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Table of Contents
 
 
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
 
 
FORM
10-K
 
 
(Mark One)
 
ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended:
December 31
, 2020
 
TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the transition period from
                    
 to
                    
Commission file number:
001-36167
 
 
KARYOPHARM THERAPEUTICS INC.
(Exact name of registrant as specified in its charter)
 
 
 
Delaware
 
26-3931704
(State or other jurisdiction of
incorporation or organization)
 
(I.R.S. Employer
Identification No.)
85 Wells Avenue, 2
nd
Floor
, Newton, Massachusetts
 
02459
(Address of principal executive offices) (zip code)
Registrant’s telephone number, including area code:
(617658-0600
Securities registered pursuant to Section 12(b) of the Act:
 
Title of each class
 
Trading Symbol(s)
 
Name of each exchange on which listed
Common Stock, $0.0001 par value
 
KPTI
 
Nasdaq Global Select Market
Securities registered pursuant to Section 12(g) of the Act: None
 
 
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.    Yes  ☒    No  ☐
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act.    Yes  ☐    No  ☒
Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.    Yes ☒    No  ☐
Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of
Regulation S-T(§232.405
of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files).    Yes  ☒    No  ☐
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a
non-accelerated
filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in
Rule 12b-2
of the Exchange Act.
 
Large accelerated filer      Accelerated filer  
       
Non-accelerated filer
     Smaller reporting company  
       
         Emerging growth company  
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.  ☐
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report.
Indicate by check mark whether the registrant is a shell company (as defined in
Rule 12b-2of
the Exchange Act).    Yes ☐    No 
The aggregate market value of the registrant’s voting and
non-voting
common stock held by
non-affiliates
of the registrant (without admitting that any person whose shares are not included in such calculation is an affiliate) computed by reference to the price at which the common stock was last sold on June 30, 2020 was approximately $1.32 billion. Shares of common stock held by each executive officer and director and by each holder of 10% or more of the outstanding common stock have been excluded in that such persons may be deemed to be affiliates. This determination of affiliate status is not necessarily a conclusive determination for other purposes.
Number of shares outstanding of the registrant’s Common Stock as of February 16, 2021: 74,634,291.
Documents incorporated by reference:
Portions of the registrant’s Proxy Statement for its 2021 Annual Meeting of Stockholders, which the registrant intends to file with the Securities and Exchange Commission no later than 120 days after the registrant’s fiscal year end of December 31, 2020, are incorporated by reference into Part III of this Annual Report on
Form 10-K.
 
 
 

Table of Contents 
TABLE OF CONTENTS
 
        
Page No.
 
     6  
Item 1.
  Business      6  
Item 1A.
  Risk Factors      64  
Item 1B.
  Unresolved Staff Comments      112  
Item 2.
  Properties      112  
Item 3.
  Legal Proceedings      112  
Item 4.
  Mine Safety Disclosures      112  
     113  
Item 5.
  Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities      113  
Item 6.
  Selected Financial Data      113  
Item 7.
  Management’s Discussion and Analysis of Financial Condition and Results of Operations      114  
Item 7A.
  Quantitative and Qualitative Disclosures about Market Risk      127  
Item 8.
  Financial Statements and Supplementary Data      127  
Item 9A.
  Controls and Procedures      128  
Item 9B.
  Other Information      130  
     131  
Item 10.
  Directors, Executive Officers and Corporate Governance      131  
Item 11.
  Executive Compensation      131  
Item 12.
  Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters      131  
Item 13.
  Certain Relationships and Related Transactions, and Director Independence      131  
Item 14.
  Principal Accountant Fees and Services      131  
     132  
Item 15.
  Exhibits and Financial Statement Schedules      132  
Item 16.
  Form 10-K Summary      132  
     178  
 
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Forward-Looking Information
This Annual Report on
Form 10-K
contains forward-looking statements regarding the expectations of Karyopharm Therapeutics Inc., herein referred to as “Karyopharm,” the “Company,” “we,” or “our,” with respect to the possible achievement of discovery and development milestones, our future discovery and development efforts, including regulatory submissions and approvals, our commercialization efforts, our partnerships and collaborations with third parties, our future operating results and financial position, our business strategy, and other objectives for future operations. We often use words such as “anticipate,” “believe,” “estimate,” “expect,” “intend,” “may,” “plan,” “predict,” “project,” “target,” “potential,” “will,” “would,” “could,” “should,” “continue,” and other words and terms of similar meaning to help identify forward-looking statements, although not all forward-looking statements contain these identifying words. You also can identify these forward-looking statements by the fact that they do not relate strictly to historical or current facts. There are a number of important risks and uncertainties that could cause actual results or events to differ materially from those indicated by forward-looking statements. These risks and uncertainties include, but are not limited to, those described in “Part I—Item 1A. Risk Factors” of this Annual Report on Form 10-K and under the heading “Summary of Risk Factors” below. As a result of these and other factors, we may not actually achieve the plans, intentions, expectations or results disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments we may make. We do not assume any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.
 
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Summary of Risk Factors
Below is a summary of the principal factors that make an investment in our common stock speculative or risky. This summary does not address all of the risks that we face. Additional discussion of the risks summarized in this risk factor summary, and other risks that we face, can be found below under the heading “Risk Factors” and should be carefully considered, together with other information in this Annual Report on Form
10-K
and our other filings with the SEC, before making an investment decision regarding our common stock.
Risks Related to Commercialization and Product Development
 
   
If we are unable to successfully commercialize XPOVIO or other products or product candidates in and outside of the U.S., our business, financial condition and future profitability will be materially harmed.
 
   
XPOVIO faces substantial competition.
 
   
If our clinical trials fail to demonstrate safety and efficacy to the satisfaction of regulatory authorities or do not otherwise produce positive results, we may incur additional costs, experience delays or be unable to complete the development of such product candidates.
 
   
We or our collaborators may not receive regulatory approvals for the commercialization of some or all of our or their product candidates in a timely manner, or at all.
 
   
Serious adverse or unacceptable side effects related to XPOVIO or future products or product candidates may delay or prevent their regulatory approval, cause us to suspend or discontinue clinical trials, or limit the commercial value of our approved indications.
 
   
The COVID-19
pandemic has adversely disrupted, and is expected to continue to adversely disrupt, our operations.
 
   
The results of previous clinical trials may not be predictive of future trial results and interim or
top-line
data may be subject to change or qualification.
 
   
We may not be successful in our efforts to identify or discover additional potential product candidates or our decisions to prioritize the development of certain product candidates over others may later prove wrong.
 
   
We may not be able to maintain or expand our sales, marketing and distribution capabilities in order to successfully commercialize XPOVIO or any of our products or product candidates, if approved.
 
   
Our approved products may not receive coverage or may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives.
 
   
Product liability lawsuits against us could divert our resources, result in substantial liabilities and limit commercialization of XPOVIO or any of our other products.
 
   
Any business that we conduct outside of the U.S. may be adversely affected by international risks and uncertainties.
Risks Related to Regulatory Matters
 
   
We may not be able to utilize accelerated development pathways to obtain regulatory approval, orphan drug exclusivity or certain other designations for our product candidates, which may result in delays receiving necessary marketing approvals, if approval is received at all.
 
   
Our ability to commercialize our products may be limited by the terms of their respective regulatory approvals and ongoing regulation of our products.
 
   
We and/or our collaborators may not obtain marketing approval in foreign jurisdictions.
 
   
Current and future legislation may negatively impact (i) our and/or our collaborators’ ability to obtain marketing approval, commercialize our products and obtain reimbursement for our products; (ii) the prices we or they obtain; and (iii) the costs for our products.
 
   
Our failure to comply with any (i) post-approval development and regulatory requirements; (ii) reporting and payment obligations under governmental drug pricing programs; (iii) applicable anti-kickback, fraud and abuse and other healthcare laws and regulations; (iv) global privacy and data security requirements; or (v) environmental, health and safety laws and regulations may have a material adverse effect on our business, financial condition or results of operations.
 
   
Our employees, independent contractors, consultants and vendors may engage in misconduct or other improper activities, which could cause significant liability for us.
 
   
Laws and regulations governing any international operations we may have in the future may preclude us from developing, manufacturing and selling certain product candidates outside of the U.S. and require us to develop and implement costly compliance programs.
 
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We are exposed to possible litigation and damages by competitors who may claim that we are not providing sufficient quantities of our approved products on commercially reasonable, market-based terms for testing in support of their ANDAs and 505(b)(2) applications.
 
   
We are subject to governmental export and import controls that could impair our ability to compete in international markets and subject us to liability if we are not in compliance with applicable laws.
Risks Related to Our Financial Position and Capital Requirements
 
   
We may never achieve or maintain profitability and will need additional funding to achieve our business objectives, which may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our product candidates.
 
   
We may not be able to satisfy our indebtedness, on a timely basis or at all, and we may be negatively impacted by various covenants and accounting methods related to our debt.
 
   
Our business, financial condition and stock price may be impacted by unstable market and economic conditions.
Risks Related to Our Dependence on Third Parties
 
   
Our dependence on third parties for certain aspects of our business, such as clinical development, manufacturing, marketing, distribution and/or commercialization of XPOVIO and/or our product candidates, could negatively impact our development and commercialization plans.
Risks Related to Our Intellectual Property
 
   
If we are unable to obtain and maintain patent protection for our product candidates and other discoveries, or the scope of the patent protection obtained is not sufficiently broad, our ability to successfully commercialize our product candidates may be adversely affected.
 
   
We may become involved in lawsuits to protect or enforce our intellectual property rights, or third parties may initiate legal proceedings against us alleging our infringement of their intellectual property rights.
 
   
If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.
Risks Related to Employee Matters and Managing Growth
 
   
We may not be able to retain our Chief Executive Officer, our President and Chief Scientific Officer and other key executives and to attract, retain and motivate qualified personnel.
 
   
Drs. Kauffman and Shacham are married to each other, and the separation or divorce of the couple could adversely affect our business.
 
   
We have expanded and expect to continue to expand our development, regulatory and sales, marketing and distribution capabilities, and as a result, we may encounter difficulties in managing our growth, which could disrupt our operations.
 
   
Information technology system failures or security breaches may materially adversely affect our business and operations.
Risks Related to Our Common Stock
 
   
Provisions in our charter and under Delaware law could make an acquisition of us more difficult and may prevent attempts by our stockholders to replace or remove our current management.
 
   
The price of our common stock has been and may continue to be volatile.
 
   
Securities or other litigation could result in substantial costs and may divert management’s time and attention from our business.
 
   
We have broad discretion in the use of our cash, cash equivalents and investments and may not use them effectively.
 
   
If we identify a material weakness in our internal controls over financial reporting, it could have an adverse effect on our business and financial results and our ability to meet our reporting obligations could be negatively affected.
 
   
If the estimates we make, or the assumptions on which we rely, in preparing our consolidated financial statements, our projected guidance and/or our projected market opportunities prove inaccurate, our actual results may vary from those reflected in our projections and accruals.
 
   
Our ability to use our net operating loss carryforwards and tax credit carryforwards to offset future taxable income may be subject to certain limitations, and changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition.
 
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PART I
 
Item 1.
Business
Overview
We are a commercial-stage pharmaceutical company pioneering novel cancer therapies and dedicated to the discovery, development and commercialization of
first-in-class
drugs directed against nuclear transport for the treatment of cancer and other diseases. Our scientific expertise is based upon an understanding of the regulation of intracellular communication between the nucleus and the cytoplasm. We have discovered and are developing and commercializing novel, small molecule
S
elective
I
nhibitor of
N
uclear
E
xport
(“SINE”) compounds that inhibit the nuclear export protein exportin 1 (“XPO1”). These SINE compounds, representing a new class of drug candidates with a novel mechanism of action that have the potential to treat a variety of diseases with high unmet medical need, were the first oral XPO1 inhibitors to receive marketing approval. Our lead asset, XPOVIO
®
(selinexor), received its initial U.S. approval from the U.S. Food and Drug Administration (the “FDA”) in July 2019 and is currently approved and marketed for the following indications:
 
   
In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Approval in this indication was supported by data from the BOSTON (
Bo
rtezomib,
S
elinexor and Dexame
t
has
on
e) study (the “BOSTON Study”).
 
   
In combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors (“PIs”), at least two immunomodulatory agents (“IMiDs”), and an anti-CD38 monoclonal antibody. We refer to myeloma that is refractory to these five agents as penta-refractory. Approval in this indication was supported by data from the STORM (
S
elinexor
T
reatment of
R
efractory
M
yeloma) study (the “STORM Study”).
 
   
For the treatment of adult patients with relapsed or refractory diffuse large
B-cell
lymphoma (“DLBCL”), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. This indication was approved under accelerated approval based on response rate and was supported by data from the SADAL (
S
elinexor
A
gainst
D
iffuse
A
ggressive
L
ymphoma) study (the “SADAL Study”). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
The commercialization of XPOVIO, for both the multiple myeloma and DLBCL indications, is currently supported by sales representatives and nurse liaisons as well as KaryForward
TM
, an extensive patient and healthcare provider support program. Our commercial efforts are also supplemented by patient support initiatives coordinated by our dedicated network of participating specialty pharmacy providers. We plan to continue to educate physicians, healthcare providers and patients about XPOVIO’s clinical profile and unique mechanism of action as we expand XPOVIO into the second-line plus multiple myeloma market and continue to penetrate the third-line DLBCL market.
XPOVIO also received its first regulatory approval outside the U.S. with an approval received in February 2021 by our partner Promedico Ltd., a member of the Neopharm Group (“Promedico”), for the treatment of patients with multiple myeloma and DLBCL, in Israel. In addition, in January 2021, the European Medicines Agency’s (“EMA”) Committee for Medicinal Products for Human Use (“CHMP”) adopted a positive opinion recommending the conditional approval of NEXPOVIO
®
(selinexor), the expected brand name for selinexor in Europe, based on the results of the Phase 2b STORM Study, which studied selinexor in combination with dexamethasone for the treatment of multiple myeloma in adult patients who have received at least four prior therapies and whose disease is refractory to at least two PIs, two IMiDs and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy. We expect a final decision from the European Commission (the “EC”) on our Marketing Authorization Application (“MAA”) by April 2021. A favorable decision based on our submission through the centralized procedure would be valid in all 27 European
 
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Union (“EU”) member countries as well as the European Economic Area countries of Iceland, Liechtenstein and Norway. Further, we plan to submit a second regulatory filing to the EMA (Type II variation) by April 2021 based on the data from the Phase 3 BOSTON Study, which evaluated once-weekly NEXPOVIO in combination with once-weekly Velcade
®
and
low-dose
dexamethasone in patients with multiple myeloma after at least one prior therapy with the goal of further expanding the global reach of NEXPOVIO to additional patients in need of new treatment options.
Our focus is on marketing XPOVIO in its currently approved indications as well as seeking the regulatory approval and potential commercialization of selinexor as an oral agent in additional cancer indications with significant unmet medical need. We plan to continue to conduct clinical trials and seek additional approvals for the use of selinexor as a single agent or in combination with other oncology therapies to expand the patient populations that are eligible for treatment with selinexor. Thus, we are advancing our clinical development program for selinexor in the areas of multiple hematological malignancies and solid tumors, among others, including the following ongoing or planned selinexor studies:
 
   
Phase 3 SIENDO (
S
elinexor/Placebo After Combination Chemotherapy
I
n Patients with Advanced or Recurrent
ENDO
metrial Cancer) study evaluating once weekly selinexor versus placebo as maintenance therapy in patients with endometrial cancer after first- or second-line chemotherapy (the “SIENDO Study”);
 
   
Phase 2/3 trial evaluating the combination of selinexor and
R-GDP
(rituximab, gemcitabine, dexamethasone, cisplatin) in patients with relapsed or refractory DLBCL. The Phase 3 portion of the study will evaluate the selected dose (as identified in the Phase 2 study) of selinexor or matching placebo given with the standard combination immunochemotherapy
R-GDP
to patients with at least one prior therapy and who are ineligible for high dose chemotherapy and cell-based intervention such as chimeric antigen receptor
T-cell
therapy
(“CAR-T”)
(the
“XPORT-DLBCL-030
Study”);
 
   
Phase 1b/2 STOMP (
S
elinexor and Backbone
T
reatments
o
f
M
ultiple Myeloma
P
atients)
multi-arm
study to evaluate combinations of selinexor with standard therapies in multiple myeloma (the “STOMP Study”);
 
   
Phase 1/2 study of selinexor in combination with standard of care therapy in patients with newly diagnosed or recurrent glioblastoma (“GBM”) (the
“XPORT-GBM-029
Study”);
 
   
Phase 1/2 study of selinexor in combination with ruxolitinib in treatment naïve patients with myelofibrosis (“MF”) (the
“XPORT-MF-034
Study”);
 
   
Phase 2 study of selinexor versus treatment per physician’s choice in participants with previously treated MF (the
“XPORT-MF-035
Study”); and
 
   
Phase 1/2 study to assess the preliminary anti-tumor activity of selinexor in combination with docetaxel in patients with non-small cell lung cancer (“NSCLC”) and with pembrolizumab in patients with colorectal cancer (“CRC”). (the “XPORT-STP-027 Study”).
Additionally, we expect to initiate a number of new clinical trials in 2021, including a Phase 3 study evaluating selinexor in combination with pomalidomide in patients with relapsed or refractory multiple myeloma as well as new Phase 1 and 2 studies evaluating selinexor in patients with a variety of solid tumor indications, including metastatic melanoma, lung cancer and colorectal cancer. A number of these studies will be investigating the treatment of selinexor in combination with other standard of care anti-cancer drugs.
In addition to selinexor, we are also advancing a pipeline of other novel product candidates including the following oral SINE compounds:
 
   
Eltanexor
: We are currently focusing on the development of eltanexor to treat patients with myelodysplastic syndrome (“MDS”) as well as evaluating additional, potential solid tumor indications for future clinical development.
 
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Verdinexor
: We are evaluating verdinexor as a potential therapy for viral, rare disease and autoimmune indications in humans, and our partner Anivive Life Sciences, Inc. (“Anivive”) is evaluating verdinexor as a therapy for cancers in companion animals. As discussed below, in January 2021, Anivive received conditional approval from the FDA for LAVERDIA
-CA1
(verdinexor) as the first oral treatment of canine lymphoma.
 
   
KPT-9274:
We are evaluating
KPT-9274,
an oral inhibitor of
p21-activated
kinase 4 (“PAK4”) and nicotinamide phosphoribosyltransferase (“NAMPT”), to treat patients with hematologic or solid tumors. In July 2020, the first patient was dosed in a Phase 1/2 clinical study of
KPT-9274
in combination with an
anti-PD1
monoclonal antibody.
Key 2020 and Recent Highlights
XPOVIO Franchise
 
   
Received FDA approval in December 2020 (three months ahead of the FDA’s Prescription Drug User Fee Act target action date) for XPOVIO to treat multiple myeloma after at least one prior therapy based on the BOSTON Study, which satisfied the post-approval requirement of a confirmatory trial for the July 2019 accelerated approval of XPOVIO based on the STORM Study.
 
   
Received FDA accelerated approval in June 2020 for XPOVIO for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy.
 
   
National Comprehensive Cancer Network (“NCCN”) added three different XPOVIO combination regimens to its NCCN Guidelines for previously treated multiple myeloma in December 2020.
 
   
Recognized XPOVIO net revenue of $76.2 million in 2020.
 
   
Saw nearly 3,900 XPOVIO prescriptions filled in 2020, driven by demand across both academic and community-based physicians.
 
   
Grew prescription refill rates for XPOVIO with the average number of prescriptions per patient reaching approximately three as of December 31, 2020.
 
   
Received a positive opinion from the CHMP in January 2021 recommending the conditional approval of NEXPOVIO in combination with dexamethasone for the treatment of multiple myeloma in adult patients who have received at least four prior therapies and whose disease is refractory to at least two PIs, two IMiDs and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.
 
   
European Hematology Association and European Society for Medical Oncology (“ESMO”) added selinexor to European multiple myeloma treatment guidelines in November 2020.
Selinexor Pipeline
 
   
Met primary endpoint in Phase 3 SEAL (
Se
linexor in
A
dvanced
L
iposarcoma) study in liposarcoma (the “SEAL Study”) in November 2020 with statistically significant increase in progression free survival (“PFS”) in patients with unresectable dedifferentiated liposarcoma. Data was presented at the Connective Tissue Oncology Society 2020 Annual Meeting.
 
   
Passed planned futility analysis in the SIENDO Study in November 2020 with a recommendation from the Data and Safety Monitoring Board (the “DSMB”) to continue without the need to add additional patients to the trial or to amend the study protocol. Top line data is expected to be available in the second half of 2021.
 
   
Dosed first patient
in February 2021 in Phase 3 confirmatory trial in the
XPORT-DLBCL-030
Study.
 
   
Dosed first patient in June 2020 in the
XPORT-GBM-029
Study.
 
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Collaborations
 
   
Entered into an exclusive distribution agreement in February 2020 with Promedico for the commercialization of XPOVIO in Israel and the Palestinian Authority. In February 2021, Promedico received a principal approval letter from the Israeli Ministry of Health granting approval of XPOVIO for the treatment of patients with either multiple myeloma or DLBCL in Israel.
 
   
Entered into a collaboration, option and license agreement in April 2020 with Curadev Pharma Pvt Ltd (“Curadev”), a privately-owned biotechnology company, to identify and
co-develop
novel small molecules against various biological targets for the treatment of cancer and other major diseases.
 
   
Amended our license agreement with Antengene Therapeutics Limited (“Antengene”) in May 2020 to expand Antengene’s development and commercial rights to our compounds in parts of Asia, Australia and New Zealand and received approximately $10.0 million in regulatory milestones from Antengene in December 2020 following certain regulatory filings by Antengene for selinexor in both multiple myeloma and DLBCL indications in Australia, Singapore and South Korea.
 
   
Entered into a Cooperative Research and Development Agreement (“CRADA”) with the National Cancer Institute’s (“NCI”) Cancer Therapy Evaluation Program in July 2020 to collaborate on studies to investigate the safety and efficacy of selinexor in various oncology indications.
 
   
Entered into an exclusive distribution agreement in December 2020 with FORUS Therapeutics Inc. (“FORUS”) for the commercialization of XPOVIO in Canada and received a $5.0 million upfront payment in December 2020.
 
   
Received, through our partner Anivive, conditional approval from the FDA in January 2021 for LAVERDIA
-CA1
(verdinexor) as the first oral treatment for canine lymphoma.
 
   
Entered into collaboration agreements with partners outside of the U.S. to establish paid named patient programs to provide opportunities to reach additional patients and generate revenue from selinexor indications that have been approved in the U.S. as a bridge to approval in certain geographies.
Corporate Highlights
 
   
Completed a
follow-on
offering in March 2020 pursuant to which we issued an aggregate of 7,187,500 shares of common stock and received aggregate net proceeds of approximately $161.8 million.
 
   
Amended our Open Market Sale Agreement with Jefferies LLC, as agent, in May 2020, pursuant to which we increased the maximum aggregate offering price of shares of our common stock that we may issue and sell from time to time under the agreement from $75.0 million to up to $175.0 million.
 
   
Ended 2020 with $276.7 million in cash, cash equivalents, restricted cash and investments.
Our Strategy
The critical components of our business strategy are to:
 
   
Maximize the Commercial Value of XPOVIO and Our Other Product Candidates.
We are executing on our U.S. commercial capabilities and supporting the ongoing launch of XPOVIO in the U.S. We plan to continue to penetrate the U.S. commercial market and further educate the medical community about the clinical data that support XPOVIO as a treatment for multiple myeloma and DLBCL. Outside of the U.S., subject to approval of selinexor, we will either work with existing and potential partners to establish the requisite commercial infrastructure.
 
   
Continue to Develop and Seek Regulatory Approvals of Selinexor Outside of the U.S.
We, or our current or future partners, continue to seek regulatory approvals of selinexor outside of the U.S. for each indication in which we receive favorable results in a registration-enabling clinical trial.
 
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Maintain Our Competitive Advantage and Scientific Expertise in the Field of Nuclear Transport.
To further our understanding of the role nuclear transport plays in the underlying biology of cancer, as well other diseases, we plan to continue research in the field of nuclear transport and related areas, primarily by fostering relationships with scientific advisors and physicians. We continue to explore a variety of standard and novel combinations of other anti-cancer agents with our SINE inhibitors, and these
non-clinical
studies are anticipated to provide support for new clinical investigations.
 
   
Continue Developing our Pipeline of Novel Product Candidates.
To date, we have identified several drug candidates: our oral SINE compounds selinexor, eltanexor and verdinexor and
KPT-9274.
We may also identify or
in-license
novel product candidates for development in oncology or other indications in the future.
 
   
Maximize the Value of Our SINE Compounds in
Non-Oncology
Indications through Collaborations.
We may seek to enter into global or regional development, marketing, and commercialization collaboration arrangements for our SINE compounds in
non-oncology
indications.
Our XPOVIO Program to Treat Cancer
Overview
According to the World Health Organization, cancer is the second leading cause of death globally and in 2020 was responsible for more than one in six deaths, or an estimated 10 million deaths. Additionally, cancer is one of the most important health issues facing patients in the U.S. The American Cancer Society (“ACS”) estimates that in 2021 there will be nearly 1.9 million new cancer cases in the U.S., with approximately 608,000 Americans expected to die of cancer.
Cancer is a disease characterized by unregulated cell growth. Cancer cells develop when DNA inside the nucleus of normal cells accumulates damage in genes that regulate cell growth and survival. In healthy cells, proteins called tumor suppressor proteins located in the cell nucleus help prevent the accumulation of DNA damage (mutations, chromosomal translocations and other abnormalities) by monitoring DNA for damage, and if damage is detected, the tumor suppressor proteins will direct the cell to attempt to repair it, or if the DNA damage is too severe, the tumor suppressor proteins will direct the cell to die in a process called apoptosis. Accumulation of tumor suppressor proteins in the nucleus of cancer cells allows them to perform their normal role of detecting DNA damage, thereby inhibiting a cancer cell’s ability to divide, and promoting apoptosis.
Many tumor suppressor proteins can only function properly when they are located inside of a cell’s nucleus. Proteins, however, are not made inside the nucleus but rather are made outside of the nucleus in an area called the cytoplasm. A membrane, called the nuclear membrane, separates the nucleus from the cytoplasm. Larger nuclear proteins, including tumor suppressor proteins, must be transported from the cytoplasm where they are made into the nucleus to perform their functions in keeping a cell healthy. Similarly, when they have completed their normal functions, these proteins are typically exported back into the cytoplasm. Proteins move between the nucleus from the cytoplasm through a protein complex embedded in the nuclear membrane called the nuclear pore. The nuclear pore works like a gate through which large molecules, including many other proteins and ribonucleic acids (“RNAs”), enter and exit the nucleus. When molecules enter the nucleus from the cytoplasm, the process is called import, and when molecules exit from the nucleus to the cytoplasm, the process is called export. The import and export of most proteins and other large molecules between the nucleus and cytoplasm require specific carrier proteins to chaperone their cargo molecules through the nuclear pore complex. Carrier proteins, which mediate the import of macromolecules into the nucleus, are called importins, and those which mediate the export of macromolecules out of the nucleus are called exportins. Therefore, the processes of import and export are carried out separately and are typically regulated independently.
One way that cancers evade detection from the body’s own defense mechanisms is by removing tumor suppressor proteins from within the cell nucleus via an overproduction of a specific chaperone protein called
 
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XPO1. XPO1 is one of eight exportins that have been identified in human cells, and it exports over 220 proteins referred to as its “cargo proteins.” In particular, XPO1 appears to be the sole exporter for most of the tumor suppressor proteins including p53, p73, p21, p27, APC, FOXO, pRB and survivin. In addition to exporting tumor suppressor proteins out of the nucleus, XPO1 mediates the nuclear export of a protein called eukaryotic initiation factor 4E, which itself binds to the mRNAs that code for these proteins (“eIF4E” and also called the “mRNA cap binding protein”). eIF4E binds to the mRNAs for many growth-regulating proteins, including
c-myc,
bcl-2,
bcl-6
and cyclin D, and depends on XPO1 to help carry these growth-promoting mRNAs from the nucleus into the cytoplasm where the mRNAs are efficiently translated into proteins. XPO1 also exports the anti-inflammatory (and anti-tumor) protein I
k
B, which inhibits a protein called NF-
k
B. NF-
k
B is found in the nucleus of most cancer cells and plays a role in cancer metastasis and chemotherapy resistance, as well as in many inflammatory and autoimmune diseases.
In nearly all cancer cells, XPO1 levels are reported to be elevated when compared to their healthy cell counterparts. Therefore, these elevated levels of XPO1 in cancer cells mediate the rapid export of tumor suppressor proteins as well as I
k
B and eIF4E out of the nucleus and can lead to reduced monitoring for DNA damage, the normal triggering of apoptosis and increased
NF-
k
B activity. Higher levels of XPO1 expression in cancer cells is also generally correlated with resistance to chemotherapy and poor prognosis in patients.
Mechanism of Action of Our SINE Compounds—Inhibition of XPO1
XPOVIO and our product candidates are novel therapies that are
first-in-class,
oral SINE compounds specifically designed to force nuclear accumulation in the levels of multiple tumor suppressor and growth regulatory proteins. One of the ways a cell regulates the function of a particular protein is by controlling that protein’s location within the cell since certain functions may only occur within a particular location in the cell. As described above, the nuclear pore is a complex gate between the nucleus and cytoplasm, regulating the import and export of most large molecules, called macromolecules, including many proteins, into and out of the nucleus. In healthy cells, nuclear transport, both into and out of the nucleus, is a normal and regular occurrence that is tightly regulated and requires the presence of specific carrier proteins. XPO1 mediates the transport of the majority of tumor suppressor proteins and appears to be the only mediator of nuclear export for these proteins.
XPO1 inhibitors, such as XPOVIO, block the nuclear export of tumor suppressor, growth-regulating, and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. Because normal cells have little or no DNA damage, accumulation of tumor suppressor proteins in their nucleus generally does not lead to apoptosis. The figure below depicts the process by which our SINE compounds inhibit the XPO1-mediated nuclear export of tumor suppressor proteins and oncoprotein mRNAs.
 
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We believe that selinexor’s novel mechanism of action, oral administration and low levels of major organ toxicities observed to date in patients treated with selinexor, along with encouraging efficacy data, support the potential for selinexor’s broad use across many cancer types, including both hematological and solid tumor malignancies. Unlike many other targeted therapeutic approaches that only work for a specific set of cancers or in a specific subgroup of patients, we believe that by restoring tumor suppressor proteins to the nucleus where they can assess a cell’s DNA, our SINE compounds may provide therapeutic benefits across a broad range of both hematological and solid tumor malignancies and can potentially benefit a wider range of patients.
Additionally, and as supported by its mechanism of action, and preclinical, clinical and post-approval data, we believe that selinexor has shown additive or synergistic benefit with approved and experimental therapies in treating cancer patients and, therefore, has the potential to serve as a backbone therapy across multiple hematological and solid tumor malignancies as part of a variety of combination therapies.
Update to NCCN Treatment Guidelines for Patients with Previously Treated Multiple Myeloma
In December 2020, the NCCN added three different XPOVIO combination regimens to its Clinical Procedure Guidelines in Oncology for Previously Treated Myeloma (the “NCCN Guidelines”).
The NCCN Guidelines are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97% of cancers affecting patients in the U.S. and are intended to ensure that all patients receive preventive, diagnostic, treatment and supportive services that will most likely lead to optimal outcomes. The XPOVIO regimens added to the NCCN Guidelines include: (i) selinexor/bortezomib/dexamethasone (once-weekly), which also received a Category 1 recommendation, which represents the highest designation assigned by NCCN, indicating the recommendation is based upon high-level evidence and that there is uniform NCCN consensus that the intervention is appropriate; (ii) selinexor/daratumumab/dexamethasone; and (iii) selinexor/pomalidomide/dexamethasone, which is an
all-oral
treatment regimen.
Summary of Our Pipeline and Key Clinical Trials
Oral selinexor is being evaluated in multiple later-phase clinical trials in patients with hematological and solid tumor malignancies, often in the relapsed and/or refractory setting. In general, relapsed disease refers to disease that progresses following the expiration of a specified period of time after discontinuation of therapy and refractory disease refers to disease that progresses while the patient is on therapy or within a specified period of time after discontinuation of therapy. Key clinical trials of selinexor are summarized in the charts below. In addition to these studies, there are several ongoing investigator-sponsored clinical trials being conducted in a variety of hematological and solid tumor malignancies.
 
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HEMATOLOGICAL MALIGNANCIES
We are currently evaluating XPOVIO in certain hematological malignancies, including multiple myeloma, DLBCL and MF.
Multiple Myeloma
Overview
Multiple myeloma is a hematological malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow, the presence of monoclonal immunoglobulin, also known as M protein, in the serum or urine, bone disease, kidney disease and immunodeficiency. Multiple myeloma is one of the most common types of blood cancer in the U.S. According to the ACS, nearly 35,000 new cases of multiple myeloma will be diagnosed in the U.S. in 2021. It is more common in elderly patients, and most frequently diagnosed among people between ages 65 to 74 years with a median age at diagnosis of 69 years. Despite recent therapeutic advances, there is currently no cure and most patients’ disease will typically progress following treatment with currently available therapies.
The treatment of multiple myeloma has improved over the last 20 years due to the use of high-dose chemotherapy and autologous stem cell transplantation (“ASCT”), which is restricted to healthier, often younger patients, and the subsequent introduction of IMiDs, such as Revlimid
®
(lenalidomide) and Pomalyst
®
(pomalidomide), and PIs such as Velcade
®
(bortezomib), Kyprolis
®
(carfilzomib), and Ninlaro
®
(ixazomib). Three monoclonal antibodies, Darzalex
®
(daratumumab), SARCLISA
®
(isatuximab-irfc), and Empliciti
®
 
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(elotuzumab), and one monoclonal antibody with a toxin conjugate, BLENREP (belantamab mafodotin-blmf), have also been approved, as has the histone deacetylase inhibitor Farydak
®
(panobinostat). The introduction of
non-chemotherapeutic
agents has led to a significant increase in the survival of patients with multiple myeloma. Although a wide variety of newly approved or experimental therapies are being used to treat relapsed and/or refractory patients, including new PIs (oprozomib and marizomiband cellular therapies such as
CAR-T
therapy), nearly all patients will eventually relapse and succumb to their disease. With nearly 12,500 deaths from multiple myeloma in the U.S. alone estimated for 2021 according to the ACS, we believe that there remains a need for therapies for patients whose disease has relapsed after, or is refractory to, available therapy.
Supporting Studies
The BOSTON Study
The December 2020 FDA approval of XPOVIO’s expanded indication as a treatment for patients with multiple myeloma after at least one prior therapy was supported by the results of the BOSTON Study, a multi-center, Phase 3, randomized study conducted at over 150 clinical sites internationally, which evaluated 402 adult patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy. The study was designed to compare the efficacy, safety and certain health-related quality of life parameters of once-weekly XPOVIO in combination with once-weekly Velcade
®
plus
low-dose
dexamethasone (the “XVd Arm”) versus twice-weekly Velcade
®
plus dexamethasone (the “Vd Arm”). The primary endpoint of the study was PFS and key secondary endpoints included overall response rate (“ORR”) and the rate of peripheral neuropathy (“PN”), among others. Additionally, the BOSTON Study allowed for patients on the Vd Arm to crossover to the XVd Arm following objective (quantitative) progression of disease verified by an Independent Review Committee (“IRC”).
Although the study had one of the highest proportions of patients with high-risk cytogenetics (~50%) as compared with other Velcade
®
-based studies in previously treated multiple myeloma, the median PFS in the XVd Arm was 13.9 months compared to 9.5 months in the Vd Arm, representing a 4.4 month (47%) increase in median PFS (hazard ratio of 0.70; p=0.0075). The XVd Arm also demonstrated a significantly greater ORR compared to the Vd Arm (76.4% vs. 62.3%, p=0.0012).
Further, XVd therapy demonstrated a significantly higher rate of deep responses, defined as
³
Very Good Partial Response (“VGPRs”) compared to Vd therapy (44.6% vs. 32.4%) as well as a longer median duration of response (“DOR”) (20.3 months vs. 12.9 months). Additionally, 17% of patients on the XVd arm achieved a Complete Response (“CR”) or a Stringent Complete Response (“sCR”) as compared to 10% of patients receiving Vd therapy. All responses were confirmed by an IRC. Rates of PN were significantly lower for patients receiving XVd therapy compared to those receiving Vd therapy (32% vs. 47%). In addition, PN rates
³
Grade 2 were also significantly lower in the XVd Arm compared to the Vd Arm (21% vs. 34%).
The most common adverse reactions (
³
20%) in patients with multiple myeloma who received XVd were fatigue (59%), nausea (50%), decreased appetite (35%), diarrhea (32%), peripheral neuropathy (32%), upper respiratory tract infection (29%), decreased weight (26%), cataract (22%) and vomiting (21%). Grade 3-4 laboratory abnormalities (
³
10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. In the BOSTON Study, fatal adverse reactions occurred in 6% of patients within 30 days of last treatment. Serious adverse reactions occurred in 52% of patients who received XVd. Treatment discontinuation rate due to adverse reactions was 19%.
Certain subgroup populations of the BOSTON Study were evaluated and reported at the American Society of Hematology (“ASH”) 2020 Annual Meeting. We believe these subgroup evaluations of XVd therapy showed consistent PFS benefit and higher ORR compared to Vd therapy, including in evaluations of the safety and efficacy of XPOVIO (i) in patients previously treated with PIs; (ii) according to the number of prior lines of therapy or prior treatment with Revlimid
®
; (iii) in patients with high risk cytogenetics; and (iv) based on age (patients younger than 65 years old versus older than 65 years old) or by frailty level (frail versus fit).
 
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The STORM Study
The July 2019 FDA approval of XPOVIO to treat patients with penta-refractory multiple myeloma was supported by the results of the STORM Study. This indication was approved under accelerated approval based on response rate. The BOSTON Study served as the confirmatory trial under the FDA’s Accelerated Approval Program and, therefore, the approval of the BOSTON supplemental new drug application in December 2020 fulfilled the accelerated approval requirements of the STORM FDA approval.
The STORM Study was a global, multi-center,
single-arm
Phase 2b clinical trial evaluating oral selinexor in combination with standard,
low-dose
dexamethasone (“Xd”) in patients with heavily pretreated, relapsed or refractory multiple myeloma. These heavily pretreated patients had a median of seven prior therapeutic regimens, including a median of 10 unique anti-myeloma agents. Specifically, the myeloma patients who were eligible for the study had prior treatment with the two PIs, Velcade
®
and Kyprolis
®
, the two IMiDs, Revlimid
®
and Pomalyst
®
, and the anti-CD38 monoclonal antibody Darzalex
®
, as well as alkylating agents, and their disease was refractory to glucocorticoids, at least one PI, at least one IMiD, Darzalex
®
, and their most recent therapy. In all patients, this myeloma was considered “triple-class refractory.” In a subset of 83 patients, their disease was designated as penta-refractory myeloma. In addition to multiple-refractory disease, patients in the STORM Study had rapidly progressing myeloma, with a median 22% increase in disease burden in the 12 days from screening to initial therapy.
For the STORM Study’s primary endpoint, oral selinexor achieved an ORR of 26%, including two (2%) sCRs, six (5%) VGPRs, and 24 (20%) partial responses (“PRs”) and the trial therefore met its primary endpoint. Both patients who had relapsed after
CAR-T
therapy achieved PRs. Minimal response per International Myeloma Working Group (“IMWG”) criteria was observed in 16 (13%) patients and 48 patients (39%) had stable disease. Median time to PR or better was 4.1 weeks. The clinical benefit rate, meaning a minimal response or better, was 39%. All responses were adjudicated by an IRC consisting of four independent experts in the treatment of multiple myeloma.
Median DOR was 4.4 months. PFS was 3.7 months and overall survival (“OS”) was 8.6 months. In the 39% of patients who achieved a minimal response or better, median OS was 15.6 months, compared to a median OS of 1.7 months in patients whose disease progressed or where response was not evaluable.
The most common adverse reactions (
³
20%) in patients with multiple myeloma who received Xd were thrombocytopenia (74%), fatigue (73%), nausea (72%), anemia (59%), decreased appetite (53%), decreased weight (47%), diarrhea (44%), vomiting (41%), hyponatremia (39%), neutropenia (34%), leukopenia (28%), constipation (25%), dyspnea (24%) and upper respiratory tract infection (21%). In the STORM Study, fatal adverse reactions occurred in 9% of patients. Serious adverse reactions occurred in 58% of patients. Treatment discontinuation rate due to adverse reactions was 27%.
The FDA’s accelerated approval of XPOVIO was based upon the efficacy and safety in a
pre-specified
subgroup analysis of the 83 patients in the STORM Study with documented penta-refractory myeloma, as the benefit-risk ratio appeared to be greater in this more heavily
pre-treated
population than in the overall trial population. The ORR in this patient population was 25.3%. Our request for conditional approval in Europe is based upon this same patient population that served as the basis for XPOVIO’s accelerated FDA approval in the U.S.
 
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The STOMP Study
The STOMP Study, an ongoing
multi-arm
Phase 1b/2 clinical trial in patients with relapsed or refractory multiple myeloma, is evaluating selinexor and
low-dose
dexamethasone in combinations with standard therapies, such as Pomalyst
®
, Kyprolis
®
, Revlimid
®
, Velcade
®
, and Darzalex
®
. We presented the following updated clinical data from the STOMP Study at the ASH 2020 Annual Meeting in December 2020, demonstrating that selinexor and
low-dose
dexamethasone plus standard anti-myeloma therapies exhibit encouraging response rates in these combination regimens:
 
 
(1)
Selinexor in Combination with Pomalyst
®
and
Low-dose
Dexamethasone (“XPd”) in Patients with Relapsed or Refractory Multiple Myeloma
In this all oral arm of the Phase 1b/2 STOMP Study, selinexor is being evaluated in combination with Pomalyst
®
 and
low-dose
dexamethasone in patients with relapsed or refractory multiple myeloma who received at least two prior lines of therapy, including a PI and an IMiD. Of note, 25% of the population enrolled in the study had previously received Darzalex
®
. The recommended Phase 2 dose (“RP2D”) was determined to be 60 mg of XPOVIO orally once-weekly, four mg of Pomalyst
®
orally once-daily and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally. The following table is a summary of the efficacy results:
 
 
Best Responses
1
 in Evaluable XPd Patients as of November 14, 2020
2
 
             
Category
 
N
   
ORR*
   
CR
   
VGPR
   
PR
   
Median PFS
 
  Pomalyst
®
 naïve or
non-refractory
    46       25 (54%)       1 (2%)       9 (20%)
3
      15 (33%)
4
      12.3 months  
             
  Pomalyst
®
 refractory
    14       5 (36%)       —         1 (7%)       4 (29%)       Not reported  
             
  RP2D
    20       12 (60%)       —         6 (30%)       6 (30%)       Not reached
5
 
             
  All patients
    60       30 (50%)       1 (2%)       10 (17%)       19 (32%)       12.2 months  
*
ORR = CR+VGPR+PR
1
 
Responses were adjudicated according to the IMWG criteria.
2
 
Based on interim unaudited data.
3
 
Two VGPRs were unconfirmed.
4
 
One PR was unconfirmed.
5
 
Median
follow-up
time for 20 patients at the RP2D was 2.5 months; median
follow-up
time for all 60 patients was 12.2 months.
Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related adverse events (“AEs”) were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common
non-hematologic
treatment-related AEs were nausea (60%), fatigue (51%), decreased appetite (44%), weight loss (38%) and diarrhea (29%), and were primarily grade 1 and 2 events. The most common treatment-related Grade 3 and 4 AEs were neutropenia (54%), anemia (33%), and thrombocytopenia (32%).
Based on these Phase 2 results, we plan to initiate a Phase 3 study investigating the XPd combination in 2021. Historical clinical trials evaluating the efficacy of Pomalyst
®
 and
low-dose
dexamethasone in less heavily pretreated populations (i.e., without prior Darzalex
®
 therapy) have demonstrated an ORR of 29% and median PFS of 3.6 months, as highlighted in the Pomalyst
®
 U.S. Full Prescribing Information.
 
 
(2)
Selinexor in Combination with Kyprolis
®
and
Low-dose
Dexamethasone (“XKd”) in Patients with Relapsed or Refractory Multiple Myeloma
 
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In this arm of the Phase 1b/2 STOMP Study, oral selinexor is being evaluated in combination with Kyprolis
®
 and
low-dose
dexamethasone in patients with relapsed or refractory multiple myeloma who have received at least two prior therapies, including a PI, one or more IMiDs (e.g., Revlimid
®
 or Pomalyst
®
) or Darzalex
®
. In these heavily pretreated patients, 100% had previously received Velcade
®
, 96% had previously received Revlimid
®
, 67% had previously received Pomalyst
®
 and 63% had previously received Darzalex
®
. The RP2D was determined to be 80 mg of XPOVIO orally once-weekly, 56 mg/m
2
 of Kyprolis
®
once-weekly and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally and enrollment continues using this regimen. The median PFS was 23.7 months for all patients. The following table is a summary of the efficacy results:
 
 
Best Responses
1
 in Evaluable XKd Patients as of October 1, 2020
2
 
           
Category
  
N
    
ORR
    
CR
    
VGPR
    
PR
 
  All
     24        18 (75%)        5 (21%)        8 (33%)        5 (21%)  
1
 
Responses were adjudicated according to the IMWG criteria.
2
 
Based on interim unaudited data.
Among the patients evaluated for safety as of the data cutoff date, the most common treatment-related AEs were cytopenias, along with gastrointestinal, constitutional and other symptoms; most were manageable with dose modifications and/or standard supportive care. The most common
non-hematologic
treatment-related AEs were nausea (71%), fatigue (58%), decreased appetite (50%) and weight loss (46%), and were mostly Grade 1 and 2 events. The most common treatment-related Grade
³
3 AEs included thrombocytopenia (58%), anemia (21%) and leukopenia (13%).
We are encouraged by these results, which indicate that the once weekly combination of XKd may induce beneficial response rates in patients with heavily pretreated double or triple class refractory multiple myeloma.
 
 
(3)
Selinexor in Combination with Revlimid
®
and
Low-dose
Dexamethasone (“XRd”) in Patients with Newly Diagnosed and Relapsed or Refractory Multiple Myeloma
In this all oral arm of the Phase 1b/2 STOMP Study, selinexor is being evaluated in combination with Revlimid
®
 and
low-dose
dexamethasone in patients with newly diagnosed or previously treated multiple myeloma. The previously treated patients received at least one prior therapy, which may include prior Revlimid
®
, as long as the patient’s myeloma was not refractory to Revlimid
®
. The RP2D was determined to be 60 mg of XPOVIO orally once-weekly, 25 mg of Revlimid
®
orally once daily, and 40 mg once weekly or 20 mg twice weekly of dexamethasone orally. The following table is a summary of the efficacy results:
 
 
Best Responses
1
 in Evaluable XRd Patients as of October 1, 2020
2
 
           
Category
 
N
   
ORR
   
CR
   
VGPR
   
PR
 
  Revlimid
®
-naïve relapsed or refractory myeloma
    12       11 (92%)       1 (8%)       4 (33%)       6 (50%)
3
 
  Revlimid
®
-treated/refractory myeloma
    8       1 (13%)       —         —         1 (13%)  
           
  Newly diagnosed (efficacy evaluable)
    7
4
 
    7 (100%)       1 (14%)       4 (57%)
5
      2 (29%)  
1
 
Responses were adjudicated according to the IMWG criteria.
2
 
Based on interim unaudited data.
3
 
Two PRs were unconfirmed.
4
 
One patient’s efficacy not evaluable due to withdrawal of consent during cycle 1.
5
 
One VGPR was unconfirmed.
Responses were highly durable with four relapsed or refractory patients remaining on study with PFS of greater than 35 months and two newly diagnosed patients remaining on study with PFS of greater than 24 months.
 
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Among the newly diagnosed patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common
non-hematologic
treatment-related AEs were fatigue (63%), weight loss (63%), diarrhea (63%), nausea (50%) and insomnia (38%) and were mostly Grade 1 and 2 events. The most common Grade
³
3 AEs were neutropenia (75%), anemia (50%) and thrombocytopenia (38%).
Among the relapsed or refractory patients evaluable for safety, the most common treatment-related AEs were cytopenias, along with gastrointestinal and constitutional symptoms; most were manageable with dose modifications and/or standard supportive care. The most common
non-hematologic
treatment-related AEs were nausea (58%), fatigue (54%), decreased appetite (50%), weight loss (42%), and diarrhea (33%), and were mostly Grade 1 and 2 events. The most common Grade
³
3 AEs were thrombocytopenia (63%), neutropenia (63%), anemia (17%) and fatigue (17%).
We are encouraged by these results, which indicate that the all oral regimen of weekly selinexor with standard Revlimid
®
 and dexamethasone may induce high response rates with good tolerability.
Diffuse Large
B-Cell
Lymphoma
Overview
DLBCL is a form of
Non-Hodgkin’s
lymphoma (“NHL”), a cancer that starts in cells called lymphocytes, which are part of the body’s immune system. Lymphocytes are found in the lymph nodes and other lymphoid tissues, such as the spleen and bone marrow, as well as in the blood. NHL is one of the most common cancers in the U.S., accounting for approximately 4% of all cancers. In 2021, the ACS estimates that more than 81,000 people will be diagnosed with NHL and approximately 20,000 deaths will result from the disease. DLBCL is the most common and most aggressive type of NHL, making up approximately 18,000 of the new cases diagnosed annually in the U.S. Most often, newly diagnosed patients are currently cured with front-line (typically
“R-CHOP”
chemotherapy). Despite the recent approval of
CAR-T
therapy, many patients with relapsed or refractory DLBCL are not medically stable enough to undergo
CAR-T
therapy and additional treatment options are necessary to address this continued unmet medical need.
In 2019, the FDA granted accelerated approval to the triplet therapy polatuzumab vedotin, bendamustine, rituximab, known as PBR, for the treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified after at least two prior therapies. The FDA also approved Monjuvi
®
 (tafasitamab-cxix) in July 2020 in combination with lenalidomide for the treatment of adult patients with relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for ASCT.
Supporting Studies
The SADAL Study
In June 2020, the FDA approved XPOVIO as the only single-agent oral treatment of adult patients with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. This approval was supported by the results of the SADAL Study, an open-label Phase 2b clinical trial evaluating single-agent oral selinexor (60 mg, twice weekly) in patients that had relapsed or refractory DLBCL after at least two prior multi-agent therapies and who were ineligible for transplantation, including high dose chemotherapy with stem cell rescue. In this population, XPOVIO demonstrated an ORR of 29%, including a CR rate of 13%. Responses were seen in all subgroups evaluated regardless of age, gender, prior therapy, DLBCL subtype or prior stem cell transplant therapy. Patient responses were durable with a median DOR of 9.3 months (23.0 months for patients who achieved a CR). Importantly, responses were associated with longer survival, underscoring the potential of oral XPO1 inhibition as an oral,
non-chemotherapeutic
option for patients with relapsed or refractory DLBCL.
 
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The most common adverse reactions (
³
20%) in patients with DLBCL who received XPOVIO were fatigue (63%), nausea (57%), diarrhea (37%), decreased appetite (37%), decreased weight (30%), constipation (29%), vomiting (28%), and pyrexia (22%).
Grade 3-4
laboratory abnormalities (
³
15%) are thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. In the SADAL Study, fatal adverse reactions occurred in 3.7% of patients within 30 days of last treatment. Serious adverse reactions occurred in 46% of patients who received XPOVIO. Treatment discontinuation rate due to adverse reactions was 17%.
Other DLBCL Studies
During 2021, we expect to conduct the following two studies in DLBCL:
 
   
The
XPORT-DLBCL-030
Study
, which will serve as a confirmatory study for the June 2020 FDA accelerated approval of XPOVIO to treat DLBCL based on the SADAL Study, is a Phase 2/3 multi-center, randomized study evaluating the combination of selinexor and
R-GDP
in patients with relapsed or refractory DLBCL. The Phase 3 portion of the study will evaluate the selected dose (as identified in the Phase 2 study) of selinexor or matching placebo given with the standard combination immunochemotherapy
R-GDP
to patients with at least one prior therapy and who are ineligible for high dose chemotherapy and cell-based intervention such as
CAR-T.
The primary endpoint of the Phase 3 portion of the
XPORT-DLBCL-030
Study is PFS. The first patient in this study was dosed in February 2021.
 
   
The
XPORT-DLBCL-025
Study
is a Phase 1/2
multi-arm
study of selinexor in combination with backbone treatments or novel therapies for the treatment of DLBCL. The first clinical trial site for the
XPORT-DLBCL-025
Study was activated in November 2020 and we plan to initiate this study in 2021. This study will inform the use of selinexor with a variety of additional agents including novel/novel combinations for the treatment of DLBCL.
Myelofibrosis
Primary MF is a rare blood cancer in which excessive scar tissue (fibrosis) forms in the bone marrow and impairs its ability to produce normal blood cells. As a result, blood cell production may move to the spleen (causing spleen enlargement) or to other areas of the body. The incidence of MF is estimated to be approximately 1.5 cases per 100,000 people in the U.S. with a median OS of 69 months. MF is more common in older patients with a median age at diagnosis of approximately 65 years.
Allogeneic hematopoietic stem cell transplantation (“HSCT”) is currently the only treatment for MF that can provide a clinical cure; patients who are not good candidates for HSCT should receive a JAK2 inhibitor, such as ruxolitinib or fedratinib to reduce spleen volume and improve symptoms. However, not all patients respond adequately to JAK2 inhibitors, and some patients cannot tolerate treatment or progress on treatment.
In preclinical studies, XPO1 inhibition by selinexor selectively suppressed colony formation in MF cells, including those exposed to prior JAK2 inhibitors, compared with normal CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and cancer cell death. In an MF mouse model, the combination of selinexor and ruxolitinib improved responses compared with monotherapy, including reductions of mutant cells and restoration of splenic architecture. This formed the preclinical rationale for investigating selinexor in patients with MF. In 2021, we plan to initiate the
XPORT-MF-034
Study, a Phase 1/2 open-label, multicenter study of selinexor to evaluate the safety and efficacy of selinexor in combination with ruxolitinib in treatment naïve patients with MF and the
XPORT-MF-035
Study, a Phase 2, randomized, open-label, multicenter study to evaluate the safety and efficacy of single agent selinexor versus treatment of physician’s choice in patients with previously treated MF.
 
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Other Hematologic Malignancies
Myelodysplastic Syndromes
MDS is a group of hematologic malignancies whereby the bone marrow does not make enough healthy blood cells (white blood cells, red blood cells, and platelets) and there are abnormal cells in the blood and/or bone marrow. The median OS of patients with high-risk MDS refractory to hypomethylating agents is less than six months and, currently, no standard therapy for such patients exists. In August 2020, safety and efficacy results from a
single-arm
investigator sponsored Phase 2 study of selinexor in patients with MDS or oligoblastic acute myeloid leukemia refractory to hypomethylating agents were published in the journal
The Lancet Haematology
. According to
The Lancet Haematology
publication, preclinical studies have shown that inhibition of XPO1 causes nuclear accumulation of p53 and disruption of
NF-
k
B signaling, both relevant targets for MDS. In the 23 patients evaluable in the clinical study, the ORR was 26% (95% CI 10 – 48); six patients had a marrow complete remission and an additional 12 patients (52%, 95% CI 31 – 73) had stable disease. The most common grade 3 or 4 AEs were thrombocytopenia (32%; 8/25 patients) and hyponatraemia (20%; 5/25 patients). There were no drug-related serious AEs and no treatment-related deaths. Based on these data and the data from a Phase 1 study of eltanexor, as discussed further below, we intend to enroll additional patients in single-agent and combination studies to evaluate eltanexor to treat MDS.
SOLID TUMOR MALIGNANCIES
Solid tumors represent the vast majority of cancer incidences. Given the large patient population with solid tumors and the mechanistic activity of selinexor that makes it potentially suitable for treating any type of cancer, we are developing selinexor to potentially play a meaningful role across multiple solid tumor indications, either alone or in combination as a backbone therapy. We have seen encouraging single-agent data for selinexor in a variety of solid tumors including PRs and durable stable disease (“SD”) with disease control greater than three months. Our Phase 2/3 study in patients with dedifferentiated liposarcoma demonstrated statistically significant prolonged PFS of heavily pretreated patients and our Phase 2 studies of selinexor in gynecological malignancies and GBM also demonstrated anti-cancer activity, including bona fide PRs as well as prolonged SD. Given the promising single-agent activity in
difficult-to-treat
indications and the potential to enhance activity in combination with existing therapies, we are currently developing selinexor in unmet needs such as liposarcoma, endometrial cancer and GBM.
In addition, we believe that the results of clinical data from investigator-sponsored studies evaluating selinexor in combination with certain established cancer therapies warrant further research into the potential utility of selinexor in solid tumors and will help us further prioritize future clinical development activities. For example, in September 2020, clinical data were presented at the ESMO Virtual Congress from advanced solid tumor studies evaluating selinexor in combination with established cancer therapies including combination data with (i) pembrolizumab for the treatment of melanoma; (ii) carboplatin and paclitaxel for the treatment of advanced or metastatic solid tumors; and (iii) topotecan for the treatment of advanced or metastatic solid tumors.
We plan to continue to develop selinexor in combination with standard of care anti-cancer drugs, including immunotherapies, with a particular interest in lung cancer, brain cancer, metastatic melanoma and colorectal cancer.
Liposarcoma
Overview
Liposarcoma is a rare cancer of connective tissues that resemble fat cells under a microscope and represents up to 18% of all soft tissue sarcoma, or approximately 2,000 new cases in the U.S. per year. Current treatment of liposarcoma largely includes a combination of radiation therapy and surgery, with or without chemotherapy. Dedifferentiated liposarcoma is an aggressive form of soft tissue sarcoma that is resistant to both standard
 
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chemotherapy and radiation. Liposarcoma has a particularly high rate of recurrence following surgery, especially in cases involving the abdomen. Except for cases that are cured with surgery, most patients with metastatic liposarcoma will succumb to this disease, and novel therapies are needed.
The SEAL Study
In November 2020, we announced positive
top-line
results from the Phase 3 portion of the randomized, double blind, placebo-controlled, cross-over, SEAL Study conducted in North America and Europe in patients with unresectable dedifferentiated liposarcoma. Patients in this study were randomized 2:1 to receive either oral selinexor (60 mg twice weekly) until disease progression or intolerability, or placebo. The SEAL Study met its primary endpoint of a statistically significant increase in PFS (hazard ratio=0.70; p=0.023) as assessed by the Independent Central Radiological Review committee based on RECIST v1.1. We believe these data indicate that treatment with selinexor reduced the risk of disease progression by approximately 30%, compared to placebo. The trial allowed patients on placebo with objective progression to cross over to the selinexor treatment arm. Among those patients who received selinexor, there was a trend towards an improvement in the median OS compared to those patients who began on the placebo arm of the study and never crossed over to the selinexor treatment arm of the study. The safety profile for selinexor was consistent with previous clinical studies with fewer hematologic and infection-related AEs as compared to selinexor studies in patients with multiple myeloma and DLBCL.
Based on preliminary regulatory feedback, expected cost, commercial potential, and strategic priorities, we are currently evaluating the optimal approach and next steps towards making selinexor available to patients with dedifferentiated liposarcoma, including potentially pursuing a strategy of presenting clinical data to support the use of selinexor in patients with unresectable dedifferentiated liposarcoma as a medically accepted indication in published drug compendia.
Endometrial Cancer
Overview
Endometrial cancer, also called uterine cancer, occurs when cells in the endometrium, which is the inner lining of uterus, begin to grow out of control. In the U.S., endometrial cancer is the most common cancer of the female reproductive organs. The ACS estimates that there will be approximately 60,000 new cases of endometrial cancer diagnosed in 2021 in the U.S., with approximately 11,600 deaths. Endometrial cancer affects mainly post-menopausal women and the average age of women diagnosed with endometrial cancer is 60. Endometrial cancer is often detected at an early stage because it frequently produces abnormal vaginal bleeding. There are currently five different types of standard treatment for patients with endometrial cancer; surgery, radiation therapy, chemotherapy, hormone therapy and targeted therapy.
The SIENDO Study
The SIENDO Study is an ongoing multicenter, randomized, double-blinded Phase 3 study evaluating the efficacy and safety of selinexor versus placebo as a maintenance therapy in patients with advanced or recurrent endometrial cancer following at least one prior platinum-based combination chemotherapy treatment. Participants with primary stage IV or recurrent disease who had a PR or CR after at least 12 weeks of standard taxane-platinum combination chemotherapy are randomized in a 2:1 manner to receive either maintenance therapy of 80 mg of XPOVIO taken once per week or placebo, until disease progression. The primary endpoint in the study is PFS with the goal of the study demonstrating a hazard ratio of 0.6.
In November 2020, following a
pre-specified
interim futility analysis for the SIENDO Study, the DSMB recommended that the study should continue, as previously planned, without the need for adding additional patients to the trial or amending the study protocol. As of the date of the planned futility analysis, 109 patients of the expected 248 patients had been enrolled in the trial. We currently expect to report topline data from the SIENDO Study in the second half of 2021.
 
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This trial was designed based on the data from a Phase 2, open-label study of efficacy and safety of oral selinexor in patients with heavily
pre-treated,
progressive gynecological cancers (the “SIGN Study”). In December 2019, the full results from the SIGN Study in patients with recurrent gynecological malignancies were published in
 Gynecologic Oncology
. According to the published data, the SIGN Study showed selinexor’s promising anti-tumor activity and disease control in gynecological malignancies. Of the 66 patients with ovarian cancer, 20 patients (30%) had disease control, meaning PR or SD for at least 12 weeks, including seven patients (11%) with a PR. The median DOR for patients that achieved a PR was 7.4 months. Median PFS for all patients with ovarian cancer was 2.6 months and median OS was 7.3 months. Of the 23 patients with endometrial cancer, eight (35%) had disease control (three PRs and five with SD for at least 12 weeks). Median PFS for the endometrial cancer arm was 2.8 months and median OS was 7.0 months. Across all arms, the most common AEs were nausea (71%), fatigue (68%), decreased appetite (57%), vomiting (53%), weight loss (48%), anemia (36%), and thrombocytopenia (34%), which were managed with supportive care and dose modifications. Notably, fewer Grade 3 and 4 AEs occurred in patients receiving once weekly compared to twice weekly selinexor, with equivalent efficacy.
Glioblastoma Multiforme
Overview
GBM is one of the most common and particularly aggressive forms of brain tumors of primarily glial cell origin, accounting for 48% of all primary malignant brain tumors. Patients with GBM face significant morbidity and mortality rates, with over 10,000 deaths per year in the U.S. GBM is an incurable disease and the prognosis for patients is typically poor due, in part, to its aggressive and extensive infiltration of surrounding central nervous system tissue and its frequent inaccessibility for surgical resection within the brain. In addition, the blood-brain barrier presents an obstacle for many chemotherapeutic agents, with only small, lipophilic molecules able to reach the tumor. The median age of diagnosis in patients is 64 years old, but GBM can occur at any age, including in childhood. Median survival in patients with newly diagnosed GBM is approximately 15 months and approximately five to seven months in patients with recurrent disease. GBM is a disease with high unmet need, with existing treatments having very limited success in increasing overall surviving rates. The current standard of care for GBM patients includes surgery, radiation therapy, and chemotherapy. Currently approved drug treatments for GBM include temozolomide and Avastin
®
(bevacizumab). Despite these treatment options, most patients diagnosed with GBM will quickly succumb to the disease and novel therapies are needed.
XPO1 is frequently overexpressed in both GBM and in high-grade gliomas and therefore may be an important, novel target in the treatment of patients with GBM. The degree of XPO1 over-expression correlates with higher tumor grade and poor overall patient survival. Nonclinical studies indicate that selinexor has potent
anti-GBM
activity as monotherapy and is synergistic when combined with radiation, temozolomide and lomustine. Additionally, in our previous clinical study known as the KING study, selinexor demonstrated that it crosses the blood-brain barrier with adequate intra-tumoral penetration and single-agent efficacy with durable response and disease stabilization in heavily pretreated GBM patients, which we believe supports the rationale for further clinical development of selinexor to treat patients with brain cancers.
The
XPORT-GBM-029
Study
We are currently conducting a global Phase 1/2 clinical study evaluating oral selinexor in combination with standard of care therapy in patients with newly diagnosed or recurrent GBM, which is expected to enroll approximately 400 patients at clinical sites in the U.S., Europe, and Israel. In June 2020, we dosed the first patient in this study. This study is expected to be conducted in two phases: a Phase 1 dose finding study followed by a Phase 2 randomized efficacy exploration study, designed to independently evaluate three different combination regimens in three treatment arms in patients with newly diagnosed GBM (Arms A and B) or with recurrent GBM (Arm C). Arms A and B will investigate selinexor in combination with radiation therapy with or without the addition of temozolomide, while Arm C will evaluate the combination of selinexor and lomustine. The primary endpoints in the study are PFS in patients with newly diagnosed GBM and OS in patients with recurrent GBM.
 
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OUR OTHER PIPELINE PROGRAMS
In addition to selinexor, we are also advancing a pipeline of novel drug candidates including our other oral SINE compounds eltanexor, verdinexor and
KPT-9274.
Eltanexor
(KPT-8602)
Eltanexor is a second-generation SINE compound that, like selinexor, selectively blocks the nuclear export protein XPO1. The mechanism of action for the biological (anti-cancer) activity of eltanexor is similar to selinexor. However, eltanexor differs from selinexor primarily because it has been confirmed to have much lower brain penetration in preclinical species, when compared with selinexor. Therefore, eltanexor may cause fewer side effects, particularly those mediated through the central nervous system such as nausea, fatigue and anorexia in humans. Following oral administration, animals treated with eltanexor showed a lower percentage of body weight loss and improved food consumption, as well as less “fatigue behavior,” in comparison to animals similarly treated with selinexor. This allows for more frequent dosing of eltanexor, enabling a longer period of exposure at higher levels than is possible with selinexor.
In many preclinical studies, an extended dosing regimen led to superior efficacy in comparison to selinexor treatment.
As a result, we believe that eltanexor represents a potent, efficacious second-generation oral SINE compound and are currently evaluating its safety, tolerability and efficacy in humans.
We currently plan to focus our clinical development of eltanexor in patients with MDS and are conducting a
first-in-human
Phase 1/2 clinical trial for eltanexor in patients with relapsed or refractory multiple myeloma, metastatic colorectal cancer, metastatic castration resistant prostate cancer, and higher risk refractory MDS to determine the safety, preliminary efficacy, and RP2D of eltanexor in patients with these advanced cancers.
At the ASH 2019 annual meeting, positive data was presented from the Phase 1/2 study evaluating the safety, tolerability and anti-tumor activity of single-agent oral eltanexor (10 mg or 20 mg once-daily for five days per week) in elderly patients with higher-risk MDS with disease refractory to hypomethylating agents. Of the 15 patients evaluable for efficacy, seven patients had a marrow CR indicating an ORR of 47%. An additional five patients (33%) achieved SD as their best response for a total disease control rate of 80% in evaluable patients. Median OS in patients receiving a 20 mg dose was 10.6 months. The most common treatment-related AEs were hematologic, gastrointestinal and constitutional. The most common
non-hematologic
treatment-related AEs were nausea (45%), decreased appetite (40%), fatigue (35%), diarrhea (35%) and dysgeusia (25%); the vast majority were Grade 1 or 2. The most common Grade
³
3 AEs were anemia (30%), neutropenia (25%), thrombocytopenia (20%) and leukopenia (15%). AEs were dose-dependent and generally managed with supportive care and dose modification. This Phase 1/2 study remains ongoing. Based on these data, we plan to amend the existing Phase 1/2 study protocol to evaluate eltanexor in combination with oral hypomethylating agents in patients with newly diagnosed or previously treated MDS. The novel combination arms are expected to begin enrollment in 2021.
Verdinexor
(KPT-335)
Lymphoma in Companion Canines
We have used spontaneously occurring canine cancers as a surrogate model for human malignancies. It is widely known that canine lymphomas are similar in many ways to the
non-Hodgkin’s
lymphomas in humans, display a comparable genetic profile and respond to chemotherapy in a fashion similar to their human counterparts. Lymphomas are one of the most common tumors in dogs and are very aggressive where, without treatment, the tumors are often fatal within weeks. The majority of canine lymphomas are DLBCL and most of the others are
T-cell
lymphomas. Given the similarities of dog and human lymphomas, prior to initiating clinical trials of selinexor in humans, we investigated verdinexor, a closely related, orally available SINE compound, in dogs with lymphomas.
 
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In May 2017, we entered into an exclusive licensing agreement with Anivive, a privately-held biotech company focused on innovations in the veterinary drug and bioinformatics space, pursuant to which Anivive received worldwide rights to research, develop and commercialize verdinexor for the treatment of cancer in companion animals. In January 2021, Anivive received conditional FDA approval of LAVERDIA
-CA1
(verdinexor) to treat dogs with lymphoma through the Minor Use/Minor Species pathway, which is an option for drugs intended for minor uses in major species, such as dogs, or for minor species. Verdinexor is the first conditionally approved oral treatment for dogs with lymphoma.
Tanovea-CA1,
an injectable product, is currently the only other treatment for lymphoma in dogs. Anivive has five years to complete effectiveness studies to support a full approval of verdinexor in this indication.
The recent approval of verdinexor was supported by a Phase 2b clinical trial conducted with 58 pet dogs with
B-
or
T-cell
lymphoma who were either newly-diagnosed or who were in their first relapse after chemotherapy and were followed for at least eight months. Seventeen of the 58 dogs (29%) did not show progression of lymphoma for at least 56 days after taking verdinexor. Three of these dogs did not show any progression for at least 182 days. The most common adverse reactions associated with verdinexor were anorexia, vomiting, diarrhea, weight loss, lethargy, increased water intake, increased urination, elevated liver enzymes, and low platelet count.
Viral, Rare Disease and Autoimmune Indications
In addition to canine lymphoma, verdinexor is being evaluated as a potential therapy for viral, inflammatory, and autoimmune indications. Several autoimmune indications are driven by aberrant
pro-inflammatory
responses, particularly uncontrolled
pro-inflammatory
cytokine expression and
NF-kB
activation. These include systemic lupus erythematosus (“SLE”), a primary focus of our work with verdinexor. The National Institute of Health funded project completed preclinical evaluation of verdinexor as a treatment for SLE and positioned the SLE program as Investigational New Drug (“IND”) ready.
In addition, several viruses exclusively utilize XPO1 to shuttle cargos necessary for viral replication, such as viral and host proteins from the nucleus to the cytoplasm. Due to the stability of host gene targets compared to viruses which rapidly adapt for best fitness in hosts, targeting host genes may offer an approach to limit drug resistance.
In 2015, we conducted a randomized, double-blind, placebo-controlled, dose-escalating Phase 1 clinical trial of verdinexor in healthy human volunteers in Australia. This study was designed to evaluate the safety and tolerability of verdinexor in healthy adult subjects. Mild to moderate AEs of similar grade and in an equivalent percentage of patients as placebo were reported, and no serious or severe AEs were observed.
As part of an exclusive license agreement we entered into with Antengene in May 2018, and as amended in May 2020, Antengene maintains the exclusive rights to develop and commercialize verdinexor for the diagnosis, treatment and/or prevention of certain human
non-oncology
indications in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam, Australia and New Zealand. Antengene has reported that it intends to conduct clinical trials of verdinexor for the treatment of chronic active Epstein Barre infection and SLE.
We plan to continue to explore strategies to pursue the clinical development of verdinexor as a treatment for viral, inflammatory, and autoimmune indications, including potentially partnering with additional collaborators or through government-funded grant or contract opportunities.
KPT-9274
KPT-9274
is our
first-in-class
dual inhibitor of PAK4 and NAMPT.
KPT-9274
is an orally bioavailable small molecule that we believe could play an important role in cancer development by targeting the two proteins PAK4 and NAMPT. PAK4 is a signaling protein regulating numerous fundamental cellular processes, including
 
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intracellular transport, cellular division, cell shape and motility, cell survival, immune defense and the development of cancer. PAK4 interacts with many key signaling molecules involved in cancer such as beta-catenin, CDC42,
Raf-1,
BAD and myosin light chain. NAMPT, also known as PBEF or Visfatin, is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor, and hormone that can be found in complex with PAK4 in the cell. NAMPT is of interest as an oncology target because it catalyzes the rate-limiting step in one of the two intracellular salvage pathways that generate nicotinamide adenine dinucleotide, a universal energy- and signal-carrying molecule involved in mitochondrial function, energy metabolism, calcium homeostasis, antioxidation, and paradoxically generation of oxidative stress, gene expression, immunological functions, aging, and cell death.
Co-inhibition
of PAK4 and NAMPT may lead to synergistic anti-tumor effects through energy depletion, inhibition of DNA repair, cell cycle arrest, inhibition of proliferation, and ultimately apoptosis. Normal cells are more resistant to inhibition by
KPT-9274
due in part to their relative genomic stability and lower metabolic rates. Hematologic and solid tumor cells that have become dependent on both PAK4 and NAMPT pathways may be susceptible to single-agent cytotoxicity of
KPT-9274.
KPT-9274
has shown broad evidence of anti-cancer activity against hematological and solid tumor malignant cells while showing minimal toxicity to normal cells in vitro. In mouse xenograft studies, oral
KPT-9274
has shown evidence of anti-cancer activity and tolerability. To our knowledge, we are the only company with an allosteric PAK4 modulator and/or NAMPT specific inhibitor currently in clinical development.
KPT-9274
is currently being evaluated in a Phase 1 open-label study in patients with advanced solid malignancies or
non-Hodgkin’s
lymphoma. As of February 2021, patient enrollment continues in Part C of the trial evaluating the combination of
KPT-9274
and Opdivo
®
(nivolumab) in patients with melanoma who progressed on an
anti-PD-1
or
anti-PD-L1
antibody in a prior line of therapy.
The Potential of Our SINE Compounds in Settings Beyond Oncology
In addition to cancer, our SINE compounds have demonstrated the potential to provide therapeutic benefit in a number of other indications, such as viral infections, neurological disorders, inflammation and autoimmune diseases. For example, in January 2018, we entered into an Asset Purchase Agreement with Biogen MA Inc., a subsidiary of Biogen Inc. (“Biogen”), pursuant to which Biogen acquired
KPT-350,
which has been renamed by Biogen as BIIB100, an IND application-ready, oral SINE compound with a preclinical data package supporting potential efficacy in a number of neuro-inflammatory conditions, as well as certain related assets with an initial focus in amyotrophic lateral sclerosis (“ALS”). XPO1 mediates the nuclear export of multiple proteins that impact neurological and inflammatory processes. Consequently, inhibition of XPO1 by BIIB100 has shown a reduction in inflammation and an increase in anti-inflammatory and neuroprotective responses. BIIB100 penetrates the blood brain barrier to a greater degree than other SINE compounds. Preclinical data generated largely by external collaborators show efficacy of BIIB100 and related SINE compounds in animal models of ALS, multiple sclerosis, traumatic brain injury, epilepsy, and other neuro-inflammatory indications. Biogen is currently conducting a Phase 1 double-blind, placebo-controlled, single-ascending-dose study to evaluate the safety, tolerability and pharmacokinetics and pharmacodynamics of BIIB100 administered orally to adult patients with ALS.
The accumulation of I
k
B in the nucleus inhibits
NF-
k
B, which may be beneficial in overcoming chemotherapy resistance and in treating autoimmune, inflammatory, and neuro-inflammatory disease, has been detected in both preclinical models and in human cancer tissues from treated patients.
SINE compounds have also demonstrated activity in animal models of viral diseases, certain rare diseases and other indications, and we are continuing to develop programs in these areas largely through academic collaborations and
non-dilutive
funding opportunities with the intent to
out-license
these programs for clinical development and future commercialization.
 
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Uncertainty Relating to the
COVID-19
Pandemic
The COVID-19
pandemic has and will continue to affect economies and businesses around the world. We continue to closely monitor the impact of the
COVID-19
pandemic on all aspects of our business, including the impact on our employees, patients and business operations. We have and may continue to experience disruptions in the future that could impact our results of operations, including product revenue, and financial condition. Although we do not currently expect that the ongoing
COVID-19
pandemic will have a material impact on our business plans or results of operations, we are unable to predict the impact that the
COVID-19
pandemic will have on our operating results and financial condition due to numerous uncertainties. These uncertainties include the availability and effectiveness of vaccines and therapeutics, the duration and scope of the pandemic, the severity of the virus, governmental, business or other actions, travel restrictions and social distancing, business closures or business disruptions, or changes to our operations, among others. We will continue to monitor
the COVID-19
situation closely and intend to follow health and safety guidelines as they evolve. Further, the impacts of a potential worsening of global economic conditions and the continued disruptions to, and volatility in, the credit and financial markets, as well as other unanticipated consequences remain unknown. The situation surrounding
the COVID-19
pandemic remains fluid and continues to rapidly evolve, and we are actively managing our response and assessing potential impacts to our operating results and financial condition, as well as adverse developments in our business.
Collaboration, License and Other Strategic Agreements
We have formed, and intend to continue to form, strategic alliances to develop and commercialize our products and product candidates. We enter into collaborations when there is a strategic advantage to us and when we believe the financial terms of the collaboration are favorable for meeting our short- and long-term strategic objectives. Currently, we maintain complete commercial rights to selinexor in the U.S., Europe, Japan, and Latin America and have entered into the following key agreements:
Antengene
In May 2020, we entered into an amendment of our May 2018 license agreement with Antengene (the “Original Antengene Agreement”, and, as amended the “Amended Antengene Agreement”). Antengene is a corporation organized and existing under the laws of Hong Kong, and a subsidiary of Antengene Corporation Co. Ltd., a corporation organized and existing under the laws of the People’s Republic of China. Under the terms of the Amended Antengene Agreement, Antengene has the exclusive rights to develop and commercialize, at its own cost, selinexor, eltanexor,
KPT-9274,
each for the diagnosis, treatment and/or prevention of all human oncology indications, and verdinexor for the diagnosis, treatment and/or prevention of certain human
non-oncology
indications in mainland China, Taiwan, Hong Kong, Macau, South Korea, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam, Australia and New Zealand (the “Antengene Territory”). Under the terms of the Original Antengene Agreement, in 2018 we received an upfront cash payment of $11.7 million. In June 2020, we received an additional $11.7 million upfront payment upon execution of the Amended Antengene Agreement.
During 2020 and early 2021, Antengene has progressed its development and regulatory plans and has submitted new drug applications (“NDAs”) for selinexor to regulatory authorities in Singapore, Australia, Hong Kong, South Korea and China for relapsed or refractory multiple myeloma and/or relapsed or refractory DLBCL indications. In addition, Antengene is currently conducting two registrational Phase 2 clinical trials of XPOVIO in China for relapsed or refractory multiple myeloma and relapsed or refractory DLBCL and has initiated clinical trials for high prevalence cancer types in the Asia Pacific region including peripheral
T-cell
lymphoma and
NK/T-cell
lymphoma and KRAS-mutant
non-small
cell lung cancer.
In December 2020, we received approximately $10.0 million from Antengene upon the submission of certain of Antengene’s recent NDAs and are entitled to receive additional milestone payments from Antengene if
 
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certain development, regulatory and commercialization goals are achieved in the future. Finally, we will be eligible to receive tiered double-digit royalties based on future net sales of selinexor and eltanexor, and tiered single- to double-digit royalties based on future net sales of verdinexor and
KPT-9274
in the Antengene Territory.
FORUS
In December 2020, we entered into an exclusive distribution agreement for the commercialization of XPOVIO in Canada with FORUS, a Canadian biopharmaceutical company. Under the terms of the agreement, we received an upfront payment of $5.0 million in December 2020 and are eligible to receive additional payments if certain prespecified regulatory and commercial milestones are achieved by FORUS. We are also eligible to receive double-digit royalties on future net sales of XPOVIO in Canada. FORUS received the exclusive rights to commercialize XPOVIO in Canada and is responsible for all regulatory filings and obligations required for registering XPOVIO. We have retained the exclusive production rights and will supply finished product to FORUS for commercial use in Canada.
Promedico, a Neopharm Company
In February 2020, we entered into an exclusive distribution agreement with Promedico for the commercialization of XPOVIO in Israel and the Palestinian Authority (the “Promedico Territory”). We will receive certain prespecified payments and are eligible to receive additional payments if certain regulatory and commercial milestones are achieved by Promedico. We are also eligible to receive double-digit royalties on future net sales in the Promedico Territory. Promedico received the exclusive rights to commercialize XPOVIO in the Promedico Territory and is responsible for all regulatory filings and obligations required for registering XPOVIO. We have retained exclusive production rights and will supply finished product for commercial use in the Promedico Territory.
Biogen
In January 2018, we entered into an asset purchase agreement with Biogen pursuant to which Biogen acquired our oral SINE compound
KPT-350,
which has been renamed by Biogen as BIIB100, and certain related assets. We received a
one-time
upfront payment of $10.0 million in 2018 from Biogen and are eligible to receive additional payments of up to $207.0 million based on the achievement by Biogen of future specified development and commercial milestones. We are also eligible to receive tiered royalty payments that reach low double digits based on future net sales until the later of the tenth anniversary of the first commercial sale of the applicable product or the expiration of specified patent protection for the applicable product, determined on a
county-by-country
basis.
Anivive
In May 2017, we entered into an exclusive licensing agreement with Anivive pursuant to which Anivive received worldwide rights to research, develop and commercialize verdinexor for the treatment of cancer in companion animals. In 2017, we received an upfront payment of $1.0 million and a subsequent milestone payment of $250,000 and are eligible to receive up to $43.25 million in future regulatory, clinical and commercial milestone payments, assuming regulatory approval of verdinexor in both the U.S. and the EU. In addition, Anivive agreed to pay us up to low double-digit royalty payments based on future net sales of verdinexor. Verdinexor received conditional approval from the FDA in January 2021 as the first oral treatment for canine lymphoma. This approval triggered an additional milestone obligation to us of $500,000 in January 2021.
 
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Curadev
In April 2020, we entered into a collaboration, option and license agreement with Curadev, a privately-owned biotechnology company, to identify and
co-develop
novel small molecules against various biological targets for the treatment of cancer and other major diseases
.
Under the terms of the agreement, we and Curadev have agreed to identify and develop small molecules against up to two targets. Curadev will conduct exploratory research, drug discovery and development for designated programs up to the conclusion of preclinical proof of concept studies, after which we will have an option to an exclusive license to develop and commercialize each target on a global basis. We and Curadev will
co-fund
and jointly oversee development up to the option exercise period.
CRADA with NCI
In July 2020, we entered into a CRADA with the NCI’s Cancer Therapy Evaluation Program. Under the terms of the CRADA, the NCI will collaborate with us on studies to investigate the safety and efficacy of selinexor in various oncology indications, based on encouraging anti-tumor activity observed in earlier studies. As data from the
NCI-sponsored
studies and other Karyopharm-sponsored studies emerge, we plan to collaborate with the NCI on trials to complement and support the further development of selinexor that could address important patient unmet medical needs. The NCI may also support
non-clinical
studies to explore important future combinations of selinexor with other targeted or standard of care cancer agents.
Intellectual Property
Our commercial success depends in part on our ability to obtain and maintain proprietary or intellectual property protection for our products and product candidates, our core technologies, and other
know-how,
to operate without infringing on the proprietary rights of others and to prevent others from infringing our proprietary or intellectual property rights. Our policy is to seek to protect our proprietary and intellectual property position by, among other methods, filing patent applications in the U.S. and in foreign jurisdictions related to our proprietary technology and products and product candidates. We also rely on trade secrets,
know-how
and continuing technological innovation to develop and maintain our proprietary and intellectual property position.
We file patent applications directed to the composition of matter and methods of use and manufacture for our products and product candidates. As of February 2, 2021, we were the sole owner of 21 patents in the U.S. and we had 16 pending patent applications in the U.S., four pending international applications filed under the Patent Cooperation Treaty (“PCT”), 77 granted patents and 71 pending patent applications in foreign jurisdictions. The PCT is an international patent law treaty that provides a unified procedure for filing a single initial patent application to seek patent protection for an invention simultaneously in each of the member states. Although a PCT application is not itself examined and cannot issue as a patent, it allows the applicant to seek protection in any of the member states through national-phase applications. The technology underlying such pending patent applications has been developed by us and was not acquired from any
in-licensing
agreement.
The intellectual property portfolios for our key products and product candidates as of February 2, 2021 are summarized below.
 
   
Selinexor
(KPT-330)
: Our selinexor patent portfolio covers the composition of matter and methods of use of selinexor and verdinexor, as well as methods of making both, and consists of seven issued U.S. patents (two patents are specific to selinexor, two patents are specific to verdinexor, two patents cover both selinexor and verdinexor and the seventh patent covers polymorphs of selinexor), 34 issued foreign patents, 39 pending foreign patent applications, two pending U.S.
non-provisional
applications, one pending PCT application and four pending U.S. provisional patent applications. The PCT application provides the opportunity to seek protection in all PCT member states. Any patents that may issue in the U.S. as part of our selinexor patent portfolio, with the exception of a patent directed to the polymorphs of selinexor and a patent based on the pending PCT application, will expire in 2032, absent any terminal disclaimer, patent term adjustment due to administrative delays by the U.S. Patent and Trademark Office (“USPTO”) or patent term extension under the Drug Price Competition and Patent
 
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Term Restoration Act of 1984, commonly referred to as the Hatch-Waxman Act. Any patents that may issue in foreign jurisdictions will likewise expire in 2032. Any patents that may issue in the U.S. directed to the polymorphs of selinexor will expire in 2035, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents issued in foreign jurisdictions will likewise expire in 2035. Any patents that may issue in the U.S. based on the pending PCT application will expire in 2040, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents issued in foreign jurisdictions will likewise expire in 2040. If
non-provisional
patent applications claiming the benefit of the pending U.S. provisional patent applications referenced above are filed in 2021, any patents that may issue from such applications will expire no earlier than 2041.
 
   
Selinexor (Wound Healing)
: Our patent portfolio covering selinexor for wound healing, including acute and chronic wounds, covers methods of using selinexor or verdinexor for wound healing, including systemic and topical uses, and consists of one issued U.S. patent and one granted European patent. The U.S. patent will expire in 2034, absent any terminal disclaimer, patent term adjustment due to administrative delay by the USPTO or patent term extension under the Hatch-Waxman Act. The European patent will likewise expire in 2034.
 
   
Verdinexor
(KPT-335)
: Our selinexor patent portfolio described above, with the exception of the applications directed to polymorphs of selinexor, the one pending PCT application and the four pending U.S. provisional applications, also covers both the composition of matter and methods of use of verdinexor, as well as methods of making verdinexor. There are four issued U.S. patents that cover verdinexor. One patent is specific to verdinexor, two patents cover both verdinexor and selinexor (also referenced above with respect to selinexor) and the other covers veterinary uses of verdinexor.
 
   
Eltanexor
(
KPT-8602)
: Our eltanexor patent portfolio covers both the composition of matter and methods of use of eltanexor, and consists of two issued U.S. patents, one pending
non-provisional
U.S. patent application, 14 issued foreign patents, 15 pending foreign patent applications and one pending PCT application. The PCT application provides the opportunity for seeking protection in all PCT member states. Any patents that may issue in the U.S. as part of our eltanexor patent portfolio, with the exception of a patent based on the pending PCT application, will expire in 2034, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents issued in foreign jurisdictions will likewise expire in 2034. Any patents that may issue in the U.S. based on the pending PCT application will expire in 2039, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents issued in foreign jurisdictions will likewise expire in 2039.
 
   
PAK4/NAMPT Inhibitors
: Our PAK4/NAMPT inhibitors patent portfolio covers both the composition of matter and methods of use of the PAK4/NAMPT inhibitors described therein, such as
KPT-9274,
and consists of five patent families with six issued U.S. patents, 11 issued foreign patents, one pending U.S.
non-provisional
patent application, and 15 pending foreign patent applications in total. Any patents that may issue in the U.S. based on the pending U.S.
non-provisional
application will expire in 2034, absent any terminal disclaimer, patent term adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents that may issue based on the pending foreign patent applications will likewise expire in 2034. Foreign patent applications covering the composition of matter and methods of use of
KPT-9274
have been filed in 22 countries/regions.
 
   
Biomarkers for XPO1 Inhibitors
: Our patent portfolio also covers biomarkers related to treatment with XPO1 inhibitors, such as selinexor and eltanexor, and consists of seven pending U.S. provisional applications and two pending PCT applications. The PCT applications provide the opportunity for seeking protection in all PCT member states. Any patents that may issue in the U.S. based on the pending PCT Applications will expire no earlier than 2039 absent any terminal disclaimer, patent term
 
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adjustment due to administrative delays by the USPTO or patent term extension under the Hatch-Waxman Act. Any patents issued in foreign jurisdictions will likewise expire no earlier than 2039. If
non-provisional
patent applications claiming the benefit of the pending U.S. provisional applications referenced above are filed in 2021, any patents that may issue from such applications will expire no earlier than 2041.
In addition to the patent portfolios covering our key products and product candidates, as of February 2, 2021, our patent portfolio also includes five patents (U.S. Patent Nos. 8,513,230, 9,428,490, 9,550,757,10,526,295 and 10,709,606) and 17 granted foreign patents and pending patent applications in the U.S. and foreign jurisdictions relating to other XPO1 inhibitors and their use in targeted therapeutics and combination therapies for XPO1 inhibitors.
In the U.S., we have trademark registrations for our name and logo, and a combination of the two, XPOVIO, and PORE for our online portal. We also have pending applications to register two additional possible product names (currently refused), and KARYFORWARD and a KARYFORWARD logo for our financial aid and charitable services. Outside the U.S., XPOVIO is registered or pending in
forty-six
additional jurisdictions, and is registered in Katakana in Japan, Hangul in South Korea, and Chinese characters in Taiwan. The KARYFORWARD logo is registered or pending in four jurisdictions outside the U.S. We also have registrations or applications for eight additional possible product names in numerous foreign jurisdictions.
The term of individual patents depends upon the legal term for patents in the countries in which they are obtained. In most countries, including the U.S., the patent term is 20 years from the earliest filing date of a
non-provisional
patent application. In the U.S., a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over an earlier filed patent. The term of a patent that covers a drug may also be eligible for patent term extension when FDA approval is granted, provided statutory and regulatory requirements are met. See “
Government Regulation—Patent Term Restoration and Extension
” below for additional information on such extensions. In the future, if and when our product candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those drugs, depending upon the length of the clinical trials for each product candidate and other factors. There can be no assurance that any of our pending patent applications will issue or that we will benefit from any patent term extension or favorable adjustment to the term of any of our patents.
As with other biotechnology and pharmaceutical companies, our ability to maintain and solidify our proprietary and intellectual property position for our products and product candidates and technologies will depend on our success in obtaining effective patent claims and enforcing those claims if granted. However, patent applications that we may file or license from third parties may not result in the issuance of patents. We also cannot predict the breadth of claims that may be allowed or enforced in our patents. Our issued patents and any issued patents that we may receive in the future may be challenged, invalidated or circumvented. For example, we cannot be certain of the priority of inventions covered by pending third-party patent applications. If third parties prepare and file patent applications that also claim technology or therapeutics to which we have rights, we may have to participate in interference proceedings to determine priority of invention, which could result in substantial costs to us, even if the eventual outcome is favorable to us. In addition, because of the extensive time required for clinical development and regulatory review of a product candidate we may develop, it is possible that, before any of our product candidates can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any advantage of any such patent.
In addition to patents, we rely upon unpatented trade secrets and
know-how
and continuing technological innovation to develop and maintain our competitive position. We seek to protect our proprietary information, in part, using confidentiality agreements with our collaborators, scientific advisors, employees and consultants, and invention assignment agreements with our employees. We also have agreements with selected consultants,
 
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scientific advisors and collaborators requiring assignment of inventions. The confidentiality agreements are designed to protect our proprietary information and, in the case of agreements or clauses requiring invention assignment, to grant us ownership of technologies that are developed through our relationship with a third party.
With respect to our proprietary drug discovery and optimization platform, we consider trade secrets and
know-how
to be our primary intellectual property. Trade secrets and
know-how
can be difficult to protect. We anticipate that with respect to this technology platform, these trade secrets and
know-how
may over time be disseminated within the industry through independent development, the publication of journal articles describing the methodology, and the movement of personnel skilled in the art from academic to industry scientific positions.
Competition
The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on proprietary products. While we believe that our technology, knowledge, experience and scientific resources provide us with certain competitive advantages, we face competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic institutions and governmental agencies and public and private research institutions. Any product candidates that we successfully develop and commercialize will compete with existing therapies and new therapies that may become available in the future.
There are numerous companies developing or marketing treatments for cancer and the other indications on which we currently plan to focus, including many major pharmaceutical and biotechnology companies. To our knowledge, there is only one other XPO1 inhibitor in clinical development. In June 2020, The Menarini Group acquired Stemline Therapeutics, Inc., including its oral XPO1 inhibitor, felezonexor. The Menarini Group is continuing a Phase 1 dose-escalation trial to evaluate felezonexor in patients with advanced solid tumors.
Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals, marketing approved products and achieving
ex-U.S.
positive coverage/reimbursement decisions than we do. Mergers and acquisitions in the pharmaceutical and biotechnology 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, commercial 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.
The key competitive factors affecting the success of any approved oncology drug product, including our products and product candidates, if approved, are likely to be their efficacy, safety, tolerability, convenience and price, the availability of alternative cancer therapies and the availability of reimbursement from government and other third-party payors. Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products, or commercialize existing products in new indications, and those products are or are perceived to be safer, more effective, more convenient, less expensive or more tolerable than any products that we have or 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. In addition, our ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic drugs. Generic drugs for the treatment of cancer and the other indications on which we currently plan to initially focus are currently on the market, and additional products are expected to become available on a generic basis over the coming years. If we obtain marketing approval for our other product candidates or for XPOVIO/NEXPOVIO in other indications, we expect that they will be priced at a significant premium over generic versions of older chemotherapy agents and other cancer therapies.
 
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The most common methods of treating patients with cancer are surgery, radiation and drug therapy. There are a variety of available drug therapies marketed for cancer. In many cases, these drugs are administered in combination to enhance efficacy. While our products and product candidates may compete with many existing drugs and other therapies, to the extent they are ultimately used in combination with or as an adjunct to these therapies, our product candidates will be complimentary with them. Some of the currently approved drug therapies are branded and subject to patent protection, and others are available on a generic basis. Many of these approved products are well-established therapies and are widely accepted by physicians, patients and third-party payors.
In addition to currently marketed therapies, there are also a number of products in late-stage clinical development to treat cancer and the other indications on which we plan to focus. These products in development may provide efficacy, safety, tolerability, convenience and other benefits that are not provided by currently marketed therapies. As a result, they may represent significant competition for any of our products or product candidates for which we obtain marketing approval.
XPOVIO/NEXPOVIO competes with and, if approved, our other lead product candidates may compete with the investigational therapies and/or currently marketed products discussed below.
Multiple Myeloma
Many therapies are approved for use in patients with multiple myeloma. Our primary competitors in this indication, including the following, currently treat patients ranging from newly diagnosed patients to those with relapsed and/or refractory multiple myeloma and are indicated for use either as single agent and/or as combination therapies:
 
   
IMiDs
: Revlimid
®
(lenalidomide), Pomalyst
®
(pomalidomide) and Thalomid
®
(thalidomide), all marketed by Celgene Corporation (“Celgene”) /Bristol-Myers Squibb Company (“BMS”);
 
   
PIs
: Velcade
®
(bortezomib) marketed by Takeda Pharmaceutical Company Limited (“Takeda”) in the U.S. and Janssen Pharmaceutical K.K. (“Janssen”) outside of the U.S., Ninlaro
®
(ixazomib) marketed by Takeda and Kyprolis
®
(carfilzomib) marketed by Amgen Inc. (“Amgen”);
 
   
Monoclonal antibodies
: Darzalex
®
(daratumumab) marketed by Janssen, Empliciti
®
(elotuzumab) marketed by BMS and Sarclisa
®
(isatuximab-irfc) marketed by Sanofi S.A. (“Sanofi”);
 
   
Antibody Drug Conjugate
: BLENREP (belantamab mafodotin-blmf) marketed by GlaxoSmithKline plc (“GSK”);
 
   
Histone Deacetylase inhibitor
: Farydak
®
(panobinostat) marketed by Novartis AG (“Novartis”); and
 
   
Anthracycline
: Doxil
®
(liposomal doxorubicin) marketed by Janssen.
Several other anti-cancer agents are in mid to late-stage development for the treatment of patients with multiple myeloma, including:
 
   
Anti-BCMA directed
CAR-T
therapies:
ciltacabtagene autoleucel
(cilta-cel,
previously known as
JNJ-68284528/
JNJ-4528)
from Janssen and Legend Biotech Corporation,
ide-cel
(previously known as bb2121) from bluebird bio, Inc. (“bluebird bio”)/Celgene/BMS, orvacabtagene Autoleucel
(orva-cel,
previously known as JCARH125) from Juno Therapeutics, Inc./Celgene/BMS and
P-BCMA-101
from Janssen/Poseida Therapeutics, Inc.;
 
   
Immunomodulator
: Iberdomide (previously known as
CC-220,
cereblon E3 ligase modulator) from Celgene/BMS and Opdivo
®
(nivolumab) from BMS;
 
   
Alkylating agent
: Ygalo
®
(melphalan flufenamide) from Oncopeptides AB;
 
   
BCL-2
inhibitor
: Venclexta
®
(venetoclax) from AbbVie Inc. (“AbbVie”)/Genentech USA (“Genentech”);
 
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Anti-CD38 Monocolonal antibodies
: mezagitamab (previously known as
TAK-079)
from Takeda;
 
   
Bi-specific
antibodies
: teclistamab (previously known as
JNJ-64007957)
from Johnson & Johnson/Janssen,
CC-93269
from bluebird bio/Celgene/BMS, AMG420 from Amgen, REGN5458 from Regeneron Pharmaceuticals, Inc. (“Regeneron”) and
PF-06863135
from Pfizer Inc.; and
 
   
Other molecules
: Imbruvica
®
(ibrutinib) from Pharmacyclics LLC (“Pharmacyclics”)/AbbVie/Janssen, nirogacestat (previously known as PF 3084014) from Springworks Therapeutics, Inc./Janssen, plitidepsin from Pharma Mar S.A. (“Pharma Mar”), masitinib from AB Science Group, filanesib from Array Biopharma Inc. and ricolinostat from Celgene.
DLBCL
The initial therapy for DLBCL typically consists of multi-agent cytotoxic drugs in combination with the monoclonal antibody rituximab (or a rituximab biosimilar). In patients with DLBCL who are not elderly and who have good organ function, high dose chemotherapy with stem cell transplantation is often used at first relapse. Over the past five years, a number of therapeutic interventions have been approved in the U.S. and/or Europe and/or other parts of the world for the treatment of patients with relapsed or refractory DLBCL who have received at least two prior therapies and/or are not eligible for ASCT/HSCT. These recently approved therapeutic interventions are also being evaluated via late-stage development in earlier lines of therapy for the treatment of patients with DLBCL:
 
   
CD19-directed
CAR-T
therapies:
Kymriah
®
(tisagenlecleucel) marketed by Novartis, Yescarta
®
(axicabtagene ciloleucel) marketed by Kite Pharma, Inc., a Gilead Company, and Breyanzi
®
(lisocabtagene maraleucel;
liso-cel)
marketed by BMS;
 
   
CD79b-directed antibody-drug conjugate
: Polivy
®
(polatuzumab vedotin-piiq) marketed by Genentech F.
Hoffmann-La/Roche
AG (“Roche”); and
 
   
CD19-directed cytolytic antibody:
Monjuvi
®
(tafasitamab-cxix, previously known as MOR208 in combination with lenalidomide) marketed by MorphoSys AG/Incyte Corporation (“Incyte”).
Other agents are listed in the NCCN and/or the ESMO guidelines for use after one to two prior therapies, although they have not been formally approved by the FDA including: Revlimid
®
(lenalidomide), Imbruvica
®
(ibrutinib) from Pharmacyclics/Abbvie, and generic multiagent chemotherapy including gemcitabine, oxaliplatin, and bendamustine.
In addition, a number of anti-cancer agents are in mid to late-stage development for the treatment of patients with DLBCL, including:
 
   
Immune modulator:
Keytruda
®
(pembrolizumab) (“Keytruda”) from Merck & Co. (“Merck”) and Imfinzi
®
(durvalumab) from AstraZeneca plc (“AstraZeneca”);
 
   
Bi-specific
antibodies:
mosunetuzumab from Genentech/Roche, epcoritamab (previously known as GEN3013) from AbbVie/Genmab A/S, glofitamab (previously known as RG6026) from Genentech/Roche, odronextomab (previously known as REGN1979) from Regeneron, plamotamab (previously known as XmAb13676) from Xencor Inc. and magrolimab from Gilead Sciences, Inc.;
 
   
Antibody drug conjugates:
loncastuximab tesirine (previously known as
ADCT-402)
from ADC therapeutics, Adcetris
®
(brentuximab vedotin in CD30+ DLBCL) from Seagen Inc./Takeda and naratuximab emtansine (previously known as Debio1562) from DebioPharm;
 
   
Small molecules:
enzastaurin from Denovo Biopharma LLC, Calquence
®
(acalabrutinib) from Acerta Pharma, LLC/AstraZeneca, Venclexta
®
(venetoclax) from AbbVie/Genentech and Brukinsa
(zanubrutinib) from Beigene, Ltd; and
 
   
Monoclonal antibodies:
umbralisib/ublituximab from TG Therapeutics Inc.
 
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Endometrial Cancer
The initial treatment for endometrial cancer is surgery, radiotherapy and where applicable taxane/platinum-based chemotherapy. Upon disease progression, various chemotherapy agents are commonly used, and recently Keytruda
®
received U.S. and European approvals as a single agent or in combination with Lenvima
®
(lenvatinib, marketed by Esai) in a subgroup of patients with recurrent disease. Both Keytruda
®
and Lenvima
®
are also being evaluated in other endometrial cancer lines of therapy.
Other anti-cancer agents are in late-stage development for the treatment of patients with endometrial cancer, specifically for the use of “maintenance” therapy following initial treatment, as in the SIENDO Study and/or in recurrent disease, including:
 
   
Immune checkpoints inhibitors:
dostarlimab from GSK/Tesaro, Inc. (“Tesaro”), Tecentriq
®
(atezolizumab) from Genentech/Roche and Imfinzi
®
(durvalumab) from AstraZeneca; and
 
   
PARP inhibitor:
Lynparza
®
(olaparib) from AstraZeneca and Zejula
®
(niraparib) from GSK/Tesaro.
Sales and Marketing
Following the July 2019 U.S. commercial launch of XPOVIO in multiple myeloma and subsequent FDA approvals in 2020 in both earlier stage multiple myeloma and DLBCL, our commercial team has focused its efforts on educating health care providers on the efficacy and safety profile of XPOVIO with the goal of enabling cancer patients access to this important new medicine. We are commercializing XPOVIO in the U.S. with our own focused, customer-facing teams, including sales specialists, reimbursement and access support specialists, and nurse liaisons, each typically with a number of years of experience in the biopharmaceutical industry in hematology/oncology. We have approximately 70 field-based employees in the U.S. who call on academic and community-based healthcare professionals who treat multiple myeloma and DLBCL, as well as our reimbursement team. We believe that the current size of our sales force is appropriate at this time to effectively reach our target audience in the specialty markets in which we currently operate. Continued growth of our current marketed products and the launch of any future products may require further expansion of our field force and support organization within and outside the U.S. For the foreseeable future, we intend to develop and commercialize XPOVIO and our product candidates alone in the U.S. and expect to rely on partners to develop and commercialize our products in territories outside the U.S. In executing our strategy, our goal is to retain oversight over the global development and commercialization of our products by playing an active role in their commercialization or finding partners who share our vision, values, and culture.
Our sales force is supported by an experienced sales leadership team and professionals in marketing, reimbursement and market access, market research and analytics, commercial operations, finance and human resources. Our sales and marketing organization uses a variety of pharmaceutical marketing strategies to promote XPOVIO, including sales calls,
peer-to-peer
education,
non-personal
promotional, and digital content. We employ third-party vendors, such as advertising agencies, market research firms and suppliers of marketing and other sales support-related services, to assist with our commercial activities.
Our patient support program, KaryForward
®
, is dedicated to providing assistance and resources to our patients with multiple myeloma and DLBCL and their caregivers throughout their XPOVIO treatment. KaryForward
®
offers support in navigating insurance coverage issues and processes and enabling continuation of our patients’ ability to access XPOVIO in the case of delays or interruptions in the insurance process. We also offer a copay card, which offers eligible commercial patients who have insurance to receive their prescription for as little as $5.00 per prescription. Further, the KaryForward
®
program assists eligible patients who do not have insurance or lack coverage to be able to access XPOVIO treatment through our Patient Assistance Program. Under our KaryForward
®
program, patients are assigned a dedicated nurse case manager, who serves as a point of contact to help patients and their caregivers navigate the treatment process, including by explaining prescription instructions, providing psychosocial support and additional nonclinical education regarding XPOVIO, highlighting expectations when taking XPOVIO and providing referrals for additional third-party support, such as transportation assistance.
 
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Manufacturing
We do not own or operate, and have no plans to establish, any manufacturing facilities for our products or product candidates. We currently rely, and expect to continue to rely, on third-party contract manufacturers to manufacture our products and product candidates for our commercial and clinical use.
We have long-term supply agreements with third-party contract manufacturers to manufacture clinical and commercial supplies of the drug product for XPOVIO and obtain all other supplies or materials for our other compounds on a purchase order basis. At this time, we rely on a single source supplier for our active pharmaceutical ingredient and drug product manufacturing requirements.
All of our products and product candidates are small molecules and are manufactured in reliable and reproducible synthetic processes from readily available starting materials. The chemistry and formulation processes of selinexor have been developed to meet our large-scale manufacturing needs and do not require unusual equipment in the manufacturing process. We maintain sufficient inventory levels throughout our supply chain to exceed our
two-year
forecasts for XPOVIO in order to minimize the risks of supply disruption.
To support the commercialization and development of our products and product candidates, we have developed a fully integrated manufacturing support system, including scientific oversight, quality assurance, quality control, regulatory affairs and inventory control policies and procedures. These support systems are intended to enable us to maintain high standards of quality for our products. We intend to continue to outsource the manufacture and distribution of our products for the foreseeable future, and we believe this manufacturing strategy will enable us to direct more of our financial resources to the commercialization and development of our products and product candidates.
Government Regulation
Government authorities in the U.S., at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export of pharmaceutical products. The processes for obtaining regulatory approvals in the U.S. and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.
Review and Approval of Drugs in the U.S.
In the U.S., the FDA regulates drug products under the Federal Food, Drug, and Cosmetic Act (the “FDCA”) and implementing regulations. The failure to comply with applicable requirements under the FDCA and other applicable laws at any time during the product development process, approval process or after approval may subject an applicant and/or sponsor to a variety of administrative or judicial sanctions, including refusal by the FDA to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters and other types of letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement of profits, or civil or criminal investigations and penalties brought by the FDA and the Department of Justice or other governmental entities.
An applicant seeking approval to market and distribute a new drug product in the U.S. must typically undertake the following:
 
   
completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice (“GLP”) regulations;
 
   
submission to the FDA of an IND, which must take effect before human clinical trials may begin;
 
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approval by an independent institutional review board (“IRB”) representing each clinical site before each clinical trial may be initiated;
 
   
performance of adequate and well-controlled human clinical trials in accordance with good clinical practices (“GCP”) to establish the safety and efficacy of the proposed drug product for each indication;
 
   
preparation and submission to the FDA of an NDA;
 
   
review of the product by an FDA advisory committee, where appropriate or if applicable;
 
   
satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practices (“cGMP”) requirements and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;
 
   
satisfactory completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;
 
   
payment of user fees and securing FDA approval of the NDA; and
 
   
compliance with any post-approval requirements, including Risk Evaluation and Mitigation Strategies (“REMS”) and post-approval studies required by the FDA.
Preclinical Studies
Preclinical studies include laboratory evaluation of the purity and stability of the manufactured drug substance or active pharmaceutical ingredient and the formulated drug or drug product, as well as
in vitro
and animal studies to assess the safety and activity of the drug for initial testing in humans and to establish a rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations. The results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND. Some long-term preclinical testing, such as animal tests of reproductive AEs and carcinogenicity, may continue after the IND is submitted.
In addition, companies usually must also develop additional information about the chemistry and physical characteristics of the investigational product and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the candidate product and, among other things, the manufacturer must develop methods for testing the identity, strength, quality and purity of the final product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the candidate product does not undergo unacceptable deterioration over its shelf life.
The IND and IRB Processes
An IND is an exemption from the FDCA that allows an unapproved drug to be shipped in interstate commerce for use in an investigational clinical trial and a request for FDA authorization to administer an investigational drug to humans. Such authorization must be secured prior to interstate shipment and administration of any new drug that is not the subject of an approved NDA. In support of a request for an IND, applicants must submit a protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND. In addition, the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND. The FDA requires a
30-day
waiting period after the filing of each IND before clinical trials may begin. This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks. At any time during this
30-day
period, the FDA may raise concerns or questions about the conduct of the trials as outlined in the IND and impose a clinical hold. In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.
 
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Following commencement of a clinical trial under an IND, the FDA may also place a clinical hold or partial clinical hold on that trial. A clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. A partial clinical hold is a delay or suspension of only part of the clinical work requested under the IND. For example, a specific protocol or part of a protocol is not allowed to proceed, while other protocols may do so. No more than 30 days after imposition of a clinical hold or partial clinical hold, the FDA will provide the sponsor a written explanation of the basis for the hold. Following issuance of a clinical hold or partial clinical hold, an investigation may only resume after the FDA has notified the sponsor that the investigation may proceed. The FDA will base that determination on information provided by the sponsor correcting the deficiencies previously cited or otherwise satisfying the FDA that the investigation can proceed.
A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND. When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met unless waived. When the foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain FDA regulatory requirements in order to use the study as support for an IND or application for marketing approval. Specifically, on April 28, 2008, the FDA amended its regulations governing the acceptance of foreign clinical studies not conducted under an IND application as support for an IND or an NDA. The final rule provides that such studies must be conducted in accordance with GCP, including review and approval by an independent ethics committee and informed consent from subjects. The GCP requirements in the final rule encompass both ethical and data integrity standards for clinical studies. The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in
non-IND
foreign clinical studies, as well as the quality and integrity of the resulting data. They further help ensure that
non-IND
foreign studies are conducted in a manner comparable to that required for IND studies.
In addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must conduct a continuing review and reapprove the study at least annually. The IRB must review and approve, among other things, the study protocol and informed consent information to be provided to study subjects. An IRB must operate in compliance with FDA regulations. An IRB can suspend or terminate approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.
Additionally, some trials are overseen by a DSMB, an independent group of qualified experts organized by the trial sponsor. This group provides authorization for whether or not a trial may move forward at designated check points based on access that only the group maintains to available data from the study. Suspension or termination of development during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk. Other reasons for suspension or termination may be made by us based on evolving business objectives and/or competitive climate.
Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health for public dissemination on its ClinicalTrials.gov website. Similar requirements for posting clinical trial information are present in the EU (EudraCT) website: https://eudract.ema.europa.eu/ and other countries, as well.
Expanded Access to an Investigational Drug for Treatment Use
Expanded access, sometimes called “compassionate use,” is the use of IND products outside of clinical trials to treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options. The rules and regulations related to expanded access are intended to improve access to investigational drugs for patients who may benefit from investigational therapies. FDA regulations allow access to investigational drugs under an IND by the company or the treating physician for
 
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treatment purposes on a
case-by-case
basis for: individual patients (single-patient IND applications for treatment in emergency settings and
non-emergency
settings);
intermediate-size
patient populations; and larger populations for use of the drug under a treatment protocol or Treatment IND Application.
When considering an IND application for expanded access to an investigational product with the purpose of treating a patient or a group of patients, the sponsor and treating physicians or investigators will determine suitability when all of the following criteria apply: patient(s) have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition; the potential patient benefit justifies the potential risks of the treatment and the potential risks are not unreasonable in the context or condition to be treated; and the expanded use of the investigational drug for the requested treatment will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the product or otherwise compromise the potential development of the product.
On December 13, 2016, the 21st Century Cures Act (the “Cures Act”) established (and the 2017 Food and Drug Administration Reauthorization Act later amended) a requirement that sponsors of one or more investigational drugs for the treatment of a serious disease(s) or condition(s) make publicly available their policy for evaluating and responding to requests for expanded access for individual patients. Although these requirements were rolled out over time, they have now come into full effect. This provision requires drug and biologic companies to make publicly available their policies for expanded access for individual patient access to products intended for serious diseases. Sponsors are required to make such policies publicly available upon the earlier of initiation of a Phase 2 or Phase 3 study; or 15 days after the drug or biologic receives designation as a breakthrough therapy, fast track product, or regenerative medicine advanced therapy.
In addition, on May 30, 2018, the Right to Try Act was signed into law. The law, among other things, provides a federal framework for certain patients to access certain IND products that have completed a Phase I clinical trial and that are undergoing investigation for FDA approval. Under certain circumstances, eligible patients can seek treatment without enrolling in clinical trials and without obtaining FDA permission under the FDA expanded access program. There is no obligation for a drug manufacturer to make its drug products available to eligible patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.
Human Clinical Trials in Support of an NDA
Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial. Clinical trials are conducted under written study protocols detailing, among other things, the inclusion and exclusion criteria, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.
Human clinical trials are typically conducted in four sequential phases, which may overlap or be combined:
 
Phase 1:
The drug is initially introduced into a small number of healthy human subjects or patients with the target disease (e.g. cancer) or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness and to determine optimal dosage.
 
Phase 2:
The drug is administered to a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage.
 
Phase 3:
The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate
 
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  the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product. These clinical trials are commonly referred to as “pivotal” studies, which denotes a study that presents the data that the FDA or other relevant regulatory agency will use to determine whether or not to approve a drug.
 
Phase 4:
Post-approval studies may be conducted after initial marketing approval. These studies are used to gain additional experience from the treatment of patients in the intended therapeutic indication.
Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious AEs occur. In addition, IND safety reports must be submitted to the FDA for any of the following: serious and unexpected suspected adverse reactions; findings from other studies or animal or
in vitro
testing that suggest a significant risk in humans exposed to the drug; and any clinically important increase in the case of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified period, or at all. The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.
Concurrent with clinical trials, companies often complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality, purity, and potency of the final product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.
Submission of an NDA to the FDA
Assuming successful completion of required clinical testing and other requirements, the results of the preclinical studies and clinical trials, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the drug product for one or more indications. Under federal law, the submission of most NDAs is subject to an application user fee, which for federal fiscal year 2021 is $2,875,842 for an application requiring clinical data. The sponsor of an approved NDA is also subject to a program fee for fiscal year 2021 of $336,432. Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for drugs with orphan designation and a waiver for certain small businesses.
The FDA conducts a preliminary review of an NDA within 60 days of its receipt and strives to inform the sponsor by the 74th day after the FDA’s receipt of the submission to determine whether the application is sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an
in-depth
substantive review. The FDA has agreed to certain performance goals in the review process of NDAs. Most such applications are meant to be reviewed within ten months from the date of filing, and most applications for “priority review” products are meant to be reviewed within six months of filing. The review process may be extended by the FDA for three additional months to consider new information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.
Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is or will be manufactured. These
pre-approval
inspections may cover all facilities associated with an NDA submission, including drug component manufacturing (such as active pharmaceutical ingredients), finished drug product manufacturing, and control testing laboratories. The FDA will not approve an application unless it
 
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determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP. The FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain drug applications, including applications for drugs in a shortage or drugs for which approval is dependent on remediation of conditions identified in the inspection report.
In addition, as a condition of approval, the FDA may require an applicant to develop a REMS. REMS use risk minimization strategies beyond the professional labeling to ensure that the benefits of the product outweigh the potential risks. To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected benefit of the product, expected duration of treatment, seriousness of known or potential AEs, and whether the product is a new molecular entity. REMS can include medication guides, physician communication plans for healthcare professionals, and elements to assure safe use (“ETASU”). ETASU may include, but are not limited to, special training or certification for prescribing or dispensing, dispensing only under certain circumstances, special monitoring, and the use of patient registries. The FDA may require a REMS before approval or post-approval if it becomes aware of a serious risk associated with use of the product. The requirement for a REMS can materially affect the potential market and profitability of a product.
The FDA may refer an application for a novel drug to an advisory committee or explain why such referral was not made. Typically, an advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
Fast Track, Breakthrough Therapy, Priority Review and Regenerative Advanced Therapy Designations
The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment of a serious or life-threatening disease or condition. These programs are referred to as fast track designation, breakthrough therapy designation, priority review designation and regenerative advanced therapy designation.
Specifically, the FDA may designate a product for fast track review if it is intended, whether alone or in combination with one or more other products, for the treatment of a serious or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition. For fast track products, sponsors may have greater interactions with the FDA and the FDA may initiate review of sections of a fast track product’s application before the application is complete. This rolling review may be available if the FDA determines, after preliminary evaluation of clinical data submitted by the sponsor, that a fast track product may be effective. The sponsor must also provide, and the FDA must approve, a schedule for the submission of the remaining information and the sponsor must pay applicable user fees. However, the FDA’s time period goal for reviewing a fast track application does not begin until the last section of the application is submitted. In addition, the fast track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial process.
Second, a product may be designated as a breakthrough therapy if it is intended, either alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The FDA may take certain actions with respect to breakthrough therapies, including holding meetings with the sponsor throughout the development process; providing timely advice to the product sponsor regarding development and approval; involving more senior staff in the review process; assigning a cross-disciplinary project lead for the review team; and taking other steps to design the clinical trials in an efficient manner.
 
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Third, the FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness. The FDA determines, on a
case-by-case
basis, whether the proposed product represents a significant improvement when compared with other available therapies. Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting product reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation. A priority designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.
Finally, with passage of the Cures Act in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as regenerative advanced therapies. A product is eligible for this designation if it is a regenerative medicine therapy (as defined in the Cures Act) that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition. The benefits of a regenerative advanced therapy designation include early interactions with FDA to expedite development and review, benefits available to breakthrough therapies, potential eligibility for priority review and accelerated approval based on surrogate or intermediate endpoints.
Accelerated Approval Pathway
The FDA may grant accelerated approval to a drug for a serious or life-threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based upon a determination that the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The FDA may also grant accelerated approval for such a condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality (“IMM”) and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments. Drugs granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.
For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints. An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on IMM. The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints, but has indicated that such endpoints generally may support accelerated approval where the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate clinical benefit of a drug.
The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of a drug, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Thus, accelerated approval has been used extensively in the development and approval of drugs for treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes large trials to demonstrate a clinical or survival benefit.
The accelerated approval pathway is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory studies to verify and describe the drug’s clinical benefit. As a result, a drug candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint. Failure to conduct required post-approval studies, or confirm a clinical benefit during post-marketing studies,
 
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would allow the FDA to withdraw the drug from the market on an expedited basis. All promotional materials for drug candidates approved under accelerated regulations are subject to prior review by the FDA.
The FDA’s Decision on an NDA
On the basis of the FDA’s evaluation of the NDA and accompanying information, including the results of the inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter. An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications. A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application. If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter. The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included. Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.
If the FDA approves a product, it may limit the approved indications for use for the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess the drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, which can materially affect the potential market and profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs. After approval, many types of changes to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.
Post-Approval Requirements
Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing, annual user fee requirements for any marketed products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data.
In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies, and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements. Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.
Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. Later discovery of previously unknown problems with a product, including AEs of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or imposition of distribution or other restrictions under a REMS program. Other potential consequences include, among other things:
 
   
restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;
 
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fines, warning letters or holds on post-approval clinical trials;
 
   
refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product license approvals;
 
   
product seizure or detention, or refusal to permit the import or export of products; or
 
   
injunctions or the imposition of civil or criminal penalties.
The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products placed on the market. This regulation includes, among other things, standards and regulations for
direct-to-consumer
advertising, communications regarding unapproved uses, industry-sponsored scientific and educational activities, and promotional activities involving the Internet and social media. Promotional claims about a drug’s safety or effectiveness are prohibited before the drug is approved. After approval, a drug product generally may not be promoted for uses that are not approved by the FDA, as reflected in the product’s prescribing information.
In the U.S., healthcare professionals are generally permitted to prescribe drugs for such uses not described in the drug’s labeling, known as
off-label
uses, because the FDA does not regulate the practice of medicine. However, FDA regulations impose rigorous restrictions on manufacturers’ communications, prohibiting the promotion of
off-label
uses. It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in nonpromotional,
non-misleading
communication regarding
off-label
information, such as distributing scientific or medical journal information. If a company is found to have promoted
off-label
uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities. This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or distributes drug products. The federal government has levied large civil and criminal fines against companies for alleged improper promotion, and has also requested that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed.
In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act (“PDMA”) and its implementation regulations, as well as the Drug Supply Chain Security Act (“DSCSA”), which regulates the distribution of and tracing of prescription drugs and prescription drug samples at the federal level, and sets minimum standards for the regulation of drug distributors by the states. The PDMA, its implementing regulations and state laws limit the distribution of prescription pharmaceutical product samples, and the DSCSA imposes requirements to ensure accountability in distribution and to identify and remove counterfeit and other illegitimate products from the market.
Section 505(b)(2) NDAs
NDAs for most new drug products are based on two full clinical studies which must contain substantial evidence of the safety and efficacy of the proposed new product. These applications are submitted under Section 505(b)(1) of the FDCA. The FDA is, however, authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA. This type of application allows the applicant to rely, in part, on the FDA’s previous findings of safety and efficacy for a similar product, or published literature. Specifically, Section 505(b)(2) applies to NDAs for a drug for which the investigations made to show whether or not the drug is safe for use and effective in use and relied upon by the applicant for approval of the application “were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.”
Thus, Section 505(b)(2) authorizes the FDA to approve an NDA based on safety and effectiveness data that were not developed by the applicant. NDAs filed under Section 505(b)(2) may provide an alternate and potentially more expeditious pathway to FDA approval for new or improved formulations or new uses of previously approved products. If the Section 505(b)(2) applicant can establish that reliance on the FDA’s
 
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previous approval is scientifically appropriate, the applicant may eliminate the need to conduct certain preclinical or clinical studies of the new product. The FDA may also require companies to perform additional studies or measurements to support the change from the approved product. The FDA may then approve the new drug candidate for all or some of the label indications for which the referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) applicant.
Abbreviated New Drug Applications for Generic Drugs
In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress authorized the FDA to approve generic drugs that are the same as drugs previously approved by the FDA under the NDA provisions of the statute. To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application (“ANDA”) to the agency. In support of such applications, a generic manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference-listed drug (“RLD”).
Specifically, in order for an ANDA to be approved, the FDA must find that the generic version is identical to the RLD with respect to the active ingredients, the route of administration, the dosage form, and the strength of the drug. At the same time, the FDA must also determine that the generic drug is “bioequivalent” to the innovator drug. Under the statute, a generic drug is bioequivalent to a RLD if “the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug...”
Upon approval of an ANDA, the FDA indicates whether the generic product is “therapeutically equivalent” to the RLD in its publication Approved Drug Products with Therapeutic Equivalence Evaluations, also referred to as the Orange Book. Clinicians and pharmacists consider a therapeutic equivalent generic drug to be fully substitutable for the RLD. In addition, by operation of certain state laws and numerous health insurance programs, the FDA’s designation of therapeutic equivalence often results in substitution of the generic drug without the knowledge or consent of either the prescribing clinicians or patient.
Under the Hatch-Waxman Amendments, the FDA may not approve an ANDA until any applicable period of
non-patent
exclusivity for the RLD has expired. The FDCA provides a period of five years of
non-patent
data exclusivity for a new drug containing a new chemical entity. For the purposes of this provision, a new chemical entity (“NCE”) is a drug that contains no active moiety that has previously been approved by the FDA in any other NDA. An active moiety is the molecule or ion responsible for the physiological or pharmacological action of the drug substance. In cases where such NCE exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the applicant may submit its application four years following the original product approval.
The FDCA also provides for a period of three years of exclusivity if the NDA includes reports of one or more new clinical investigations, other than bioavailability or bioequivalence studies, that were conducted by or for the applicant and are essential to the approval of the application. This three-year exclusivity period often protects changes to a previously approved drug product, such as a new dosage form, route of administration, combination or indication. Three-year exclusivity would be available for a drug product that contains a previously approved active moiety, provided the statutory requirement for a new clinical investigation is satisfied. Unlike five-year NCE exclusivity, an award of three-year exclusivity does not block the FDA from accepting ANDAs seeking approval for generic versions of the drug as of the date of approval of the original drug product. The FDA typically makes decisions about awards of data exclusivity shortly before a product is approved.
The FDA must establish a priority review track for certain generic drugs, requiring the FDA to review a drug application within eight months for a drug that has three or fewer approved drugs listed in the Orange Book and is no longer protected by any patent or regulatory exclusivities, or is on the FDA’s drug shortage list. The new legislation also authorizes the FDA to expedite review of competitor generic therapies or drugs with inadequate generic competition, including holding meetings with or providing advice to the drug sponsor prior to submission of the application.
 
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Hatch-Waxman Patent Certification and the
30-Month
Stay
Upon approval of an NDA or a supplement thereto, NDA sponsors are required to list with the FDA each patent with claims that cover the applicant’s product or an approved method of using the product. Each of the patents listed by the NDA sponsor is published in the Orange Book. When an ANDA applicant files its application with the FDA, the applicant is required to certify to the FDA concerning any patents listed for the reference product in the Orange Book, except for patents covering methods of use for which the ANDA applicant is not seeking approval. To the extent that the Section 505(b)(2) applicant is relying on studies conducted for an already approved product, the applicant is required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would.
Specifically, the applicant must certify with respect to each patent that:
 
   
the required patent information has not been filed;
 
   
the listed patent has expired;
 
   
the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration; or
 
   
the listed patent is invalid, unenforceable or will not be infringed by the new product.
A certification that the new product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is called a Paragraph IV certification. If the applicant does not challenge the listed patents or indicates that it is not seeking approval of a patented method of use, the ANDA application will not be approved until all the listed patents claiming the referenced product have expired (other than method of use patents involving indications for which the ANDA applicant is not seeking approval).
If the ANDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA and patent holders once the ANDA has been accepted for filing by the FDA. The NDA and patent holders may then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV certification. The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA until the earlier of 30 months after the receipt of the Paragraph IV notice, expiration of the patent, or a decision in the infringement case that is favorable to the ANDA applicant.
To the extent that the Section 505(b)(2) applicant is relying on studies conducted for an already approved product, the applicant is required to certify to the FDA concerning any patents listed for the approved product in the Orange Book to the same extent that an ANDA applicant would. As a result, approval of a Section 505(b)(2) NDA can be stalled until all the listed patents claiming the referenced product have expired, until any
non-patent
exclusivity, such as exclusivity for obtaining approval of an NCE, listed in the Orange Book for the referenced product has expired, and, in the case of a Paragraph IV certification and subsequent patent infringement suit, until the earlier of 30 months, settlement of the lawsuit or a decision in the infringement case that is favorable to the Section 505(b)(2) applicant.
Pediatric Studies and Exclusivity
Under the Pediatric Research Equity Act of 2003, an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the drug product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. With enactment of the Food and Drug Administration Safety and Innovation Act (“FDASIA”) in 2012, sponsors must also submit pediatric study plans prior to the assessment data. Those plans must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests, and other information required by regulation. The applicant, the FDA, and the FDA’s internal review committee must then review the information submitted,
 
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consult with each other, and agree upon a final plan. The FDA or the applicant may request an amendment to the plan at any time. For drugs intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of an applicant, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments. In addition, FDA will meet early in the development process to discuss pediatric study plans with drug sponsors. The legislation requires FDA to meet with drug sponsors by no later than the
end-of-phase
1 meeting for serious or life-threatening diseases and by no later than ninety days after FDA’s receipt of the study plan.
The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements. Additional requirements and procedures relating to deferral requests and requests for extension of deferrals are contained in FDASIA. Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation.
Pediatric exclusivity is another type of
non-patent
marketing exclusivity in the U.S. and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the
non-patent
and orphan exclusivity. This
six-month
exclusivity may be granted if an NDA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data. The data do not need to show the product to be effective in the pediatric population studied; rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted. If reports of requested pediatric studies are submitted to and accepted by the FDA within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patent protection cover the product are extended by six months. This is not a patent term extension, but it effectively extends the regulatory period during which the FDA cannot approve another application. With regard to patents, the
six-month
pediatric exclusivity period will not attach to any patents for which a generic (ANDA or 505(b)(2) NDA) applicant submitted a paragraph IV patent certification, unless the NDA sponsor or patent owner first obtains a court determination that the patent is valid and infringed by a proposed generic product.
Orphan Drug Designation and Exclusivity
Under the Orphan Drug Act, the FDA may designate a drug product as an “orphan drug” if it is intended to treat a rare disease or condition (generally meaning that it affects fewer than 200,000 individuals in the U.S., or more in cases in which there is no reasonable expectation that the cost of developing and making a drug product available in the U.S. for treatment of the disease or condition will be recovered from sales of the product). A company must request orphan product designation before submitting an NDA. If the request is granted, the FDA will disclose the identity of the therapeutic agent and its potential use. Orphan product designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.
If a product with orphan status receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or condition for which it was designated, the product generally will receive orphan product exclusivity. Orphan product exclusivity means that the FDA may not approve any other applications for the same product for the same indication for seven years, except in certain limited circumstances. Competitors may receive approval of different products for the indication for which the orphan product has exclusivity and may obtain approval for the same product but for a different indication. If a drug or drug product designated as an orphan product ultimately receives marketing approval for an indication broader than what was designated in its orphan product application, it may not be entitled to exclusivity.
Orphan drug exclusivity will not bar approval of another orphan drug under certain circumstances, including if a subsequent product with the same drug for the same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand. Legislation reverses prior precedent holding that the Orphan Drug Act unambiguously required the FDA to recognize orphan exclusivity regardless of a showing of clinical superiority.
 
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Patent Term Restoration and Extension
A patent claiming a new drug product may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent restoration of up to five years for patent term lost during product development and the FDA regulatory review. The restoration period granted is typically
one-half
the time between the effective date of an IND and the submission date of an NDA, plus the time between the submission date of an NDA and the ultimate approval date. Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date. Only one patent applicable to an approved drug product is eligible for the extension, and the application for the extension must be submitted prior to the expiration of the patent in question. A patent that covers multiple drugs for which approval is sought can only be extended in connection with one of the approvals. The USPTO reviews and approves the application for any patent term extension or restoration in consultation with the FDA. We cannot provide any assurance that any patent term extension with respect to any U.S. patent will be obtained and, if obtained, the duration of such extension, in connection with any of our product candidates.
Review and Approval of Animal Drugs in the U.S.
In addition to pursuing approval of our product candidates for use in human beings, we may also seek approval of certain product candidates for veterinary applications. As with new drug products for human beings, new animal drugs may not be marketed in the U.S. until they have been approved by the FDA as safe and effective. The requirements and phases governing approval of a new animal drug are analogous to those for new human drugs. Specifically, the Center for Veterinary Medicine (“CVM”) at FDA is responsible for determining whether a new veterinary product should be approved on the basis of a New Animal Drug Application (“NADA”) filed by the applicant. A NADA must contain substantial evidence of the safety and effectiveness of the animal drug, as well as data and controls demonstrating that the product will be manufactured and studied in compliance with, among other things, applicable cGMP and GLP practices.
To begin this process, an applicant must file an Investigational New Animal Drug application (“INAD”) with the CVM. The applicant will hold a
pre-development
meeting with the CVM to reach general agreement on the plans for providing the data necessary to fulfill requirements for a NADA. In this context, an applicant must submit pivotal protocols to the CVM for review and concurrence prior to conducting the required studies. The applicant will gather and submit data on safety, efficacy and chemistry, manufacturing and controls (“CMC”) to the CVM for review, as below:
 
Safety:
The design and review of the safety study and the study protocol are completed prior to initiation of the study to help assure that the data generated will meet FDA requirements. These studies are conducted under rigorous quality control, including GLP, to assure integrity of the data. They are designed to clearly define a safety margin, identify any potential safety concerns, and establish a safe dose for the product. This dose and effectiveness is then evaluated in the pivotal field efficacy study where the product is studied in the animal patient population in which the product is intended to be used.
 
Efficacy:
Early pilot studies may be done in laboratory cats or dogs to establish effectiveness and the dose range for each product. When an effective dose is established, a study protocol to test the product in real world conditions is developed prior to beginning the study. The pivotal field efficacy study protocol is submitted for review and concurrence prior to study initiation, to help assure that the data generated will meet requirements. This study must be conducted with the formulation of the product that is intended to be commercialized, and is a multi-site, randomized, controlled study, generally with a placebo control.
 
CMC:
To assure that the new animal drug product can be manufactured consistently, FDA will require applicants to provide documentation of the process by which the active ingredient is made and the controls applicable to that process that assure the active ingredient and the formulation of the final commercial product meet certain criteria, including purity and stability. After a product is approved, applicants will be required to communicate with FDA before any changes are made to these procedures or at the manufacturing site. Both the active ingredient and commercial formulations are required to be manufactured at facilities that practice cGMP.
 
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Once all data have been submitted and reviewed for each technical section—safety, efficacy and CMC—the CVM will issue a technical section complete letter as each section review is completed. When the three letters have been issued, the applicant will compile a draft of the Freedom of Information Summary, the proposed labeling, and all other relevant information, and submit these as an administrative NADA for CVM review. Generally, if there are no deficiencies in the submission, the NADA will be issued within four to six months after submission of the administrative NADA. This review will be conducted according to timelines specified in the Animal Drug User Fee Act. The FDA’s basis for approving a NADA is documented in a Freedom of Information Summary. Post-approval monitoring of products is required by law, with reports being provided to the CVM’s Surveillance and Compliance group. Reports of product quality defects, AEs or unexpected results must also be produced in accordance with the relevant regulatory requirements.
Review and Approval of Drug Products in the European Union
In order to market any product outside of the U.S., a company must also comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of products. Whether or not it obtains FDA approval for a product, the company would need to obtain the necessary approvals by the comparable foreign regulatory authorities before it can commence clinical trials or marketing of the product in those countries or jurisdictions. The approval process ultimately varies between countries and jurisdictions and can involve additional product testing and additional administrative review periods. The time required to obtain approval in other countries and jurisdictions might differ from and be longer than that required to obtain FDA approval. Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.
Procedures Governing Approval of Drug Products
Pursuant to the European Clinical Trials Directive, a system for the approval of clinical trials in the EU has been implemented through national legislation of the member states. Under this system, an applicant must obtain approval from the competent national authority of an EU member state in which the clinical trial is to be conducted. Furthermore, the applicant may only start a clinical trial after a competent ethics committee has issued a favorable opinion. Clinical trial application must be accompanied by an investigational medicinal product dossier (“IMPD”) with supporting information prescribed by the European Clinical Trials Directive and corresponding national laws of the member states and further detailed in applicable guidance documents.
To obtain marketing approval of a product under EU regulatory systems, an applicant must submit an MAA either under a centralized or decentralized procedure. The centralized procedure provides for the grant of a single marketing authorization by the EC that is valid for all EU member states. The centralized procedure is compulsory for specific products, including for medicines produced by certain biotechnological processes, products designated as orphan medicinal products, advanced therapy products and products with a new active substance indicated for the treatment of certain diseases. For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, the centralized procedure may be optional.
Under the centralized procedure, the CHMP established at the EMA is responsible for conducting the initial assessment of a product. The CHMP is also responsible for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization. Under the centralized procedure in the EU, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops, when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CHMP. Accelerated evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation. In this circumstance, the EMA ensures that the opinion of the CHMP is given within 150 days.
 
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The decentralized procedure is available to applicants who wish to market a product in various EU member states where such product has not received marketing approval in any EU member states before. The decentralized procedure provides for approval by one or more other, or concerned, member states of an assessment of an application performed by one member state designated by the applicant, known as the reference member state. Under this procedure, an applicant submits an application based on identical dossiers and related materials, including a draft summary of product characteristics, and draft labeling and package leaflet, to the reference member state and concerned member states. The reference member state prepares a draft assessment report and drafts of the related materials within 210 days after receipt of a valid application. Within 90 days of receiving the reference member state’s assessment report and related materials, each concerned member state must decide whether to approve the assessment report and related materials.
If a member state cannot approve the assessment report and related materials on the grounds of potential serious risk to public health, the disputed points are subject to a dispute resolution mechanism and may eventually be referred to the EC, whose decision is binding on all member states.
Within this framework, manufacturers may seek approval of hybrid medicinal products under Article 10(3) of Directive 2001/83/EC. Hybrid applications rely, in part, on information and data from a reference product and new data from appropriate preclinical tests and clinical trials. Such applications are necessary when the proposed product does not meet the strict definition of a generic medicinal product, or bioavailability studies cannot be used to demonstrate bioequivalence, or there are changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration of the generic product compared to the reference medicinal product. In such cases the results of tests and trials must be consistent with the data content standards required in the Annex to the Directive 2001/83/EC, as amended by Directive 2003/63/EC.
Hybrid medicinal product applications have automatic access to the centralized procedure when the reference product was authorized for marketing via that procedure. Where the reference product was authorized via the decentralized procedure, a hybrid application may be accepted for consideration under the centralized procedure if the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation, or the granting of a community authorization for the medicinal product is in the interest of patients at the community level.
Clinical Trial Approval
Requirements for the conduct of clinical trials in the EU including GCP are set forth in the Clinical Trials Directive 2001/20/EC and the GCP Directive 2005/28/EC. Pursuant to Directive 2001/20/EC and Directive 2005/28/EC, as amended, a system for the approval of clinical trials in the EU has been implemented through national legislation of the EU member states. Under this system, approval must be obtained from the competent national authority of each EU member state in which a study is planned to be conducted. To this end, a clinical trial application is submitted, which must be supported by an IMPD and further supporting information prescribed by Directive 2001/20/EC and Directive 2005/28/EC and other applicable guidance documents. Furthermore, a clinical trial may only be started after a competent ethics committee has issued a favorable opinion on the clinical trial application in that country.
In April 2014, the EU passed the new Clinical Trials Regulation, (EU) No 536/2014, which will replace the current Clinical Trials Directive 2001/20/EC. To ensure that the rules for clinical trials are identical throughout the EU, the new EU clinical trials legislation was passed as a regulation that is directly applicable in all EU member states. All clinical trials performed in the EU are required to be conducted in accordance with the Clinical Trials Directive 2001/20/EC until the new Clinical Trials Regulation (EU) No 536/2014 becomes applicable. The Clinical Trials Directive 2001/20/EC will, however, still apply three years from the date of entry into application of the Clinical Trials Regulation to (i) clinical trials applications submitted before the entry into application and (ii) clinical trials applications submitted within one year after the entry into application if the sponsor opts for old system.
 
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The new Clinical Trials Regulation aims to simplify and streamline the approval of clinical trials in the EU. The main characteristics of the regulation include: a streamlined application procedure via a single entry point, the EU portal; a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures that will spare sponsors from submitting broadly identical information separately to various bodies and different member states; a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts (Part I is assessed jointly by all member states concerned, and Part II is assessed separately by each member state concerned); strictly defined deadlines for the assessment of clinical trial applications; and the involvement of the ethics committees in the assessment procedure in accordance with the national law of the member state concerned but within the overall timelines defined by the Clinical Trials Regulation.
The Regulation was published on June 16, 2014 but has not yet become effective. As of January 1, 2020, the website of the EC reported that the implementation of the Clinical Trials Regulation was dependent on the development of a fully functional clinical trials portal and database, which would be confirmed by an independent audit, and that the new legislation would come into effect six months after the EC publishes a notice of this confirmation. The website indicated that the audit was expected to commence in December 2020. In late 2020, the EMA indicated that it plans to focus on the findings of a system audit; improving the usability, quality and stability of the clinical trial information system; and knowledge transfer to prepare users and their organizations for the new clinical trial system. The EMA has indicated that the system will go live in December 2021.
As in the U.S., parties conducting certain clinical trials must post clinical trial information in the EU at the EudraCT website: https://eudract.ema.europa.eu.
PRIME Designation
In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist. The PRIority Medicines (“PRIME”) scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation reviewed under the centralized procedure. Products from small- and
medium-sized
enterprises (“SMEs”) may qualify for earlier entry into the PRIME scheme than larger companies. Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated MAA assessment once a dossier has been submitted. Importantly, a dedicated Agency contact and rapporteur from the CHMP or Committee for Advanced Therapies are appointed early in PRIME scheme facilitating increased understanding of the product at EMA’s Committee level. A
kick-off
meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.
Periods of Authorization and Renewals
Marketing authorization is valid for five years in principle and the marketing authorization may be renewed after five years on the basis of a
re-evaluation
of the risk-benefit balance by the EMA or by the competent authority of the authorizing member state. To this end, the marketing authorization holder must provide the EMA or the competent authority with a consolidated version of the file with respect to quality, safety and efficacy, including all variations introduced since the marketing authorization was granted, at least six months before the marketing authorization ceases to be valid. Once renewed, the marketing authorization is valid for an unlimited period, unless the EC or the competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal. Any authorization which is not followed by the actual placing of the drug on the EU market (in case of centralized procedure) or on the market of the authorizing member state within three years after authorization ceases to be valid (the
so-called
sunset clause).
 
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Data and Market Exclusivity
In the EU, NCEs qualify for eight years of data exclusivity upon marketing authorization and an additional two years of market exclusivity. This data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic (abbreviated) application for eight years, after which generic marketing authorizations can be submitted, and the innovator’s data may be referenced, but not approved for two years. The overall
ten-year
period will be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies. Even if a compound is considered to be a new chemical entity and the sponsor is able to gain the prescribed period of data exclusivity, another company nevertheless could also market another version of the product if such company can complete a full MAA with a complete database of pharmaceutical test, preclinical tests and clinical trials and obtain marketing approval of its product.
Orphan Drug Designation and Exclusivity
Regulation 141/2000 provides that a drug shall be designated as an orphan drug if its sponsor can establish: that the product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the European Community when the application is made, or that the product is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the European Community and that without incentives it is unlikely that the marketing of the drug in the European Community would generate sufficient return to justify the necessary investment. For either of these conditions, the applicant must demonstrate that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the European Community or, if such method exists, the drug will be of significant benefit to those affected by that condition.
Regulation 847/2000 sets out criteria and procedures governing designation of orphan drugs in the EU. Specifically, an application for designation as an orphan product can be made any time prior to the filing of an application for approval to market the product. Marketing authorization for an orphan drug leads to a
ten-year
period of market exclusivity. This period may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan drug designation, for example because the product is sufficiently profitable not to justify market exclusivity. Market exclusivity can be revoked only in very selected cases, such as consent from the marketing authorization holder, inability to supply sufficient quantities of the product, demonstration of “clinically relevant superiority” by a similar medicinal product, or, after a review by the Committee for Orphan Medicinal Products, requested by a member state in the fifth year of the marketing exclusivity period (if the designation criteria are believed to no longer apply). Medicinal products designated as orphan drugs pursuant to Regulation 141/2000 shall be eligible for incentives made available by the European Community and by the member states to support research into, and the development and availability of, orphan drugs.
Regulatory Requirements after Marketing Authorization
As in the U.S., both marketing authorization holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA and the competent authorities of the individual EU Member States both before and after grant of the manufacturing and marketing authorizations. The holder of an EU marketing authorization for a medicinal product must, for example, comply with EU pharmacovigilance legislation and its related regulations and guidelines which entail many requirements for conducting pharmacovigilance, or the assessment and monitoring of the safety of medicinal products. The manufacturing process for medicinal products in the EU is also highly regulated and regulators may shut down manufacturing facilities that they believe do not comply with regulations. Manufacturing requires a manufacturing authorization, and the manufacturing authorization holder must comply with various requirements set out in the applicable EU laws, including compliance with EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients.
 
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In the EU, the advertising and promotion of approved products are subject to EU Member States’ laws governing promotion of medicinal products, interactions with clinicians, misleading and comparative advertising and unfair commercial practices. In addition, other legislation adopted by individual EU Member States may apply to the advertising and promotion of medicinal products. These laws require that promotional materials and advertising in relation to medicinal products comply with the product’s Summary of Product Characteristics (“SmPC”) as approved by the competent authorities. Promotion of a medicinal product that does not comply with the SmPC is considered to constitute
off-label
promotion, which is prohibited in the EU.
General Data Protection Regulation
The collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the EU, including personal health data, is subject to the EU General Data Protection Regulation (“GDPR”), which became effective on May 25, 2018. The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors. The GDPR also imposes strict rules on the transfer of personal data to countries outside the EU, including the U.S., and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater. The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the GDPR.
Brexit and the Regulatory Framework in the United Kingdom
On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the EU, commonly referred to as Brexit. Following protracted negotiations, the United Kingdom left the EU on January 31, 2020. Under the withdrawal agreement, there was a transitional period until December 31, 2020 (extendable by up to two years). On December 24, 2020, the United Kingdom and the EU entered into a Trade and Cooperation Agreement. The agreement sets out certain procedures for approval and recognition of medical products in each jurisdiction. Since the regulatory framework for pharmaceutical products in the United Kingdom covering quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit could materially impact the future regulatory regime that applies to products and the approval of product candidates in the United Kingdom.
Furthermore, while the Data Protection Act of 2018 in the United Kingdom that “implements” and complements the GDPR, has achieved Royal Assent on May 23, 2018 and is now effective in the United Kingdom, it is still unclear whether transfer of data from the European Economic Area (“EEA”) to the United Kingdom will remain lawful under GDPR. The Trade and Cooperation Agreement provides for a transitional period during which the United Kingdom will be treated like an EU member state in relation to processing and transfers of personal data for four months from January 1, 2021. This may be extended by two further months. After such period, the United Kingdom will be a “third country” under the GDPR unless the EC adopts an adequacy decision with respect to transfers of personal data to the United Kingdom. The United Kingdom has already determined that it considers all of the EU 27 and EEA member states to be adequate for the purposes of data protection, ensuring that data flows from the United Kingdom to the EU/EEA remain unaffected.
 
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Pricing Decisions for Approved Products
In the EU, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only after a reimbursement price has been agreed. Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular product candidate to currently available therapies or
so-called
health technology assessments, in order to obtain reimbursement or pricing approval. For example, EU Member States have the option to restrict the range of products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. EU Member States may approve a specific price for a product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market. Other EU Member States allow companies to fix their own prices for products, but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions. Recently, many countries in the EU have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries attempt to manage health care expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the EU. The downward pressure on health care costs in general, particularly prescription products, has become intense. As a result, increasingly high barriers are being erected to the entry of new products. Political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Reference pricing used by various EU Member States, and parallel trade, i.e., arbitrage between
low-priced
and high-priced EU Member States, can further reduce prices. There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries.
Pharmaceutical Coverage, Pricing and Reimbursement
Significant uncertainty exists as to the coverage and reimbursement status of products approved by the FDA and other government authorities. Sales of products will depend, in part, on the extent to which third-party payors, including government health programs in the U.S. such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage, and establish adequate reimbursement levels for, such products. The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved. Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the approved products for a particular indication.
In order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the product, in addition to the costs required to obtain FDA or other comparable regulatory approvals. Payors also set other criteria to govern the uses of a drug that will be deemed medically appropriate and therefore reimbursed or otherwise covered. In particular, many public and private health care payors limit reimbursement and coverage to the uses of a drug that are either approved by the FDA or that are supported by other appropriate evidence (for example, published medical literature) and appear in a recognized drug compendium. Drug compendia are publications that summarize the available medical evidence for particular drug products and identify which uses of a drug are supported or not supported by the available evidence, whether or not such uses have been approved by the FDA. Nonetheless, product candidates may not be considered medically necessary or cost effective. Additionally, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Further, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage for the drug product. Third-party reimbursement may not be sufficient to maintain price levels high enough to realize an appropriate return on investment in product development.
 
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The containment of healthcare costs also has become a priority of federal, state and foreign governments and the prices of drugs have been a focus in this effort. Governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on reimbursement and requirements for substitution of generic products. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit a company’s revenue generated from the sale of any approved products. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which a company or its collaborators receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.
In the U.S., we participate in, and have certain price reporting obligations to, the Medicaid Drug Rebate program, several state Medicaid supplemental rebate programs, and other governmental pricing programs. We also have obligations to report the average sales price for certain of our drugs to the Medicare program. Under the Medicaid Drug Rebate program, we are required to pay a rebate to each state Medicaid program for our covered outpatient drugs that are dispensed to Medicaid beneficiaries and paid for by a state Medicaid program as a condition of having federal funds being made available to the states for our drugs under Medicaid.
Medicaid is a joint federal and state program that is administered by the states for low income and disabled beneficiaries. Medicaid rebates are based on pricing data reported by us on a monthly and quarterly basis to the Centers for Medicare & Medicaid Services (“CMS”), the federal agency that administers the Medicaid and Medicare programs. These data include the average manufacturer price and, in the case of innovator products, the best price for each drug which, in general, represents the lowest price available from the manufacturer to any entity in the U.S. in any pricing structure, calculated to include all sales and associated rebates, discounts, and other price concessions. The amount of the rebate is adjusted upward if average manufacture price increases more than inflation (measured by reference to the Consumer Price Index—Urban). If we become aware that our reporting for a prior quarter was incorrect, or has changed as a result of recalculation of the pricing data, we are obligated to resubmit the corrected data for up to three years after those data originally were due, which revisions could affect our rebate liability for prior quarters.
Medicare is a federal program that is administered by the federal government that covers individuals age 65 and over or that are disabled as well as those with certain health conditions. Manufacturer-submitted information is used by CMS to calculate Medicare payment rates. Civil monetary penalties can be applied if we are found to have knowingly submitted any false pricing or other information to the government, if we are found to have made a misrepresentation in the reporting of our average sales price, or if we fail to submit the required data on a timely basis. Such conduct also could be grounds for CMS to terminate our Medicaid drug rebate agreement, in which case federal payments may not be available under Medicaid for our covered outpatient drugs.
Federal law requires that any company that participates in the Medicaid Drug Rebate program also participate in the Public Health Service’s 340B drug pricing program (the “340B program”) in order for federal funds to be available for the manufacturer’s drugs under Medicaid. The 340B program, which is administered by the Health Resources and Services Administration (“HRSA”) requires participating manufacturers to agree to charge statutorily defined covered entities no more than the 340B “ceiling price” for the manufacturer’s covered outpatient drugs. Covered entities include hospitals that serve a disproportionate share of financially needy patients, community health clinics, and other entities that receive certain types of grants under the Public Health Service Act. The 340B ceiling price is calculated using a statutory formula, which is based on the average manufacturer price and Medicaid rebate amount for the covered outpatient drug as calculated under the Medicaid Drug Rebate program. In general, products subject to Medicaid price reporting and rebate liability are also subject to the 340B ceiling price calculation and discount requirement. HRSA requires the federal ceiling price to be reported quarterly.
HRSA issued a final regulation regarding the calculation of the 340B ceiling price and the imposition of civil monetary penalties on manufacturers that knowingly and intentionally overcharge covered entities, which became effective on January 1, 2019. It is currently unclear how HRSA will apply its enforcement authority
 
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under the new regulation. Any charge by HRSA that we have violated the requirements of the regulation could result in civil monetary penalties. HRSA also implemented a new price reporting system during the first quarter of 2019, under which manufacturers are now required to report their 340B ceiling prices to HRSA on a quarterly basis. In addition, legislation may be introduced that, if passed, would further expand the 340B program to additional covered entities or would require participating manufacturers to agree to provide 340B discounted pricing on drugs used in an inpatient setting.
Outside the U.S., ensuring adequate coverage and payment for our product candidates will face challenges. Pricing of prescription pharmaceuticals is subject to governmental control in many countries. Pricing negotiations with governmental authorities can extend well beyond the receipt of regulatory marketing approval for a product and may require us to conduct a clinical trial that compares the cost effectiveness of our product candidates or products to other available therapies. The conduct of such a clinical trial could be expensive and result in delays in our commercialization efforts.
 
Healthcare Law and Regulation
Healthcare providers and third-party payors play a primary role in the recommendation and prescription of drug products that are granted regulatory approval. Arrangements with providers, consultants, third-party payors and customers are subject to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain our business and/or financial arrangements. Such restrictions under applicable federal and state healthcare laws and regulations, include the following:
 
   
the federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;
 
   
the federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalties laws, which prohibit individuals or entities from, among other things, 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 civil monetary penalty and false statement laws and regulations relating to pricing and submission of pricing information for government programs, including penalties for knowingly and intentionally overcharging 340B eligible entities and the submission of false or fraudulent pricing information to government entities;
 
   
the federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”), which created additional federal criminal laws that prohibit, among other things, knowingly and willingly executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;
 
   
HIPAA and HITECH and their implementing regulations, which also imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
 
   
the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the Patient Protection and Affordable Care Act, as amended by the Health Care Education Reconciliation Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to CMS within the U.S. Department of Health and Human Services, information related to payments and other transfers of value to clinicians and teaching hospitals (and beginning in 2022, additional
non-physician
clinicians including physician assistants and nurse practitioners) and clinician ownership and investment interests; and
 
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analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to healthcare items or services that are reimbursed by
non-governmental
third-party payors, including private insurers.
Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government in addition to requiring drug manufacturers to report information related to payments to clinicians 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 preempted by HIPAA, thus complicating compliance efforts.
Healthcare Reform
A primary trend in the U.S. healthcare industry and elsewhere is cost containment. There have been a number of federal and state proposals during the last few years regarding the pricing of pharmaceutical and biopharmaceutical products, limiting coverage and reimbursement for drugs and other medical products, government control and other changes to the healthcare system in the U.S.
By way of example, the U.S. and state governments continue to propose and pass legislation designed to reduce the cost of healthcare. In March 2010, Congress enacted the Patient Protection and Affordable Care Act (“ACA”), which, among other things, includes changes to the coverage and payment for products under government health care programs. Among the provisions of the ACA of importance to our products and product candidates are:
 
   
an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents, apportioned among these entities according to their market share in certain government healthcare programs, although this fee would not apply to sales of certain products approved exclusively for orphan indications;
 
   
expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate liability;
 
   
expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and generic drugs and revising the definition of “average manufacturer price” for calculating and reporting Medicaid drug rebates on outpatient prescription drug prices and extending rebate liability to prescriptions for individuals enrolled in Medicare Advantage plans;
 
   
addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected;
 
   
expanded the types of entities eligible for the 340B drug discount program;
 
   
established the Medicare Part D coverage gap discount program by requiring manufacturers to provide a 50%
point-of-sale-discount
off the negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’ outpatient drugs to be covered under Medicare Part D;
 
   
a Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research;
 
   
the Independent Payment Advisory Board (“IPAB”), which has authority to recommend certain changes to the Medicare program to reduce expenditures by the program that could result in reduced payments for prescription drugs. However, the IPAB implementation has been not been clearly defined. The ACA provided that under certain circumstances, IPAB recommendations will become law unless Congress enacts legislation that will achieve the same or greater Medicare cost savings; and
 
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established the Center for Medicare and Medicaid Innovation within CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending. Funding has been allocated to support the mission of the Center for Medicare and Medicaid Innovation from 2011 to 2019.
Other legislative changes have been proposed and adopted in the U.S. since the ACA was enacted. In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs. This includes aggregate reductions of Medicare payments to providers up to 2% per fiscal year, which went into effect in April 2013 and, due to subsequent legislative amendments, will remain in effect through 2029 unless additional Congressional action is taken. The Coronavirus Aid, Relief, and Economic Security Act (the “CARES Act”) and other
COVID-19
relief legislation, suspended the 2% Medicare sequester from May 1, 2020 through March 3, 2021, and extended the sequester by one year, through 2030. In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
Since enactment of the ACA, there have been and continue to be numerous legal challenges and Congressional actions to repeal and replace provisions of the law. For example, with enactment of the Tax Cuts and Jobs Act of 2017, which was signed by President Trump on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019. Additionally, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the
ACA-mandated
“Cadillac” tax on high-cost employer-sponsored health coverage and medical device tax and, effective January 1, 2021, also eliminates the health insurer tax. Further, the Bipartisan Budget Act of 2018, among other things, amended the ACA, effective January 1, 2019, to increase from 50 percent to 70 percent the
point-of-sale
discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole”. The Congress will likely consider other legislation to replace elements of the ACA during the next Congressional session.
In addition, on December 14, 2018, a U.S. District Court judge in the Northern District of Texas ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Cuts and Jobs Act, the remaining provisions of the ACA are invalid as well. On December 18, 2019, the Court of Appeals for the Fifth Circuit affirmed the lower court’s ruling that the individual mandate portion of the ACA is unconstitutional and it remanded the case to the district court for reconsideration of the severability question and additional analysis of the provisions of the ACA. On January 21, 2020, the U.S. Supreme Court declined to review this decision on an expedited basis but subsequently agreed to hear the case on its regular calendar. On November 10, 2020, the Court heard oral argument. It is expected to issue a decision sometime this year. Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.
The Trump Administration also took executive actions to undermine or delay implementation of the ACA, including directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices. On January 28, 2021, however, President Biden issued a new Executive Order which directs federal agencies to reconsider rules and other policies that limit Americans’ access to health care, and consider actions that will protect and strengthen that access. Under this Order, federal agencies are directed to re-examine: policies that undermine protections for people with pre-existing conditions, including complications related to COVID-19; demonstrations and waivers under Medicaid and the ACA that may reduce
 
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coverage or undermine the programs, including work requirements; policies that undermine the Health Insurance Marketplace or other markets for health insurance; policies that make it more difficult to enroll in Medicaid and the ACA; and policies that reduce affordability of coverage or financial assistance, including for dependents.
Further, there have been several recent U.S. congressional inquiries and proposed federal and proposed and enacted state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products. For example, on May 11, 2018, the Trump Administration issued a plan to lower drug prices. In addition, the Trump Administration published a final rulemaking that allows states or certain other
non-federal
government entities to submit importation program proposals to the FDA for review and approval. Applicants would be required to demonstrate that their importation plans pose no additional risk to public health and safety and will result in significant cost savings for consumers. At the same time, FDA issued draft guidance that would allow manufacturers to import their own
FDA-approved
drugs that are authorized for sale in other countries (multi-market approved products). In addition, President Trump issued five executive orders intended to lower the costs of prescription drug products. Several of these orders are reflected in recently promulgated regulations, and one of these regulations is currently subject to a nationwide preliminary injunction. It remains to be seen whether these orders and resulting regulations will remain in force during the Biden Administration.
At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs. These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our products or additional pricing pressures.
Human Capital Resources
We believe that the success of our business is fundamentally due to our greatest asset, our employees. To that end, we have invested significant resources towards the attraction, retention and development of personnel and the promotion and maintenance of diversity in our workforce. To support these objectives, our human resources programs reflect our commitment to our core values (Innovation, Courage, Urgency, Resiliency and Energy) and are designed to prioritize our employees’ well-being, support their career goals, offer competitive wages and benefits, and enhance our culture through efforts aimed at making the workplace more satisfying, engaging and inclusive.
In order to attract, retain and reward our employees, we provide competitive compensation and benefits packages. We currently offer all new employees equity in the company and as incentive awards to all our employees in connection with our annual performance reviews. Our equity and cash incentive plans are aimed to increase stockholder value and the success of our company by motivating our employees to perform to the best of their abilities and achieve our and their objectives. In addition, many of our employees are stockholders of the Company through participation in our Employee Stock Purchase Plan, which aligns the interests of our employees with our stockholders by providing stock ownership on a
tax-deferred
basis. We also provide a 4% match for employee contributions to our Section 401(k) retirement savings plan.
We strive to provide our employees with a safe and healthy work environment and believe that the overall health, safety and wellness of our employees is critical to our long-term success and our growth as a business. As
 
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such, we provide our employees and their families with access to a variety of innovative, flexible and convenient health and wellness programs, including benefits that provide protection and security so they can have peace of mind concerning events that may require time away from work or that impact their financial well-being. Our full-time employees are all eligible to participate in our health, vision, dental, life, and long-term disability insurance plans. To encourage employees to keep up with routine medical care and participate in our wellness program, we fund a Health Reimbursement Account for participating employees and to help our employees cover medical expenses
pre-tax,
we also offer employees a Flexible Spending Account. Our employees outside the U.S. receive competitive compensation and benefits that are regularly benchmarked to ensure market norms and reflect our standards.
We encourage and support the growth and development of our employees and, wherever possible, seek to fill positions by promotion, transfer from within the organization and through our employee referral process. Continual learning and career development is advanced through ongoing performance and development conversations with employees, training programs, customized corporate training engagements and seminars and other training events employees are encouraged to attend in connection with their job duties.
Further, we strongly believe that diversity is a key driver of success. We strive to bring together employees with a wide variety of backgrounds, skills and culture and encourage all of our employees to maintain a work environment in which our differences are respected.
As of February 16, 2021, we had 432 employees. None of our employees are represented by a labor union or covered by a collective bargaining agreement, nor have we experienced work stoppages. We believe that relations with our employees are good.
Corporate Responsibility
We are highly committed to policies and practices focused on environmental, social and corporate governance (“ESG”) positively impacting our social community and maintaining and cultivating good corporate governance. By focusing on such ESG policies and practices, we believe we can affect a meaningful and positive change in our community and maintain our open, collaborative corporate culture. Some of the initiatives that we were most proud of in 2020 included donating thousands of personal protection equipment items to hospitals, cancer centers, veterans organizations, and various community groups across the U.S. and around the globe in response to the
COVID-19
pandemic. We were also proud to actively support a number of scholarship and mentoring programs for students in underserved communities as well as those interested in pursuing degrees in science and technology.
We look forward to continuing our commitment to giving back to our local communities in 2021 and beyond.
 
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Information about our Executive Officers
The following table lists the positions, names and ages of our current executive officers:
 
Name
  
Age
    
Position
Michael G. Kauffman, M.D., Ph.D.
     57      Chief Executive Officer and Director
Sharon Shacham, Ph.D., M.B.A.
     50      President and Chief Scientific Officer
John Demaree
     53      Chief Commercial Officer
Ran Frenkel, RPh.
     52      Executive Vice President, Chief Development Officer
Tanya Lewis, M.S.
     50      Executive Vice President, Chief Regulatory Affairs and Strategic Operations
Michael Mano
     44      Senior Vice President, General Counsel and Secretary
Michael Mason
     46      Senior Vice President, Chief Financial Officer and Treasurer
Stephen Mitchener
     42      Senior Vice President, Chief Business Officer
Jatin Shah, M.D.
     46      Executive Vice President, Chief Medical Officer
Michael G. Kauffman, M.D., Ph.D
. Dr. Kauffman has served as Karyopharm’s Chief Executive Officer since January 2011 and has been one of our directors since 2008. Dr. Kauffman
co-founded
Karyopharm with Dr. Sharon Shacham in 2008 and served as our President from 2011 to 2013 and as Chief Medical Officer from 2012 to 2013. Prior to joining Karyopharm, he was Chief Medical Officer of Onyx Pharmaceuticals Inc. (“Onyx”), a public biopharmaceutical company, from 2009 to 2010. From 2008 to 2009, Dr. Kauffman was Chief Medical Officer of Proteolix Inc., which was acquired by Onyx. At Proteolix, he led the development of Kyprolis
®
(carfilzomib), a novel proteasome inhibitor approved in refractory myeloma by the FDA in 2012. Dr. Kauffman was an operating partner at Bessemer Venture Partners from 2006 to 2008, where he led investments in biotechnology companies. From 2006 to 2008, he was President and Chief Executive Officer of Epix Pharmaceuticals, Inc. (“Epix”), a public biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009. Dr. Kauffman was President and Chief Executive Officer of Predix Pharmaceuticals, Inc. (“Predix”), a private biopharmaceutical company focused on G protein-coupled receptors, from 2002 until its merger into Epix in 2006. In that role, he led the merger of Predix and Epix, oversaw the discovery and development of four new clinical candidates and led collaboration transactions with Amgen and GlaxoSmithKline plc. From 2000 to 2002, Dr. Kauffman was Vice President, Clinical at Millennium Pharmaceuticals, Inc. (“Millennium”), a biopharmaceutical company, where he led the Velcade
®
development program. From 1997 to 2000, Dr. Kauffman held a number of senior positions at Millennium Predictive Medicine, Inc., a biopharmaceutical company and a subsidiary of Millennium, where he led the discovery and development of novel molecular diagnostics for major cancers, including melanoma and led transactions with Becton-Dickenson and Bristol Myers Squibb. From 1995 to 1997, Dr. Kauffman held a number of senior positions at Biogen Idec, Inc., a biopharmaceutical company, where he led the clinical development of anti-CD40L antibodies in autoimmune and inflammatory diseases, and acted as the main medical advisor to the Biogen business development group. Dr. Kauffman has served on the Board of Directors, the Audit Committee and as Chairman of the Compensation Committee of Kezar Life Sciences, Inc., a public biopharmaceutical company, since December 2016 and has been the lead director and a member of the Compensation Committee of Verastem Inc., a public biopharmaceutical company, since 2012. Dr. Kauffman previously served on the Board of Directors, Nominating and Governance Committee and Research and Development Committee of Infinity Pharmaceuticals, Inc., a public biopharmaceutical company, from April 2017 to March 2020. Dr. Kauffman received his B.A. in Biochemistry from Amherst College and his M.D. and Ph.D. from Johns Hopkins Medical School, and he trained in internal medicine and rheumatology at Beth Israel Hospital (now Beth Israel Deaconess Medical Center) and Massachusetts General Hospital. He is board certified in internal medicine.
 
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Sharon
Shacham
, Ph.D., M.B.A.
Dr. Shacham founded Karyopharm in 2008, has served as our Chief Scientific Officer since 2010 and as our President since 2013. Dr. Shacham served as our President of Research and Development from 2012 to 2013, as our Head of Research and Development from 2010 to 2012 and as our President and Chief Executive Officer from 2010 to 2011. Dr. Shacham established the company to focus on the discovery and development of small molecule inhibitors of nuclear export and has led our scientific progress since inception. Her computational drug discovery algorithms formed a critical part of the technological basis for our drug discovery and optimization expertise, which was used for the discovery of selinexor, our lead product. Dr. Shacham
co-chairs
our Scientific Advisory Board. Prior to founding Karyopharm, from 2006 to 2009, she was Senior Vice President of Drug Development at Epix, a biopharmaceutical company that underwent liquidation proceedings through an assignment for the benefit of creditors under Massachusetts law in 2009. She was Director, Algorithm and Software Development at Predix from 2000 until Predix’s merger into Epix in 2006, where she led the company’s efforts in GPCR modeling, computational chemistry, lead optimization and development of clinical trials. Dr. Shacham received her B.Sc. in Chemistry, Ph.D. and M.B.A. from Tel Aviv University.
John Demaree, M.B.A.
Mr. Demaree
has served as our Chief Commercial Officer since March 2020. Prior to joining Karyopharm, Mr. Demaree
served as Chief Commercial Officer at G1 Therapeutics, Inc. (“G1”), a biopharmaceutical company, from July 2018 to March 2020 led its integrated commercial functions. Prior to G1, Mr. Demaree served as Vice President, Oncology Marketing at Astellas Pharma US, a pharmaceutical company, from July 2016 to July 2018 and as Executive Director from 2011 to July 2016, where he was responsible for establishing and leading the oncology marketing function, including the successful launch of XTANDI
®
(enzalutamide). Previously, Mr. Demaree led oncology business development and alliance management at Abbott Laboratories. He began his career serving in marketing leadership positions at Novartis and Eli Lilly. Mr. Demaree
holds an M.B.A. in marketing and finance and a B.S. in marketing from Indiana University.
Ran Frenkel, RPh.
Mr. Frenkel was appointed Executive Vice President, Worldwide Development Operations of Karyopharm in 2014, Executive Vice President, Chief Development Operations Officer from 2015 to August 2020 and EVP, Chief Development Officer in August 2020. Prior to joining Karyopharm, Mr. Frenkel held a number of senior management roles in Europe, Israel and the U.S., most recently as Managing Director EMEA from 2013 to 2014 for Clinipace Worldwide, an international clinical research organization, where he had responsibility for the overall management of the organization in Europe, the Middle East and Africa. Prior to becoming Managing Director EMEA, Mr. Frenkel was Vice President of International Business Development at Clinipace Worldwide from 2011 to 2013. Prior to joining Clinipace Worldwide, from 2007 to 2011, Mr. Frenkel established and managed the Israeli office of PFC Pharma Focus AG, which was acquired by Clinipace Worldwide in 2011, and from 2004 to 2007, he held the position of Managing Director at Actelion Pharmaceuticals with responsibility for all science and business affairs of the company in Israel. Mr. Frenkel received a BPharm from Hebrew University.
Tanya Lewis, M.S.
Ms. Lewis joined Karyopharm in November 2018 as Senior Vice President, Regulatory and Quality Affairs and was appointed Executive Vice President, Chief Regulatory and Quality Officer in October 2019 and Executive Vice President, Chief Regulatory Affairs and Strategic Operations in October 2020. Prior to joining Karyopharm, Ms. Lewis held several leadership roles across the biopharmaceutical industry where she was instrumental in the successful negotiations for registration trial designs, approval, and/or commercialization of Velcade
®
, Varubi
®
, Integrilin
®
and Zejula
®
. Most recently Ms. Lewis served as Vice President, Regulatory and Quality Affairs for Syros Pharmaceuticals, Inc. (“Syros”), a pharmaceutical company, from January 2017 to July 2018. Prior to joining Syros, Ms. Lewis served as Vice President, Regulatory Affairs and Quality Assurance for Idera Pharmaceuticals, Inc. (“Idera”), a pharmaceutical company, from 2015 to December 2016. Prior to joining Idera, Ms. Lewis served as Vice President, Regulatory Affairs for Tesaro, Inc., a pharmaceutical company, from 2011 to 2015. Ms. Lewis has served on the board of directors of Replimune, Inc., a biotechnology company, since November 2020. Ms. Lewis holds a B.S. in Biology from Northeastern University and a M.S. in Regulatory Affairs and Public Health from Massachusetts College of Pharmacy and Allied Health Science.
Michael Mano, J.D.
Mr. Mano joined Karyopharm as Senior Vice President, General Counsel and Secretary in December 2020 with over 15 years of legal experience. Prior to joining Karyopharm, Mr. Mano served as
 
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Counsel, Business Development for Biogen Inc., a biotechnology company, from January 2018 to December 2020, where he supported Biogen’s global business development platform. Prior to that he was Senior Counsel at Proskauer Rose LLP, an international law firm, from 2013 to January 2018 where he represented clients in a broad range of corporate matters. Prior to Proskauer Rose LLP, Mr. Mano was in private legal practice where he represented clients in the life sciences industry in a broad range of corporate matters. Mr. Mano received a B.A. in Political Science and Sociology from Saint Michael’s College and a Juris Doctor from Washington University School of Law.
Michael Mason, C.P.A., M.B.A.
Mr. Mason has served as our Senior Vice President, Chief Financial Officer and Treasurer since February 2019. Mr. Mason served as Vice President of Finance and Treasurer of Alnylam Pharmaceuticals, Inc., a public biopharmaceutical company, from 2011 until February 2019, as its Principal Accounting Officer from 2011 to October 2018, and as its Principal Financial Officer from 2011 to June 2016 and from January 2017 to May 2017. From 2005 to 2011, Mr. Mason served as Alnylam’s Corporate Controller. From 2000 through 2005, Mr. Mason served in several finance and commercial roles at Praecis Pharmaceuticals Incorporated (“Praecis”), a public biotechnology company, most recently as Corporate Controller. Prior to Praecis, Mr. Mason worked in the audit practice at KPMG LLP, a national audit, tax and advisory services firm. Mr. Mason received a B.A. in Business Administration from Stetson University and an M.B.A. from Babson College and is a certified public accountant.
Stephen Mitchener, Pharm.D.
Dr. Mitchener has served as our Chief Business Officer since December 2020. Prior to joining Karyopharm, Dr. Mitchener served as Chief Business Officer and Head, Strategic Finance from August 2019 to December 2020 and as Senior Vice President, Chief Business Officer from September 2018 to August 2019 at Axcella Health Inc. (“Axcella”), a biotechnology company. Before joining Axcella, Dr. Mitchener spent 15 years at Novartis, a pharmaceutical company, in roles of increasing responsibility, in both U.S. and international roles within its Oncology Business. He served as Head of Strategy, Partnering and Operations from July 2016 to August 2018 and as Oncology Franchise Head for Australia and New Zealand from 2013 to June 2016. During his tenure at Novartis, he also held various commercial, medical and business development roles, including Business Franchise Head, Oncology, Global Pharma Strategy Director, and Global New Product Director. Dr. Mitchener was involved in securing partnerships in oncology with multiple big pharma, technology, academic and healthcare partners. Dr. Mitchener received a PharmD from the University of North Carolina at Chapel Hill.
Jatin Shah, M.D.
Dr. Shah joined Karyopharm in May 2017 as Vice President, Clinical Strategy, and was appointed Senior Vice President, Clinical Development in April 2018 and Executive Vice President, Chief Medical Officer in July 2019. Prior to joining Karyopharm, Dr. Shah held numerous roles at The University of Texas MD Anderson Cancer Center. From 2007 to August 2016, Dr. Shah served as an Assistant Professor, Associate Professor, and Associate Program Director of the Malignant Hematology Fellowship, as well as Director of Myeloma Clinical and Translational Research in the Department of Lymphoma/Myeloma, Division of Cancer Medicine. Dr. Shah received his M.D. from The Ohio State University College of Medicine, Columbus, Ohio and holds a degree in Mechanical Engineering from The Ohio State University. Dr. Shah completed his residency in internal medicine at the Cleveland Clinic Foundation, Cleveland, Ohio, and a fellowship in hematology/oncology at the University of Alabama at Birmingham. Dr. Shah holds board certification in hematology and oncology from the American Board of Internal Medicine.
 
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Information about our Directors
The following table lists the positions, names and ages of our current directors:
 
Name
 
Age
    
Position
Michael G. Kauffman, M.D., Ph.D.
    57      Chief Executive Officer of Karyopharm
Barry E. Greene
    57      Chief Executive Officer of Sage Therapeutics, Inc., a biopharmaceutical company
Garen Bohlin
    73      Former Executive Vice President of Constellation Pharmaceuticals, Inc., a biopharmaceutical company
Mikael Dolsten, M.D., Ph.D.
    62      President of Worldwide Research, Development and Medical, Chief Scientific Officer and Executive Vice President of Pfizer Inc., a pharmaceutical company
Mansoor Raza Mirza, M.D.
    59      Chief Oncologist at the Department of Oncology, Rigshopitalet – the Copenhagen University Hospital, Denmark and Medical Director of the Nordic Society of Gynaecological Oncology
Christy Oliger
    51      Former Senior Vice President of the Oncology Business Unit at Genentech, Inc., a biotechnology company
Deepa R. Pakianathan, Ph.D.
    56      Managing Member at Delphi Ventures, a venture capital firm focused on biotechnology and medical device investments
Richard Paulson.
    53      Executive Vice President of Ipsen Pharmaceuticals, Inc., a biopharmaceutical company, and Chief Executive Officer of Ipsen North America
Chen Schor
    48      President, Chief Executive Officer and Director of Adicet Bio, Inc., a biotechnology company
Available Information
Our Internet website is http://www.karyopharm.com. We make available free of charge through our website our annual report on
Form 10-K,
quarterly reports on
Form 10-Q,
current reports on
Form 8-K
and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended. We make these reports available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the U.S. Securities and Exchange Commission. In addition, we regularly use our website to post information regarding our business, development programs and governance, and we encourage investors to use our website, particularly the information in the section entitled “Investors” as a source of information about us. References to our website are inactive textual references only and the content of our website should not be deemed incorporated by reference into this Annual Report on
Form 10-K.
Our Code of Business Conduct and Ethics, Corporate Governance Guidelines and the charters of the Audit, Compensation, Nominating, Corporate Governance & Compliance Committees of our Board of Directors are all available on our website at http://www.karyopharm.com at the “Investors” section under “Corporate Governance.” Stockholders may request a free copy of any of these documents by writing to Investor Relations, Karyopharm Therapeutics Inc., 85 Wells Avenue, 2
nd
floor, Newton, Massachusetts 02459, U.S.A.
 
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Item 1A.    Risk
Factors
Careful consideration should be given to the following material risk factors, in addition to the other information set forth in this Annual Report on
Form 10-K
and in other documents that we file with the U.S. Securities and Exchange Commission (“SEC”) in evaluating us and our business. Investing in our common stock involves a high degree of risk. If any of the following risks and uncertainties actually occurs, our business, prospects, financial condition and results of operations could be materially and adversely affected. The risks described below are not intended to be exhaustive and are not the only risks we face. New risk factors can emerge from time to time, and it is not possible to predict the impact that any factor or combination of factors may have on our business, prospects, financial condition and results of operations.
Risks Related to Commercialization and Product Development
Our business is substantially dependent on the commercial success of XPOVIO. If we are unable to successfully commercialize our current and future indications of XPOVIO or other products or product candidates on a timely basis, including our ability to achieve the widespread market acceptance by physicians, patients, third-party payors and others in the medical community, our business, financial condition and future profitability will be materially harmed.
Our business and our ability to generate product revenue from the sales of drugs that treat cancer and other diseases in humans depend heavily on our ability to successfully commercialize our lead drug, XPOVIO
®
(selinexor) on a global basis, in currently approved and future indications and the level of market adoption for, and the continued use of, our products and product candidates, if approved. XPOVIO is currently approved in the U.S. in multiple hematologic malignancy indications, including in combination with Velcade
®
(bortezomib) and dexamethasone for the treatment of patients with multiple myeloma after at least one prior therapy, in combination with dexamethasone for the treatment of patients with heavily pretreated multiple myeloma and as a monotherapy for the treatment of patients with relapsed or refractory diffuse large
B-cell
lymphoma (“DLBCL”). Efforts to drive adoption within the medical community and third-party payors based on the benefits of our products and product candidates require significant resources and may not be successful. The success of XPOVIO and any current or future product candidates, whether alone or in collaboration with third-parties, including achieving and maintaining an adequate level of market adoption, depends on several factors, including:
 
   
our ability to successfully launch and achieve broad adoption of our approved products, such as the recently approved expanded XPOVIO indication based on the results from our Phase 3 BOSTON study or in any future indications for which XPOVIO may be approved, or any product candidates for which we obtain marketing approval;
 
   
Actual or perceived advantages or disadvantages of our products or product candidates as compared to alternative treatments, including their respective safety, tolerability and efficacy profiles, the potential convenience and ease of administration or cost effectiveness;
 
   
the competitive landscape for our products, including the timing of new competing products entering the market, such as BLENREP (belantamab mafodotin) and Monjuvi
®
 (tafasitamab-cxix), which were both approved in 2020 and several new competing products expected to be approved in 2021, and the level and speed at which these products achieve market acceptance;
 
   
the consistency of any new data we collect and analyses we conduct with prior results, whether they support a favorable safety, efficacy and effectiveness profile of XPOVIO and any potential impact on our U.S. Food and Drug Administration (“FDA”) accelerated approval and/or FDA package insert for XPOVIO;
 
   
our ability to comply with FDA post-marketing requirements and commitments, including through successfully conducting, on a timely basis, additional studies that confirm clinical efficacy, effectiveness and safety of XPOVIO and acceptance of the same by the FDA, such as requirements in connection with the FDA’s June 2020 approval of XPOVIO based on the results of the SADAL study to treat patients with DLBCL, which was approved under the FDA’s Accelerated Approval Program;
 
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acceptance of current and future indications of XPOVIO and, if approved, our other product candidates, by patients, the medical community and third-party payors;
 
   
obtaining and maintaining coverage, adequate pricing and reimbursement by third-party payors, including government payors, for XPOVIO and our product candidates, if approved;
 
   
the willingness of patients to pay
out-of-pocket
in the absence of third-party coverage or as
co-pay
amounts under third-party coverage;
 
   
our ability to enforce intellectual property rights in and to our products to prohibit a third-party from marketing a competing product and our ability to avoid third-party patent interference or intellectual property infringement claims;
 
   
current and future restrictions or limitations on our approved or future indications and patient populations or other adverse regulatory actions;
 
   
the performance of our manufacturers, license partners, distributors, providers and other business partners, over which we have limited control;
 
   
any significant misestimations of the size of the market and market potential for any of our products or product candidates;
 
   
establishing and maintaining commercial manufacturing capabilities or making arrangements with third-party manufacturers;
 
   
the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies, based, in part, on their perception of our clinical trial data and/or the actual or perceived safety, tolerability and effectiveness profile;
 
   
the effectiveness of our sales, marketing, manufacturing and distribution strategies and operations;
 
   
maintaining an acceptable safety and tolerability profile of our approved products, including the prevalence and severity of any side effects;
 
   
the ability to offer our products for sale at competitive prices;
 
   
adverse publicity about our products or favorable publicity about competitive products;
 
   
our ability to maintain compliance with existing and new health care laws and regulations, including government pricing, price reporting and other disclosure requirements related to such laws and regulations and the potential impact of such requirements on physician prescribing practices and payor coverage; and
 
   
the impact of the novel coronavirus disease
(“COVID-19”)
pandemic on the above factors, including the limitation of our sales professionals to meet in person with healthcare professionals as the result of travel restrictions or limitations on access for
non-patients.
If we do not achieve one or more of these factors in a timely manner, or at all, we could experience significant delays or an inability to successfully commercialize XPOVIO or our product candidates, if approved, which would materially harm our business.
We face substantial competition, which may result in others discovering, developing or commercializing drugs before or more successfully than we do.
The discovery, development and commercialization of new drugs is highly competitive, particularly in the cancer field. We face competition with respect to XPOVIO and will face competition with respect to any product candidates that we may seek to discover and develop or commercialize in the future, from major pharmaceutical companies, specialty pharmaceutical companies, biotechnology companies, academic institutions and governmental agencies as well as public and private research institutions worldwide, many of which have
 
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significantly greater financial resources and expertise in research and development, manufacturing, preclinical studies, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do. There are a number of major pharmaceutical, specialty pharmaceutical and biotechnology companies that currently market and sell drugs and/or are pursuing the development of drugs for the treatment of cancer and the other disease indications for which we are developing our product candidates. For example, BLENREP and Monjuvi
®
were approved by the FDA in August and July 2020, respectively. In addition, several new mechanism of actions may be introduced into the multiple myeloma market, including
Car-T
therapies, which may have a significant impact on the multiple myeloma landscape and our product revenues. See Item 1 under the heading
Business—Competition
in this Annual Report on Form
10-K
for more information on competition.
We are initially focused on developing and commercializing our current products and product candidates for the treatment of cancer and there are a variety of available therapies marketed for cancer. In many cases, cancer drugs are administered in combination to enhance efficacy. Some of these drugs are branded and subject to patent protection, and others are available on a generic basis. Many of these approved drugs are well-established therapies and are widely accepted by physicians, patients and third-party payors. Insurers and other third-party payors may also encourage the use of generic drugs. Our products are priced at a significant premium over competitive generic drugs, which may make it difficult for us to achieve our business strategy of using our products in combination with existing therapies or replacing existing therapies with our products.
Further, our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize drugs that are or are perceived to be more effective, safer, more tolerable, more convenient and/or less costly than any of our currently approved products or product candidates or that would render our products obsolete or
non-competitive.
Our competitors may also obtain marketing approval from the FDA or other regulatory authorities for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a stronger market position before we are able to enter the market or preventing us from entering into a particular indication at all.
Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even 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 that may be necessary for, our programs.
If we are not able to compete effectively against current or potential competitors, our business will not grow and our financial condition and operations will suffer.
Clinical development is a lengthy and expensive process, with uncertain timelines and outcomes. If clinical trials of our product candidates fail to demonstrate safety and efficacy to the satisfaction of regulatory authorities or do not otherwise produce positive results, we may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of such product candidates.
Our long-term success depends in a large part on our ability to continue to successfully develop new indications of XPOVIO, our other product candidates or any new product candidates we may develop or acquire. Clinical testing is expensive, time consuming, difficult to design and implement, inherently uncertain as to outcome and can fail at any stage of testing. Furthermore, the failure of any product candidates to demonstrate safety and efficacy in any clinical trial could negatively impact the perception of XPOVIO or our other product candidates and/or cause the FDA or other regulatory authorities to require additional testing before any of our product candidates are approved.
 
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We may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing approval of our product candidates, including, but not limited to, the following:
 
   
delays or failure to reach agreement with regulatory authorities on a trial design or the receipt of feedback requiring us to modify the design of our clinical trials, perform additional or unanticipated clinical trials to obtain approval or alter our regulatory strategy;
 
   
clinical trials of our product candidates may produce negative or inconclusive results or other patient safety concerns, including undesirable side effects or other unexpected characteristics, and we may decide, or regulatory authorities may require us, to conduct additional clinical trials, suspend ongoing clinical trials or abandon drug development programs, including as a result of a finding that the participants are being exposed to unacceptable health risks;
 
   
enrollment in our clinical trials may be slower than we anticipate, including as a result of competition with other ongoing clinical trials for the same indications as our product candidates;
 
   
regulators may revise the requirements for approving our product candidates, even after providing a positive opinion on or otherwise reviewing and providing comments to a clinical trial protocol, or such requirements may not be as we anticipate;
 
   
delays or failure in obtaining the necessary authorization from regulatory authorities or institutional review boards (“IRBs”) to permit us or our investigators to commence a clinical trial, conduct a clinical trial at a prospective trial site, or the suspension or termination of a clinical trial once commenced;
 
   
delays or failure to reach agreement on acceptable terms with prospective clinical trial sites or contract research organizations (“CROs”);
 
   
the number of patients required for clinical trials of our product candidates may be larger than we anticipate or participants may drop out of these clinical trials at a higher rate than we anticipate;
 
   
our third-party contractors, including manufacturers or CROs, may fail to comply with regulatory requirements, perform effectively, or meet their contractual obligations to us in a timely manner, or at all;
 
   
we or our investigators might be found to be
non-compliant
with regulatory requirements;
 
   
the cost of clinical trials of our product candidates may be greater than we anticipate;
 
   
the supply or quality of our product candidates or other materials necessary to conduct clinical trials may be insufficient or inadequate;
 
   
any partners or collaborators that help us conduct clinical trials may face any of the above issues, and may conduct clinical trials in ways they view as advantageous to them but that are suboptimal for us; and
 
   
negative impacts resulting from the ongoing
COVID-19
pandemic, including impacts to healthcare systems and our trial sites’ ability to conduct trials.
The
COVID-19
pandemic may continue to have an impact on our clinical trials. At this time, however, we cannot fully forecast the scope of the impact that
the COVID-19
pandemic may have on our ability to, among other things, initiate trial sites, enroll and assess patients, supply study drug and report trial results. In addition, we have and may continue to experience delays in the regulatory process as a result of the
COVID-19
pandemic, which may impact our approval timelines, such as delays we encountered related to our reduced access to clinical trial sites in order to complete remonitoring activities associated with our Marketing Authorization Application (“MAA”) for selinexor in multiple myeloma based on the results on the STORM study. Further, in response to the
COVID-19
pandemic, the FDA issued guidance on March 18, 2020, and updated it on July 2, 2020 and January 27, 2021, to address the conduct of clinical trials during the pandemic. The guidance sets out a number
 
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of considerations for sponsors of clinical trials impacted by the pandemic, including the requirement to include in the clinical study report (or as a separate document) contingency measures implemented to manage the study, and any disruption of the study as a result of
COVID-19;
a list of all study participants affected by
COVID-19-related
study disruptions by a unique subject identifier and by investigational site, and a description of how the individual’s participation was altered; and analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the study.
If we are required to conduct additional clinical trials or other testing of our product candidates beyond those that we currently contemplate, if we are unable to successfully complete clinical trials of our product candidates or other testing, on a timely basis or at all, and/or if the results of these trials or tests are not positive or are only modestly positive or if there are safety concerns, we may:
 
   
not obtain marketing approval at all for the indication or product candidate;
 
   
be delayed in obtaining marketing approval;
 
   
obtain marketing approval in some countries and not in others;
 
   
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, including boxed warnings;
 
   
be subject to additional post-marketing testing requirements;
 
   
not receive royalty or milestone revenue under our collaboration agreements for several years, or at all; or
 
   
have the product removed from the market after obtaining marketing approval.
Further, we do not know whether clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all, particularly as a result of the
COVID-19
pandemic. Significant clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our products, allow our competitors to bring products to market before we do or impair our ability to successfully commercialize our products, which would harm our business and results of operations. In addition, many of the factors that cause, or lead to, clinical trial delays may ultimately lead to the denial of regulatory approval of our product candidates.
Even if we or our collaborators complete the necessary preclinical studies and clinical trials for our product candidates, the marketing approval process is expensive, time-consuming and uncertain and we or they may not receive approvals for the commercialization of some or all of our or their product candidates in a timely manner, or at all.
Our long-term success and ability to sustain and grow revenue depends on our and our collaborators’ ability to continue to successfully develop our product candidates and obtain regulatory approval to market our or their products both in and outside of the U.S. The FDA and comparable foreign regulatory authorities, whose laws and regulations may differ from country to country, impose substantial requirements on the development of product candidates to become eligible for marketing approval and have substantial discretion in the process and may refuse to accept any application or may decide that the data are insufficient for approval and require additional preclinical studies, clinical trials or other studies and testing. In addition, the FDA and foreign regulatory authorities retain broad discretion in evaluating the results of our clinical trials and in determining whether the results demonstrate that selinexor or any of our other product candidates is safe and effective. If we are required to conduct additional clinical trials of selinexor or our other product candidates prior to approval of additional indications in earlier lines of therapy or in combination with other drugs, including additional earlier phase
 
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clinical trials that may be required prior to commencing any later phase clinical trials, or additional clinical trials following completion of our current and planned later phase clinical trials, we may need substantial additional funds, and there is no assurance that the results of any such additional clinical trials will be sufficient for approval.
The process of obtaining marketing approvals, both in the U.S. and abroad, is lengthy, expensive and uncertain. We have limited experience in conducting and managing the clinical trials necessary to obtain marketing approvals. The approval of our and our collaborators’ current or future product candidates for commercial sale could be delayed, limited or denied or we or they may be required to conduct additional studies for a number of reasons, including, but not limited to, the following:
 
   
regulatory authorities may determine that our or our collaborators’ product candidates do not demonstrate safety and efficacy in accordance with regulatory agency standards based on a number of considerations, including adverse events (“AEs”) that are reported during clinical trials;
 
   
regulatory authorities could analyze and/or interpret data from clinical trials and preclinical testing in different ways than we or our collaborators interpret them and determine that our data is insufficient for approval;
 
   
regulatory authorities may require more information, including additional preclinical or clinical data or trials, to support approval;
 
   
regulatory authorities could determine that our manufacturing processes are not properly designed, are not conducted in accordance with federal or other laws or otherwise not properly managed and we may be unable to obtain regulatory approval for a commercially viable manufacturing process for our product candidates in a timely manner, or at all;
 
   
the supply or quality of our or our collaborators’ product candidates for our clinical trials may be insufficient, inadequate or delayed;
 
   
the size of the patient population required to establish the efficacy of our or our collaborators’ product candidates to the satisfaction of regulatory agencies may be larger than we or they anticipated;
 
   
the failure of clinical investigational sites and the records kept at such sites, including the clinical trial data, to be in compliance with the FDA’s current good clinical practices regulations (“GCP”) or comparable regulations outside of the U.S., including the failure to pass inspections of clinical trial sites, such as a March 2019 European Medicines Agency (“EMA”) GCP inspection at our corporate headquarters and two clinical sites that participated in Part 2 of the STORM study, which resulted in certain findings that, although ultimately addressed, caused a delay in the approval process;
 
   
regulatory authorities may change their approval policies or adopt new regulations;
 
   
regulatory authorities may not be able to undertake reviews or approval processes in a timely manner, including delays as a result of the ongoing
COVID-19
pandemic, such as with the EMA review of our MAA for selinexor in multiple myeloma based on the results of the STORM study and the resulting impact to the timing of our expected submission of an MAA for selinexor in multiple myeloma supported by the results of the BOSTON study or any future MAA;
 
   
the results of our earlier clinical trials may not be representative of our future, larger trials;
 
   
regulatory authorities may not agree with our or our collaborators’ regulatory approval strategies or components of our or their regulatory filings, such as the design or implementation of the relevant clinical trials; or
 
   
a product may not be approved for the indications that we or our collaborators’ request or may be limited or subject to restrictions or post-approval commitments that render the approved drug not commercially viable.
 
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Finally, disruptions at the FDA and other agencies may prolong the time necessary for new drugs to be reviewed and/or approved by necessary government agencies, which would adversely affect our business. For example, over the last several years, the U.S. government has shut down several times and certain regulatory agencies, such as the FDA, have had to furlough critical employees and stop critical activities. If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business. The Trump Administration also took several executive actions that could impose significant burdens on, or otherwise materially delay, the FDA’s ability to engage in routine regulatory and oversight activities.
Any failure, delay or setback in obtaining regulatory approval for our or our collaborators’ product candidates could materially adversely affect our or our collaborators’ ability to generate revenue from a particular product candidate, which could result in significant harm to our financial position and adversely impact our stock price.
Serious adverse or unacceptable side effects related to XPOVIO or future products or product candidates may delay or prevent their regulatory approval, cause us or our collaborators to suspend or discontinue clinical trials, limit the commercial value of our approved indications or result in significant negative financial consequences following any marketing approval.
We currently have four product candidates in clinical development for the treatment of human diseases: selinexor, eltanexor, verdinexor and
KPT-9274.
Their risk of failure is high. If our current or future indications of XPOVIO or any of our product candidates are associated with undesirable side effects or have characteristics that are unexpected in clinical trials or following approval and/or commercialization, we may need to abandon or limit their development or limit marketing to certain 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.
AEs in our clinical trials to date have been generally predictable and typically manageable, including through prophylactic care or dose reductions, although some patients have experienced more serious AEs. The most common drug-related AEs in our clinical trials for XPOVIO were fatigue, nausea, anorexia, diarrhea, peripheral neuropathy, upper respiratory tract infection, vomiting, cytopenias, hyponatremia, weight loss, decreased appetite, cataract, dizziness, syncope, depressed level of consciousness, and mental status changes. These side effects were generally mild or moderate in severity. The most common AEs that were Grade 3 or Grade 4, meaning they were more than mild or moderate in severity, included thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia. To date, the most common AEs in the multiple myeloma patient population have been managed with supportive care and dose modifications. However, a number of patients have withdrawn from our clinical trials as a result of AEs and some patients across our clinical trials have experienced serious AEs deemed by us and the clinical investigator to be related to selinexor. Serious adverse events generally refer to AEs that result in death, are life threatening, require hospitalization or prolonging of hospitalization, or cause a significant and permanent disruption of normal life functions, congenital anomalies or birth defects, or require intervention to prevent such an outcome.
The occurrence of AEs in either our clinical trials or following regulatory approval could result in a more restrictive label for any product candidates approved for marketing or could result in the delay or denial of approval to market any product candidates by the FDA or comparable foreign regulatory authorities, which could prevent us from generating sufficient revenue from product sales or ultimately achieving profitability. Treatment-related side effects could also affect patient recruitment or the ability of enrolled patients to complete the trial, result in potential product liability claims or cause patients and/or healthcare providers to elect alternative courses of treatment. In addition, these side effects may not be appropriately recognized or managed by the treating medical staff. We engage in training programs for medical personnel using selinexor to help them understand and manage the side effect profiles for our clinical trials and following commercialization of any of our product candidates. Inadequate training in recognizing or managing the potential side effects of XPOVIO or our product candidates could result in increased treatment-related side effects and cause patients to discontinue treatment. Any of these occurrences may harm our business, financial condition and prospects significantly.
 
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Results of our trials could reveal an unacceptably high severity and prevalence of side effects. In such an event, our trials could be suspended or terminated and the FDA or comparable foreign regulatory authorities could order us or our collaborators to cease further development of or deny approval of our product candidates for any or all targeted indications. Many compounds that initially showed promise in early-stage trials for treating cancer or other diseases have later been found to cause side effects that prevented further development of the compound. If such an event occurs after any of our or our collaborators’ product candidates are approved and/or commercialized, a number of potentially significant negative consequences may result, including
 
   
regulatory authorities may withdraw the approval of such drug;
 
   
regulatory authorities may require additional warnings on the label or impose distribution or use restrictions;
 
   
patients and/or healthcare providers may elect to utilize other treatment options that have or are perceived to have more tolerable side effects;
 
   
regulatory authorities may require one or more post-marketing studies;
 
   
we may be required to create a medication guide outlining the risks of such side effects for distribution to patients;
 
   
we could be sued and held liable for harm caused to patients; and
 
   
our reputation may suffer.
Further, we, our collaborators and our clinical trial investigators, currently determine if serious adverse or unacceptable side effects are drug-related. The FDA or foreign regulatory authorities may disagree with our, our collaborators’ or our clinical trial investigators’ interpretation of data from clinical trials and the conclusion by us or our clinical trial investigators that a serious adverse effect or unacceptable side effect was not drug-related. The FDA or foreign regulatory authorities may require more information related to the safety of our products or product candidates, including additional preclinical or clinical data to support approval, which may cause us to incur additional expenses, delay or prevent the approval of one of our product candidates, and/or delay or cause us to change our commercialization plans, or we may decide to abandon the development of the product candidate altogether.
Any of these events could prevent us or our collaborators from achieving or maintaining market acceptance of the affected product candidate, if approved, or could substantially increase costs and expenses of development or commercialization, which could delay or prevent us from generating sufficient revenue from the sale of our products and harm our business and results of operations.
The COVID-19
pandemic has adversely disrupted, and is expected to continue to adversely disrupt, our operations, including our clinical trial activities and commercial operations, which could have an adverse effect on our business and financial results.
As a result of the
COVID-19
pandemic that has affected many segments of the global economy, we have experienced, and we expect to continue to experience, disruptions that could adversely impact our business, clinical trial activities and commercial operations, including:
 
   
negative impact to revenue for XPOVIO, which may continue as the
COVID-19
pandemic persists, including as a result of decreased new patient starts due to the inability of our sales force and our patients to meet with healthcare professionals;
 
   
delays or difficulties in enrolling patients in our clinical trials, including our SIENDO and STOMP trials;
 
   
delays or difficulties in initiating new clinical studies, including clinical site initiation and difficulties in recruiting clinical site investigators and clinical site staff;
 
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reduction or diversion of healthcare resources away from the conduct of clinical trials, including the diversion of hospitals serving as our clinical trial sites and hospital staff supporting the conduct of our clinical trials;
 
   
interruption of key clinical trial activities, such as clinical trial site data monitoring, due to limitations on travel imposed or recommended by government officials or entities, employers and others or interruption of clinical trial patient visits and study procedures (particularly any procedures that may be deemed
non-essential),
which may impact the integrity of clinical trial data and clinical study endpoints;
 
   
interruption or delays in the operations of the FDA and comparable foreign regulatory agencies, including the EMA, which may impact regulatory review and approval timelines, such as the EMA review of our MAA for selinexor in multiple myeloma based on the results on the STORM study and any resulting impact to the timing of our expected submission of an MAA for selinexor in multiple myeloma supported by the results of the BOSTON study or any future MAA;
 
   
negative impacts on any or all aspects of our operations due to business disruptions related to
COVID-19
at our third-party vendors who we rely upon in the conduct of our business; and
 
   
limitations on employee resources that would otherwise be focused on the conduct of our business, including because of sickness of employees or their families, the desire of employees to avoid contact with large groups of people, and an increased reliance on working from home.
The COVID-19
pandemic continues to evolve, and its ultimate scope, duration and effects remain unknown. The extent of the impact of the disruptions to our business, including commercial sales and clinical trials, as a result of the pandemic will depend on the availability and effectiveness of vaccines and therapeutics and future developments, which are highly uncertain and cannot be predicted with confidence, such as the duration and scope of the pandemic, and the effectiveness of actions taken in the U.S. and other countries to contain and treat the disease, such as travel restrictions, social distancing and quarantines or lock-downs in the U.S. and other countries, business closures or business disruptions.
The results of previous clinical trials may not be predictive of future trial results and interim or
top-line
data may be subject to change or qualification based on the complete analyses of data.
Clinical failure can occur at any stage of the clinical development process and, therefore, the outcome of preclinical studies and early-stage clinical trials may not be predictive of the success of later stage clinical trials. For example, certain data from our Phase 1 and Phase 2 clinical trials of selinexor are based on unaudited data provided by our clinical trial investigators. Finalization and cleaning of this data may change the conclusions drawn from this unaudited data provided by our clinical trial investigators indicating less promising results than we currently anticipate. Further, there can be significant variability in safety and/or efficacy results between different trials of the same product candidate due to numerous factors, including changes in trial protocols, differences in size and type of the patient populations, adherence to the dosing regimen and other trial protocols and the dropout rate among clinical trial participants. We do not know whether any Phase 2, Phase 3 or other clinical trials we may conduct will demonstrate consistent or adequate efficacy and safety data sufficient to obtain regulatory approval to market our product candidates, if approved. Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies have suffered significant setbacks in late-stage clinical trials after achieving positive results in earlier development, and we could face similar setbacks.
We may publicly disclose preliminary, interim or
top-line
data from our clinical trials. These interim updates are based on a preliminary analysis of then-available data, and the results and related findings and conclusions are subject to change as further patient data become available and following a more comprehensive review of the data related to the particular study or trial. For example, in November 2020, we announced that our ongoing Phase 3 SIENDO study passed its planned interim futility analysis without the need to modify the study protocol or add additional patients. For this study or any other that we report preliminary, interim or
top-line
 
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data, we make assumptions, estimations, calculations and conclusions as part of our analyses of data, and we may not have received or had the opportunity to fully and carefully evaluate all data. Consequently, the preliminary, interim or
top-line
data results that we report may differ from future results of the same studies, or different conclusions or considerations may qualify such results, once additional data have been received and fully evaluated. Preliminary, interim or
top-line
data also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data we previously published. As a result, these early data points should be viewed with caution until the final data are available.
Further, even if our product candidates achieve their primary endpoints in Phase 3 clinical trials or other registration trials, the FDA or foreign regulatory authorities may disagree with our trial design or our interpretation of data from preclinical studies and clinical trials. If the FDA, or other regulatory authorities, disagree about the overall benefit-risk assessment and data analyses, we may decide not to pursue regulatory approval or we may not obtain approval for our product candidates, which could harm our business, financial condition, results of operations and prospects.
We expect that in any later phase clinical trial where patients are randomized to receive either selinexor on the one hand, or standard of care, supportive care or placebo on the other hand, the primary endpoint will be either progression-free survival, meaning the length of time on treatment until objective tumor progression, or overall survival, while the primary endpoint in any later phase clinical trial that is not similarly randomized may be different. In some instances, the FDA and other regulatory bodies have accepted overall response rate as a surrogate for a clinical benefit and have granted regulatory approvals based on this or other surrogate endpoints, such as in our SADAL study and our STORM study. These clinical trials were not randomized against control arms and the primary endpoints of these trials were overall response rate. If selinexor does not demonstrate sufficient overall response rates for any other indication for which a clinical trial has overall response rate as a primary endpoint, or if the FDA or foreign regulatory authorities do not deem overall response rate a sufficient endpoint, or deem a positive overall response rate to be insufficient, selinexor will likely not be approved for that indication based on the applicable study.
Further, others, including regulatory agencies, may not accept or agree with our assumptions, estimates, calculations, conclusions or analyses or may interpret or weigh the importance of data differently, which could impact the value of the particular program, the approvability or commercialization of the particular product candidate or product and our company in general. In addition, the information we choose to publicly disclose regarding a particular study or clinical trial is typically selected from a more extensive amount of available information. Furthermore, we may report interim analyses of only certain endpoints rather than all endpoints. Investors may not agree with what we determine is the material or otherwise appropriate information to include in our disclosure, and any information we determine not to disclose may ultimately be deemed significant with respect to future decisions, conclusions, views, activities or otherwise regarding a particular product, product candidate or our business.
We may not be successful in our efforts to identify or discover additional potential product candidates or our decisions to prioritize the development of certain product candidates over others may later prove wrong.
Part of our strategy involves identifying and developing product candidates to build a pipeline of product candidates. Our drug discovery efforts may not be successful in identifying compounds that are useful in treating cancer or other diseases. Our research programs may initially show promise in identifying potential product candidates, yet fail to yield product candidates for clinical development for a number of reasons, including:
 
   
the research methodology used may not be successful in identifying potential product candidates;
 
   
potential product candidates may, on further study, be shown to have harmful side effects or other characteristics that indicate that they are unlikely to be drugs that will receive marketing approval and/or achieve market acceptance; or
 
   
potential product candidates may not be effective in treating their targeted diseases.
 
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We are currently advancing multiple clinical development studies of selinexor, which may create a strain on our limited human and financial resources. As a result, we may not be able to provide sufficient resources to any single product candidate to permit the successful development and commercialization of such product candidate, which could result in material harm to our business. Further, because we have limited financial and managerial resources, we focus on research programs and product candidates that we identify for specific indications. As a result, we may forego or delay pursuit of opportunities with other product candidates or for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and development programs and product candidates for specific indications may not yield any additional commercially-viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.
If we are unable to maintain or expand our sales, marketing and distribution capabilities, we may not be successful in commercializing XPOVIO or any of our products or product candidates, if approved, that we may acquire or develop.
We have built a commercial infrastructure in the U.S. for XPOVIO, our first commercial product, in hematological malignancies and our company did not previously have any prior experience in the sales, marketing or distribution of pharmaceutical drugs. If XPOVIO or any of our other product candidates is approved for additional indications beyond hematological malignancies, such as solid tumors, we will need to substantially evolve our sales, marketing and distribution capabilities and we may not be able to do so successfully or on a timely basis. In the future, we may choose to expand our sales, marketing and distribution infrastructure to market or
co-promote
one or more of our product candidates, if and when they are approved, or enter into additional collaborations with respect to the sale, marketing and distribution of our product candidates. We intend to work with existing and potential partners to establish the commercial infrastructure to support a potential launch of selinexor outside of the U.S.
There are risks involved with establishing and maintaining our own sales, marketing and distribution capabilities. For example, recruiting and training a sales force is expensive and time-consuming and could delay any commercial launch of a product candidate. Further, we may underestimate the size of the sales force required for a successful product launch and we may need to expand our sales force earlier and at a higher cost than we anticipated. If the commercial launch of any of our product candidates is delayed or does not occur for any reason, including if we do not receive marketing approval in the timeframe we expect, we may have prematurely or unnecessarily incurred 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 successfully commercialize XPOVIO or any product candidates, if approved, on our own include:
 
   
our inability to recruit, train and retain adequate numbers of effective sales, market access, market analytics, operations and marketing personnel;
 
   
the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe current or future products;
 
   
the lack of complementary drugs, which may put us at a competitive disadvantage relative to companies with more extensive drug lines;
 
   
unforeseen costs and expenses associated with creating an independent sales, marketing and distribution organization;
 
   
our inability to obtain sufficient coverage and reimbursement from third-party payors and governmental agencies; and
 
   
existing or new competitors taking share from XPOVIO or preventing XPOVIO from gaining share in its approved indications.
 
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Even if we or our collaborators are able to effectively commercialize XPOVIO or any product candidate that we may develop or acquire, the products may not receive coverage or may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, all of which would harm our business.
The legislation and regulations that govern marketing approvals, pricing and reimbursement for new drug products vary widely from country to country. As a result, we might obtain marketing approval for a drug in a particular country, but then be subject to price regulations that delay our commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues we or our collaborators are able to generate from product sales in that country. In the U.S., approval and reimbursement decisions are not linked directly, but there is increasing scrutiny from the Congress, regulatory authorities, payers, patients and pathway organizations of the pricing of pharmaceutical products. Adverse pricing limitations may also hinder our ability to recoup our investment in one or more product candidates, even if our product candidates obtain marketing approval.
Our ability to successfully commercialize XPOVIO or any of our product candidates that we may develop or acquire will depend, in part, on the extent to which reimbursement for these products is available from government health administration authorities, private health insurers and other organizations. Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels. Obtaining and maintaining adequate reimbursement for XPOVIO and any of our product candidates, if approved, may be difficult. Moreover, the process for determining whether a third-party payor will provide coverage for a product may be separate from the process for setting the price of a product or for establishing the reimbursement rate that such a payor will pay for the product. Further, one payor’s determination to provide coverage for a product does not assure that other payors will also provide coverage and reimbursement for our products by third-party payors. Even with payer coverage, patients may be unwilling or unable to pay the copay required and may choose not to take XPOVIO.
A primary trend in the healthcare industry in the U.S. and elsewhere is cost containment. Government authorities and third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. Third-party payors may also seek, with respect to an approved product, additional clinical evidence that goes beyond the data required to obtain marketing approval. They may require such evidence to demonstrate clinical benefits and value in specific patient populations or they may call for costly pharmaceutical studies to justify coverage and reimbursement or the level of reimbursement relative to other therapies before covering our products. Accordingly, we cannot be sure that reimbursement will be or will continue to be available for XPOVIO and any product that we commercialize and, if reimbursement is available, we cannot be sure as to the level of reimbursement and whether it will be adequate. Coverage and reimbursement may impact the demand for or the price of XPOVIO or any product candidate for which we obtain marketing approval. If reimbursement is not available or is available only at limited levels, we may not be able to successfully commercialize XPOVIO or any other approved products.
There may be significant delays in obtaining reimbursement for newly-approved drugs, and coverage may be more limited than the indications for which the drug is approved by the FDA or comparable regulatory authorities outside of the U.S. Moreover, eligibility for reimbursement does not imply that any drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution. Interim reimbursement levels for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent. Reimbursement rates may vary according to the use of the drug and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost drugs and may be incorporated into existing payments for other services. Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the U.S. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting
 
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their own reimbursement policies. Our inability to promptly obtain coverage and profitable payment rates from both government-funded and private payors for any approved drugs that we develop could have a material adverse effect on our operating results, our ability to raise capital needed to commercialize our products and our overall financial condition.
Product liability lawsuits against us could divert our resources, cause us to incur substantial liabilities and limit commercialization of XPOVIO or any other products that we may develop or acquire.
We face an inherent risk of product liability exposure related to our commercialization of XPOVIO and the testing of our product candidates in human clinical trials as the administration of our products to humans may expose us to liability claims, whether or not our products are actually at fault for causing any harm or injury. As XPOVIO is used over longer periods of time by a wider group of patients taking numerous other medicines or by patients with additional underlying conditions, the likelihood of adverse drug reactions or unintended side effects, including death, may increase. For example, we may be sued if any drug we develop allegedly causes injury or is found to be otherwise unsuitable during clinical testing, manufacturing, marketing or sale. Any such product liability claims may include allegations of defects in manufacturing, defects in design, a failure to warn of dangers inherent in the product, negligence, strict liability or a breach of warranties. Claims could also be asserted under state consumer protection acts. If we cannot successfully defend ourselves against claims that our products or product candidates caused injuries, we will incur substantial liabilities or be required to limit commercialization of our products. Regardless of merit or eventual outcome, liability claims may result in:
 
   
decreased demand for XPOVIO and any other products that we may develop or acquire;
 
   
injury to our reputation and significant negative media attention;
 
   
withdrawal of clinical trial participants;
 
   
initiation of investigations by regulators;
 
   
product recalls, withdrawals or labeling, marketing or promotional restrictions;
 
   
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 successfully commercialize XPOVIO and any other products that we may develop or acquire.
We currently hold clinical trial and general product liability insurance coverage, but that coverage may not be adequate to cover any and all liabilities that we may incur. 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.
The business that we conduct outside of the U.S. may be adversely affected by international risks and uncertainties.
Although our operations are primarily based in the U.S., we conduct business outside of the U.S. and expect to continue to do so in the future. For instance, many of the sites at which our clinical trials are being conducted are located outside of the U.S. In addition, we and our collaborators are seeking and continue to plan to seek approvals to sell our and their products in foreign countries. Any business that we or our collaborators conduct outside of the U.S. will be subject to additional risks that may materially adversely affect our or their ability to conduct business in international markets, including: </