option for an additional year, to be conducted under a mutually agreed research plan. We are entitled to select a specified number of AAV variants from the research collaboration. We will have exclusive rights to further research, develop, manufacture and commercialize the selected AAV variants, as well as AAV vectors and products containing such AAV variant and gene constructs, or licensed products, and, during the research collaboration and for the term of the agreement, 4D retains no rights to the selected AAV variants for any use. During the research collaboration and throughout the term of the agreement, 4D has agreed to work exclusively with us to research, develop, manufacture and commercialize AAV variants, AAV vectors and products containing AAV vectors and gene constructs, for delivery of gene constructs to CNS or liver cells for the diagnosis, treatment, palliation or prevention of any disease or medical condition.

Our research collaboration with 4D is guided by a joint research steering committee. Subject to limitations specified in the agreement, if the joint research steering committee is not able to make a decision by consensus and the parties are not able to resolve the issue through escalation to specified senior executives of the parties, then we have final decision-making authority with respect to all matters except for certain matters that will be decided by an independent scientific panel, certain matters that will be decided by binding arbitration, and certain matters that require mutual agreement.

We and 4D must each use commercially reasonable efforts to conduct the research collaboration in accordance with the research plan. We must use commercially reasonable efforts to develop, manufacture and commercialize licensed products under the agreement. After the research collaboration ends, 4D may notify us from time to time as to one or more products that 4D or a third party proposes to develop and commercialize using the intellectual property rights that are exclusively licensed to us. If we are, or are interested in, researching or developing any such proposed product or a product that is competitive with such proposed product, then we are obligated to use commercially reasonable efforts to research, develop, manufacture and commercialize such product. If we are not, and are not interested in, researching or developing any such proposed product or a product that is competitive with such proposed product, then we may be required to negotiate and enter into a sublicense to such third party, or an amendment to the

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agreement, that grants such third party or 4D, respectively, the right to research, develop, manufacture and commercialize such proposed product on commercially reasonable terms.

Under the agreement, we have agreed to make a one-time upfront payment of $100,000 and another one-time payment of $100,000 upon the joint research steering committee's approval of the research plan, including an associated budget. Our payment obligations under the agreement include the research collaboration funding described above as well as payments for the achievement of specified pre-clinical, clinical and regulatory milestones of up to $5,000,000 for each licensed product that we develop under the collaboration, and, for each licensed product, each indication. We have also agreed to pay 4D royalties equal to a single-digit percentage of net sales, if any, of licensed products by us or our affiliates. We will also pay 4D a double-digit percentage of any sublicensing income we receive, subject to a floor of a low single-digit percentage of net sales, if any, by sublicensees of certain licensed products. Our obligation to pay royalties expires on a product-by-product and country-by-country basis, upon the latest of:

    the expiration of the last valid claim of specified patent rights covering the relevant product in the relevant country;

    the expiration of any applicable exclusivity, including orphan drug status or data exclusivity, and any extension thereto, granted by a regulatory authority in the relevant country with respect to the relevant product; or

    10 years after the first commercial sale of the relevant product in the relevant country.

Term and Termination.    The agreement will remain in force until all of our payment obligations under the agreement expire or we or 4D exercise our rights to terminate it. Either party may terminate the agreement in the event of an uncured material breach by the other party or, in the event the other party becomes subject to specified bankruptcy, insolvency or similar circumstances. 4D will be deemed in material breach under specified circumstances involving Dr. Shaffer's unavailability. If we materially breach the agreement in a manner that relates to a specific AAV vector or product, and not to the agreement as a whole, 4D may only terminate the agreement as to the indication for which such AAV vector or product was being developed. We may terminate the agreement for convenience after the research collaboration ends, subject to a specified notice period. We may also terminate the agreement at any point prior to the first anniversary of the effective date if the joint research steering committee determines that it would be futile to continue the research collaboration or that 4D is not making bona fide efforts to achieve the timelines in the research plan. Our research collaboration funding obligation continues for specified periods following certain terminations.

Competition

The biotechnology and pharmaceutical industries, including in the gene therapy field, are characterized by rapidly advancing technologies, intense competition and a strong emphasis on intellectual property. We face substantial competition from many different sources, including large and specialty pharmaceutical and biotechnology companies, academic research institutions and governmental agencies and public and private research institutions.

We are aware of several companies focused on developing gene therapies in various indications, including bluebird bio, Sangamo BioScience, AGTC, Oxford Biosciences, Spark Therapeutics, Audentes Therapeutics, RegenX and Asklepios, as well as several companies addressing other methods for modifying genes and regulating gene expression. Although companies and research institutions in the gene therapy field tend to focus on particular target indications, any advances in gene therapy technology made by a competitor may be used to develop therapies competing against Glybera or one of our product candidates. We may also face competition with respect to the treatment of some of the diseases that we are seeking to target with our gene therapies from protein pharmaceuticals under development at pharmaceutical and biotechnology companies such as Pfizer, Baxter, Bayer, Novo Nordisk, Genzyme, Shire, BioMarin, Biogen Idec and numerous other pharmaceutical and biotechnology firms.

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We must also compete with existing standards of care, therapies and symptomatic treatments, as well as any new therapies that may become available in the future for the indications we are targeting. For example, for our internal programs, our competition includes the following:

    Glybera.  The current standard of care for the treatment of LPLD is a restricted diet. We are aware that Novartis is developing a diacylglycerol acyltransferase-1, or DGAT-1, inhibitor, which is currently in a Phase III clinical trial for the treatment of familial chylomicronemia syndrome, and which could compete with Glybera as a treatment alternative for LPLD for a subset of patients if proven effective and approved for marketing.

    Hemophilia B.  Hemophilia B is typically treated through a program of protein replacement therapy. There are a number of companies that manufacture and market protein therapies for this condition. Biogen Idec has filed a BLA with the FDA seeking approval to market and distribute a longer-acting protein replacement therapy product that would only have to be administered twice a month as opposed to several times a week. In addition, we understand that several companies are developing gene therapies for hemophilia B. Asklepios and Spark Therapeutics have announced Phase I/II studies with AAV-based gene therapy approaches.

Many of our current or potential competitors, either alone or with their collaboration partners, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, and marketing approved products than we do. Mergers and acquisitions in the pharmaceutical, biotechnology and gene therapy industries may result in even more resources being concentrated among a smaller number of our competitors. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market. The key competitive factors affecting the success of all of our programs are likely to be their efficacy, safety, convenience, price and the availability of reimbursement from government and other third party payors. We also believe that, due to the small size of the patient populations in the orphan indications we target, being first to market will be a significant competitive advantage. We believe that our advantages in vector and manufacturing technology will allow us to reach market in