Corporate Overview August 5th, 2021 Exhibit 99.1
© 2021 Exicure, Inc. All Rights Reserved. | Cautionary Note Regarding Forward Looking Statements 2 This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "anticipate," "expect," "plan," "may," "will," and similar expressions (as well as other words or expressions referencing future events or circumstances) are intended to identify forward-looking statements. All statements other than statements of historical fact in this presentation are forward looking including, but not limited to, statements regarding of Exicure, Inc. (“Exicure” or the “Company”); including the development of product candidates based on its proprietary SNA™ technology; the initiation, timing, progress, scope and results of the Company’s preclinical studies, clinical trials and research and development programs; its plans for development of cavrotolimod (AST-008), including its ongoing Phase 1b/2 clinical trial; the timing, availability and presentation of preclinical, clinical and regulatory developments; the potential benefits of the Company’s product candidates and notably, cavrotolimod; the development and the commercial potential, growth potential and market opportunity for the Company’s product candidates, if approved, and the drivers, timing, impact and results thereof; potential and future results of current and planned collaborations; and the timing or likelihood of regulatory filings and approvals. Forward-looking statements are based on management’s current beliefs and assumptions that are subject to risks and uncertainties and are not guarantees of future performance. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including, without limitation: the risk that the COVID-19 pandemic and the associated containment efforts may have a material adverse impact on the Company’s business, operations and financial results; the Company’s preclinical or clinical programs do not advance or result in approved products on a timely or cost effective basis or at all; unexpected safety or efficacy data observed during preclinical or clinical studies; the failure of the data from the Company’s preclinical trials to be indicative in human trials; clinical site activation rates or clinical trial enrollment rates that are lower than expected; the cost, timing and results of clinical trials; changes in the regulatory environment; unexpected litigation or other disputes; the ability of the Company to protect its intellectual property rights; and the actual funding required to develop and commercialize the Company’s product candidates and operate the Company. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Company’s actual results to differ from those contained in the forward-looking statements, see the section titled “Risk Factors” in the Company’s most recent Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in its subsequent filings with the Securities and Exchange Commission. The forward-looking statements in this presentation speak only as of the date of this presentation, and the Company undertakes no obligation to update these forward-looking statements, unless required by law.
© 2021 Exicure, Inc. All Rights Reserved. | Exicure Snapshot 3 • Developing therapeutics for genetic disorders based on proprietary Spherical Nucleic Acid (SNA™) platform • SNAs enable differentiated oligonucleotides ideal for CNS applications: – Increased cellular uptake: Higher Potency at Same Dose – Uptake in all neuronal subtypes: Broad CNS Penetration – Higher persistence in the CNS: Prolonged Efficacy • XCUR-FXN: lead CNS program upregulates frataxin, targeting molecular cause of Friedreich’s Ataxia (FA) – ~3x frataxin upregulation in mouse model indicates potential for disease resolution – Well-tolerated in repeat dose range finding rat study – IND filing anticipated by YE 2021, with first patient to be dosed in 1H 2022 • Deep neuroscience pipeline: SCN9A (NaV1.7) and CLN3 most advanced – Potential for multiple additional INDs beginning in 2022 • Cavrotolimod: TLR9 agonist in Phase 1b/2 with Fast-Track/Orphan Disease designation in CSCC and MCC • Partnered platform: option agreements in Neuroscience (Ipsen), Dermatology (AbbVie)
© 2021 Exicure, Inc. All Rights Reserved. | Key Value Inflections Across Platform & Programs in 2021 & 2022 Q2 2021 • Rat dose-range finder for XCUR-FXN • Commencement of GLP tox studies for XCUR-FXN • In vivo PoC (eye) for CLN3 program for Batten Disease Q3-4 2021 • Neuroscience collaboration with Ipsen for Huntington’s and Angelman’s • IND filing for XCUR-FXN (on track) • Neuroscience pipeline progress (SCN9A, CLN3, and discovery programs) • Interim results from cavro P1b/2 trial H1 2022 • First patient dosed with XCUR-FXN • 2nd neuro program to enter IND-enabling studies • Final cavro P1b/2 results H2 2022 • Potential for first biomarker readouts from XCUR-FXN P1b 4
© 2021 Exicure, Inc. All Rights Reserved. | Spherical Nucleic Acids (SNAs™) are the Next Generation of Oligonucleotide Therapeutics 5 • Entered IND-enabling studies in 4Q20 • IND filing anticipated by end of 2021 • Potential for early target engagement read-out in FIH via CSF frataxin levels Friedreich’s Ataxia Program Rapidly Progressing to P1 Building Deep Neuroscience Pipeline • SCN9A (NaV1.7) and CLN3 Batten Disease program in preclinical studies • Promising discovery efforts in sALS1, SCAs2, Huntington’s and Angelman’s SNAs: Potential Best-in-Class CNS Pharmacodynamics SNAs vs. Linear Oligos • Dramatically improved cellular uptake • Increased tissue persistence • Highly favorable CNS biodistribution, including deep brain regions Component A Component B In Vivo Increase of Frataxin to Carrier- Equivalent Levels (Mouse Cerebellum) 1) Sporadic ALS 2) Spino-cerebellar ataxias SCAs Angelman’s Sporadic ALS Batten Disease Friedreich’s Ataxia Pain Huntington’s
© 2021 Exicure, Inc. All Rights Reserved. | SNA 3D Architecture Drives Receptor-Mediated Uptake Into Cells 6 Synthetic Oligonucleotides Benign Lipid Nanoparticle Scaffold1 SNA Spherical Nucleic Acid • Compatible with virtually all oligonucleotide classes/chemistries (e.g. ASOs, siRNA, TLRs) • Maximum sequence length ~80 nucleotides • Scaffold for oligonucleotides • ~20 nm diameter • Dense, radial arrangement of oligonucleotides • Creates elevated local concentration of nucleic acids • Facilitates receptor interaction, increases cell uptake 1) Composition: 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) liposome; DOPC is in the FDA-approved drug DepoDur®, a morphine sulfate extended-release liposome injection for lumbar epidural administration
© 2021 Exicure, Inc. All Rights Reserved. | Established and Proven Management Team 7 David A. Giljohann Chief Executive Officer Matthias Schroff Chief Operating Officer Douglas Feltner Chief Medical Officer Tim Walbert Chairman Jeffrey L. ClelandJames SulatBali Muralidhar Bosun Hau Elizabeth Garofalo Andrew Sassine MANAGEMENT BOARD OF DIRECTORS Brian Bock Chief Financial Officer
© 2021 Exicure, Inc. All Rights Reserved. | SNAs are a Highly Differentiated and Versatile Platform for Drug Development 8 Increased SNA potency results in greater efficacy at same dose SNA Benefits Drive Superior In Vivo Efficacy Multi-Targeting Capability Cell-specific delivery of defined ratios of oligonucleotides 2 1 3 Oligo vs. Target A Oligo vs. Target B Oligo vs. Target C Potential for improved clinical efficacy, safety and less frequent dosing; as demonstrated in nonclinical studies. Access targets and diseases inaccessible by traditional methods Splice Switching Increased Gene Expression ASO/siRNA Mediated Knockdown Full Spectrum Oligonucleotide Platform 1) Spinal muscular atrophy
© 2021 Exicure, Inc. All Rights Reserved. | Three Drivers of Superior SNA Efficacy in Neuroscience 9 1 Higher Cell Uptake, Leading to Higher Potency at Same Dose 2 Broad CNS Penetration and Uptake in all Neuronal Subtypes SNA Linear SNA with 3x lower IC50 (141 nM) vs. linear oligonucleotides (464 nM) for MALAT1 knockdown in cortical neurons (in vitro) Anti-MALAT1 SNA reaches deep brain regions and achieves nuclear uptake in neurons, microglia and astrocytes 3 Higher Persistence in the CNS, Leading to Prolonged Efficacy Nusinersen Alone SNA- Nusinersen SNA-nusinersen with superior persistence in rat radiolabeled biodistribution study after seven days compared to linear nusinersen In Situ Hybridization of SNA in the Brain (Rat) via ICM dosing
© 2021 Exicure, Inc. All Rights Reserved. | Exicure Continues to Focus its Pipeline and Invest in Neuroscience DISCOVERY PRECLINICAL DEV PHASE 1 PHASE 2 NEUROSCIENCE XCUR-FXN Friedreich’s Ataxia SCN9A Neuropathic Pain CLN3 Batten Disease Undisclosed Huntington’s Disease Undisclosed Angelman Syndrome Undisclosed ALS, SCAs IMMUNO-ONCOLOGY Cavrotolimod1 Merkel Cell Carcinoma2 Cutaneous Squamous Cell Carcinoma2 DERMATOLOGY Undisclosed Hair Loss Disorders IND-enabling 1) Cavrotolimod is a TLR9 Agonist 2) In combination with checkpoint inhibitors 3) On November 13, 2019, Exicure announced this partnership with Allergan plc and on May 8, 2020, AbbVie Inc. acquired Allergan plc 10 3
SNA Differentiation in Neuroscience
© 2021 Exicure, Inc. All Rights Reserved. | SNA-Nusinersen Outperforms Linear Nusinersen in Mouse Models 12 Days Survival Note: Survival data presented at 2018 Annual Cure SMA Conference; Nusinersen curve (red) in line with published Ionis data for single dose administration in SMA mice (Hua et al., 2011) PROOF OF CONCEPT (MICE) commercially available linear oligonucleotide therapeutic to treat spinal muscular atrophy (SMA) Spinraza® (nusinersen) 2x levels of healthy, full-length SMN2 mRNA and protein in SMA patient fibroblasts 4x longer survival vs. nusinersen and mitigated nusinersen toxicity SNA Control
© 2021 Exicure, Inc. All Rights Reserved. | SNA Efficacy is Driven by Longer CNS Persistence 13 0 Hours Nusinersen Alone SNA- Nusinersen 24 Hours Nusinersen Alone SNA- Nusinersen 7 Days Nusinersen Alone SNA- Nusinersen Highest levels of drug present in CNS (50 SUV) Drug still present in CNS (0.5 SUV) Note: Identical amount of oligonucleotide (180 µg) dosed for “Nusinersen Alone” and “SNA-Nusinersen” SNA-Nusinersen Persistence in spinal cord and brain Rat Distribution Study
© 2021 Exicure, Inc. All Rights Reserved. | SNA Persistence Translates to Non-Human Primates (IT Dosing) 14 • Broad distribution throughout the CNS • Strong SNA signals in the cerebellum, a region particularly important for FA, as well as midbrain, hippocampus and occipital lobe • Strong SNA persistence with >50% of day 1 signal remaining after 14 days ConclusionsRelative Biodistribution in the CNS (NHP)1 Occipital Lobe Cerebellum Midbrain Hippocampus FA, CLN3 FA, CLN3 CLN3 CLN3 Data ? n 1) Exicure data on file for 46 specific brain regions presented in a poster at the 145th Annual Meeting of the American Neurological Association October 4, 2020 124I-labeled SNA dosed intrathecally, followed by PET/CT through 14 days post dose to measure decay-adjusted radioactivity signals. Data are means ± SD of n=3 monkeys
XCUR-FXN: Friedreich’s Ataxia
© 2021 Exicure, Inc. All Rights Reserved. | Friedreich’s Ataxia (FA) is a Progressive Neurological Disorder 16 • Degenerative, debilitating, life-shortening, neuromuscular disorder causing loss of coordination (ataxia) in arms and legs • Monogenic disorder: FXN mutations result in reduced levels of frataxin • Leads to progressive childhood disability and early death - Mean onset of symptoms between age 10 to 151 - Most patients wheelchair-bound within 2 decades of onset - Loss of coordination, neuropathy, hearing and vision loss, cardiomyopathy, diabetes - Most patients succumbing to disease in their 30s and 40s • Most common inherited ataxia: ~13,500 cases across major reimbursable markets2,3; majority of these patients already known • No approved therapy for FA • No therapies in late development which address the molecular cause of FA 1) Gene Review, Bidichandani SI, Delatycki MB. 2017. 2) OrphaNet, NIH, FARA. 3) US, EU28, Canada, Australia Kyle Bryant, FA patient – FARA Spokesperson
© 2021 Exicure, Inc. All Rights Reserved. | Reduced Frataxin Expression Due To Expanded GAA Repeats Cause Neuronal Dysfunction in FA 17 Friedreich’s Ataxia Key CNS Tissues: • Cerebellum • Dorsal Root Ganglia Neuronal Dysfunction & Death DNA Reduced FXN ProteinReduced FXN mRNA GAAGAAGAAGAAGAAGA … Mitochondrial Dysfunction NEURON CNS NUCLEUS CYTOPLASM Expanded GAA Repeats (~70-1000+)
© 2021 Exicure, Inc. All Rights Reserved. | Neurodegeneration Drives All Components of the mFARS Rating Scale, the Validated Registrational Endpoint for FA 18 1) Bürk, K., Cerebellum & Ataxias, 2017 2) Puccio, et al., Rev Neurol, 2014; Parkinson et al., J Neurochem, 2013 3) mFARS used as the primary outcome measure in most contemporary clinical studies in FA; Rummey et al., Neurol Genet, 2019; www.ataxia-study-group.net Core Areas of FA Pathology Peripheral sensory neuropathy Muscle weakness due to prior neurodegeneration2 DRG neuron degeneration1 Cardiomyopathy Cerebellar dysfunction1 CNS-related symptoms Other symptoms Diabetes Bulbar Function (speech, cough, facial/tongue atrophy) – 5 pts Upper Limb Coordination (finger, arms) – 36 pts Lower Limb Coordination (legs, feet) – 16 pts Upright Stability (sitting, walking, etc.) – 36 pts mFARS Clinical Rating Scale (Validated, Approvable Endpoint for FA3) mFARS
© 2021 Exicure, Inc. All Rights Reserved. | 0 20 40 60 80 100 Pe rc en t o f P at ie nt s For Patients, the CNS Manifestations of FA Have the Most Significant Impact on Function and Quality of Life 19 CNS Manifestations “CNS manifestations of FA are the most significant in terms of function and quality of life for individuals living with FA” – Jennifer Farmer, CEO FARA Which FA Symptoms Most Impact Your Daily Quality of Life? Data from FARA’s FA PFDD Meeting, June 2, 2017, N = 136; graphical illustration adapted from FARA version presented on Jan 7, 2021
© 2021 Exicure, Inc. All Rights Reserved. | Increased Frataxin Levels Elicited by Oligonucleotides Expected to Slow or Stop Disease Progression 20 Frataxin Levels in Blood from FA Patients vs Controls • Patients with FA have substantial residual frataxin • Residual frataxin levels support Exicure’s protein upregulation approach • “Classic”, typical onset1 FA patients with frataxin levels of ~25% of healthy control in whole blood • Late onset2 FA patients with 45-60% of healthy control levels, below carrier levels of 65-70% • Differential in disease onset based on frataxin levels strongly supports therapeutic rationale for increasing frataxin to slow disease progression Conclusions cFRDA = Classic, typical onset FA; LOFA = Late onset FA; pFRDA = heterozygous for repeat + point mutation Whisker plot: Box outlines represent 95% CI, whiskers represent 99% CI, x = outliers beyond 99% CI Source: Deutsch et al., 2014 1) Mean age at onset 11.3 years 2) Mean age at onset 36.7 years
© 2021 Exicure, Inc. All Rights Reserved. | Cytoplasm XCUR-FXN (bi-specific SNA) Carries two distinct oligonucleotides ( )1 2 1 2 XCUR-FXN Leverages Multi-Targeting Approach for FXN Upregulation 21 DNA mRNA CytoplasmNucleus Degradation of Natural Antisense Transcript 1 1 Increased Frataxin Production MitochondrionEnzyme mRNA Stabilization Increased FXN mRNA We believe XCUR-FXN increases production of the FXN mRNA by degrading a natural antisense transcript and increasing FXN mRNA half-life in the cytosol , enabling more translational cycles per mRNA molecule. 2 2 1 2
© 2021 Exicure, Inc. All Rights Reserved. | Increased Mitochondrial Frataxin Levels2 • XCUR-FXN restores protein levels to non- disease controls in mitochondria, the main target cellular compartment of FA XCUR-FXN Dose-Dependently Upregulates Frataxin Protein and Restores Mitochondrial Function in Induced Neurons from FA Patients1,2 22 • XCUR-FXN showed dose-dependent increase in frataxin up to healthy control levels • Synergistic effects of increased frataxin mRNA and protein with bi-specific SNA (XCUR-FXN) vs mono-specific SNA components (data not shown) Dose-Dependent Frataxin Increase with XCUR-FXN1 • XCUR-FXN increases mitochondrial energy metabolism (SDH activity), indicating improved mitochondrial health • Highest reported potency in a transfection- free system for improving mitochondrial activity in patient-derived mitochondria Restoration of Mitochondrial Function3 1) All graphs are from FA patient iPSC with experiments done on induced neurons. No use of transfection agents or electroporation 2) Experimental conditions: (left) Total frataxin: 541/420 GAA, N = 2; (middle and right) Donor 1: 330/380 GAA, Donor 2: 541/420 GAA; (middle) Mitochondrial frataxin: N = 3; (right) SDH = succinate dehydrogenase: N = 3
© 2021 Exicure, Inc. All Rights Reserved. | Magnitude of In Vivo Frataxin Upregulation by the Components of XCUR-FXN Showed Possibility for Disease Resolution in Patients 23 • The highest fold changes (2-3x) are observed in the cerebellum and across all DRG regions, the areas with highest known disease relevance for FA • The two component oligonucleotides shown are the individual components of XCUR-FXN; in vitro results show synergy in FXN upregulation via combination of individual oligonucleotides into a multi-targeting SNA Frataxin Protein Levels Measured Across Brain and DRG Regions at 2 Dose Levels XCUR-FXN Component A - 12 μg dose XCUR-FXN Component A - 60 μg dose XCUR-FXN Component B - 12 μg dose XCUR-FXN Component B - 60 μg dose Vehicle Brain Regions Frataxin upregulation observed following ICV administration of a single dose to 6-8-week-old Pook800J mice *Error bar and third individual data point for thoracic DRG not shown, out of range DRG Regions
© 2021 Exicure, Inc. All Rights Reserved. | SNA Oligonucleotides Observed in Both the Cytoplasm and Nucleus of Neurons in the Deep Cerebellum 24 In Situ Hybridization of SNA in the Brain (Rat)1 via ICM dosing • Co-localization of anti-MALAT1 oligonucleotides with nuclei suggests nuclear uptake of SNAs • MALAT1-targeting SNAs are visible in the deeper regions of the cerebellum – In the image to the left, SNAs populate large neurons of the deep cerebellar nuclei • The primary site of FA cerebellar pathology is the dentate nuclei Co-localization of probes show SNA uptake in nuclei Nucleus (hematoxylin) anti-MALAT1 ON probe Conclusions 1) Rats received single ICM dose of 415 µg (~2 mg/kg) MALAT1-targeting oligonucleotide in SNA format. Rats were sacrificed for in situ hybridization 2 weeks after dosing
© 2021 Exicure, Inc. All Rights Reserved. | Rat Dose Range Finder Results for XCUR-FXN Show No Test Article- Related Adverse Findings 25 • XCUR-FXN was overall well tolerated at all dose levels in this study • No adverse, test article-related histopathologic findings at any of the 3 dose levels evaluated • No test article-related preterminal deaths, organ weight changes, or macroscopic findings at the end of the study • Based on these draft results, the no-observed-adverse- effect level (NOAEL) was considered to be the highest dose level evaluated (782 µg) • Results are highly encouraging as we await the readout of the ongoing GLP-toxicology studies of XCUR-FXN in rat and NHP in Q4’2021 • Objective: Determine tolerability of our bi-specific development candidate XCUR-FXN in rats following 3 repeat intrathecal (IT) injections • Three dose levels, N=3 / sex / dose group: highest dose 782 µg/injection Intrathecal Injection Day 1 Day 15 Day 29 Day 32 Sacrifice and Histopathology ResultsStudy Design Rats
© 2021 Exicure, Inc. All Rights Reserved. | FA Competition: Late-Stage Programs Do Not Address the Genetic Cause of FA; Early-Stage Programs Unlikely to Sufficiently Reach CNS 26 Program Omaveloxolone Vatiquinone Leriglitazone CTI-1601 XCUR-FXN FA GeneTAC AAV Gene Therapies MoA Oxidative stress reduction Oxidative stress reduction PPARɣ agonist Modified frataxin replacement therapy FXN upregulation in the CNS via bispecific antisense oligonucleotide FXN upregulation via small molecule AAV gene therapies targeting the CNS and/or heart Key Observations Achieved modest mFARS improvement (2.4 improvement on a 93-point scale) in P2; FDA has cleared for a pre- NDA meeting suggesting potential approvability on the modestly observed clinical improvement Initiated P3 study with three times a day (TID) dosing regimen; P2 results showed no effect vs. placebo during randomized controlled study1 Edema observed as prominent AE in P2a, in line with mechanism of action and its known cardiovascular safety risk Preclinical mouse data showed only ~5% frataxin replacement rate in the CNS upon repeat dosing2; top SAD dose of 100 mg SC and OD unlikely to provide substantially higher exposures3; currently on clinical hold due to mortalities in 180- day NHP study In vivo frataxin upregulation of ~3x in the CNS of mice following intrathecal single dose administration of the individual components of XCUR-FXN at comparatively low doses (60 µg) ~80x lower drug exposures in brain vs heart & large molecular weight of 1,600-1,800 Da suggest limited CNS exposure with anticipated clinical IV dosing regimen Delivery of AAV vectors to the CNS is associated with DRG toxicity4 Most preclinical programs without progress for >12 months Pre-NDA Phase 3 Phase 2 Phase 1 Preclinical Sources: Company websites, corporate SEC filings, www.clinicaltrials.gov 1) Zesiewicz et al. 2018; Post-hoc analysis and comparison of 24-month open label data to natural history data suggested a potential benefit in FA patients. 2) IARC conference 2019 3) Using simple allometric dose scaling 4) Hordeaux et al., 2020 OD: Once Daily SC: Subcutaneous
© 2021 Exicure, Inc. All Rights Reserved. | Rapid Path to Clinical Validation for XCUR-FXN 27 • IND filing expected end of 2021 to initiate Phase 1b First-in-Human study in FA patients in H1 '22 • Phase 1b goals: Demonstrate safety and characterize PK of multiple ascending doses in FA patients and inform P2/3 dose selection • Phase 1b trial design and site selection in close collaboration with FARA • Translational biomarkers, including brain imaging and frataxin in CSF to provide fast read-out for target engagement and PD effects – potential for first biomarker readouts from XCUR-FXN in P1b • Exploratory endpoints to measure clinical outcomes (mFARS and other functional assessments) in preparation for pivotal trial – Preclinical efficacy suggests potential for disease resolution • Robust and scalable platform GMP manufacturing process in place – Exicure has previously successfully scaled up 3 SNA programs for clinical trials in oncology and inflammation CSF: Cerebral spinal fluid FARA: Friedreich’s Ataxia Research Alliance mFARS: modified Friedreich’s Ataxia Rating Scale PD: Pharmacodynamic PK: Pharmacokinetics
© 2021 Exicure, Inc. All Rights Reserved. | Pharmacodynamic Endpoints for Phase 1b Selected to Provide Robust Data Package to Assess Effects of XCUR-FXN in Patients 28 PD Marker Significance of Change Frataxin protein (in CSF) Target engagement by XCUR-FXN in most proximal compartment Neurofilament light chain (NfL) and phosphorylated heavy chain (pNfH) in CSF and serum Beneficial effect on CNS neurons/axons as a result of increased frataxin levels indicating correction of FA pathophysiology Ferritin (in serum) Normalization of iron distribution as downstream marker of FA pathophysiology PD Marker Significance of Change Quantitative susceptibility mapping (QSM) of cerebellar dentate nucleus by MRI (measuring iron content) Decrease in iron indicates correction of FA pathology Magnetic resonance spectroscopy (MRS) of key CNS metabolites Normalizing effect on key CNS metabolites (n-acetylaspartate, myo-inositol, etc.) as marker of correction of FA pathophysiology Diffusion tensor imaging (DTI) of superior cerebellar peduncle by MRI Improved white matter/axonal microstructure indicate correction of FA pathology Neuroimaging CSF / Serum Biomarkers
Deep Neuroscience Pipeline
© 2021 Exicure, Inc. All Rights Reserved. | Small Molecule Inhibitor of Nav1.7 (nM) C ha nn el A ct iv at io n • Past small molecules required unbound plasma concentrations substantially above the IC50 to sufficiently inhibit Nav1.7 in DRGs • Due to small selectivity margins, SMs failed to reach target inhibition levels in DRG • Knockdown via SNAs is exquisitely selective, with SNA screening hits not exhibiting homology with other Nav family members Illustrative Example of Nav1.7 Selectivity Profile for Small Molecule Inhibitor (Xenon/ Genentech; Bankar et al., 2018) Nav1.7, a Validated Pain Target, is Ideally Suited to Exicure’s SNA Platform Due to SNA Selectivity and Biodistribution Profile 30 • Nav1.7 is a trans-membrane sodium channel key for pain signal transduction to the brain • Gain-of-function mutations lead to severe pain conditions such as inherited erythromelalgia and small fiber neuropathy • Loss-of-function mutations lead to congenital insensitivity to pain SCN9A Gain-of-Function Mutations SCN9A Loss-of-Function Mutations Severe Pain Lack of Pain • Intrathecal SNA achieves in vivo delivery to dorsal root ganglion (DRG) neurons, the key cell type expressing Nav1.7 and which mediates transmission of peripheral pain signals to the brain Oligonucleotide Selectivity vs Small Molecules (SMs)2Human Genetic Validation1 SNA Distribute to DRGs3
© 2021 Exicure, Inc. All Rights Reserved. | Potent CLN3 Splice Modulating SNAs for Treatment of Both the CNS and Ocular Disease Manifestations of CLN3 Batten Disease 31 • SNAs restore CLN3 mRNA expression to wild-type level in retina of Batten disease mouse model • Supports pursuit of ocular manifestations in Batten disease • CLN3 advancement will de-risk platform for large number of eye disorders • ~50% of U.S. patients known by KOLs • High unmet need supports attractive pricing for a clinically meaningful therapy • Limited competition (Amicus gene therapy in P1/2; Abeona preclinical gene therapy; Ionis discovery project) >1,800 in U.S. and EU • Potent splice modulating SNAs identified • SNAs convert up to 95% of mRNA into splice-corrected, functional transcript • Observed splice modulation translates into increased total CLN3 mRNA levels (see prior slide), suggesting effects on protein levels PoC: Proof of Concept In Vivo PoC for Eye in Batten Disease Mouse Model Commercially Attractive Indication Extremely Potent Splice Modulating SNAs Identified21 3 Increase in Total CLN3 mRNA
Cavrotolimod Differentiated TLR9 Agonist in P1b/2 for Solid Tumors
© 2021 Exicure, Inc. All Rights Reserved. | SNAs Are Ideal for TLR9 Activation 33 • Toll like receptor 9 (TLR9) agonism can produce the desired pharmacodynamics • TLR9 is found in the endosome of cells – SNAs are colocalized in the endosome after internalization into cells • The SNAs are coated externally with oligonucleotides allowing for facile interaction with TLR9 • SNAs have high cellular uptake, driving potency SNAScavenger Receptors Endosome Activated NK cell Activated T cell IP-10IL-12 TLR9s Key Takeaways
© 2021 Exicure, Inc. All Rights Reserved. | Cavrotolimod Phase 2 Expansion Stage 34 Merkel Cell Carcinoma (MCC) N = up to 29 1 Enroll 10 Cavro at RP2D and pembro per label N=10 Enroll 19 Cavro at RP2D and pembro per label N=29 ≥ 1 partial response or complete response Cutaneous Squamous Cell Carcinoma (CSCC) N = up to 29 2 Enroll 10 Cavro at RP2D and cemiplimab per label (Assess safety after first 6) N=10 Enroll 19 Cavro at RP2D and cemiplimab per label N=29 ≥ 1 partial response or complete response Design of Phase 2 Dose-Expansion Cohorts • P2 patients are refractory to anti-PD-(L)1 therapy at study entry • Fast Track and Orphan Drug designations granted for MCC • Fast Track designation granted for CSCC • Potential for trial to be registration study • Exploratory cohorts underway in melanoma and with SC dosing Final results expected H1-2022Completed Stage Current Stage Expansion Threshold Met
© 2021 Exicure, Inc. All Rights Reserved. | Phase 1b/2 Summary of Cavrotolimod Clinical Findings 35 Clinically meaningful overall response rate Confirmed ORR 21% in all evaluable MCC patients in P1b/2 (3 out of 14; 2 P1b and 1 P2) P2 CSCC and exploratory cohorts continuing enrollment and data accrual Systemic (abscopal) effects Regression of noninjected regional and distant lesions in all 3 MCC responders in P1b/2 Safety & adverse events (AE) In P2, two patients experienced treatment-related serious AEs: hypotension, flu-like symptoms and infusion-related reaction Durable response In P1b, all 4 responders with durable response ≥6 months Median duration of response in P1b 14 months Longest response 17 months and ongoing In P2, 93% of treatment-related AEs were grade 1 or 2 Most common TRAEs were flu-like symptoms, injection site reactions, expected from mechanism of action Phase 2 Interim Results and Phase 1b Update as of Data Cut-off Date of July 1, 2021
© 2021 Exicure, Inc. All Rights Reserved. | Phase 1b/2 MCC: Regression of Noninjected Regional & Distant Lesions 36 CR**PR*Overall Response (RECIST v1.1) P1b Stage -36% R axillary LN † -34% R axillary LN -50% L axillary LN † -100% L leg -100% L leg * Patient progressing on anti-PD-1 therapy at the time of trial enrollment ** Patient previously treated with anti-PD-1 therapy but not on anti-PD-1 therapy at the time of trial enrollment" CR* -100% R lower arm -100% R upper arm Best overall response per RECIST v1.1 in all evaluable Merkel cell carcinoma patients as of July 1, 2021 -100% R lower arm P1b Stage P2 Stage †Biopsy showed no residual tumor
© 2021 Exicure, Inc. All Rights Reserved. | Phase 2 MCC Patient with Overall Complete Response by RECIST v1.1 37 Baseline Week 36 Overall Response (RECIST v1.1) - Complete Response #1 - Injected Target Lesion Right wrist 20 mm 0 mm #2 - Injected Target Lesion Right lower arm 53 mm 0 mm #3 - Noninjected Lesion Right upper arm 25 mm 0 mm Sum of 3 Lesion Diameters 98 mm 0 mm 92-year-old Male Patient w/ Documented Progression on Pembrolizumab Monotherapy
Existing Partnerships & Near-Term Value Inflections
© 2021 Exicure, Inc. All Rights Reserved. | Exicure & Abbvie: Active Collaboration for Hair Loss Disorders 39 • $25M upfront • Up to $50M in option/IND- enabling payments • Up to $195M in development and regulatory milestones • Up to $530M in commercial milestones • Tiered royalties of mid single-digit to mid-teen percentage The EconomicsThe Partnership • Discover and develop two SNA-based treatments for hair loss disorders • Initiated November 2019 • Exicure responsible for discovery costs prior to option exercise by Allergan; Allergan responsible afterwards 1) On November 13, 2019, Exicure announced this partnership with Allergan plc and on May 8, 2020, AbbVie Inc. acquired Allergan plc 1
© 2021 Exicure, Inc. All Rights Reserved. | Ipsen Neuroscience Collaboration for Huntington’s and Angelman’s 40 • $1B+ total deal value • $20M cash upfront • Up to $10M in preclinical milestones • Up to $50M in option exercise payments • Up to $180M in development and regulatory milestones • Up to $762M in commercial milestones • Tiered royalties percentages from mid single-digits to mid-teens The EconomicsThe Partnership • Discover and develop two SNA-based treatments for Huntington’s Disease and Angelman Syndrome • Initiated August 2021 • Both indications are an ideal fit for the SNA platform differentiation of deep brain penetration and persistence • Exicure funds discovery and pre-clinical work up to candidate selection • Ipsen funds all work post candidate selection, including IND-enabling activities
© 2021 Exicure, Inc. All Rights Reserved. | Key Value Inflections Across Platform & Programs in 2021 & 2022 Q2 2021 • Rat dose-range finder for XCUR-FXN • Commencement of GLP tox studies for XCUR-FXN • In vivo PoC (eye) for CLN3 program for Batten Disease Q3-4 2021 • Neuroscience collaboration with Ipsen for Huntington’s and Angelman’s • IND filing for XCUR-FXN (on track) • Neuroscience pipeline progress (SCN9A, CLN3, and discovery programs) • Interim results from cavro P1b/2 trial H1 2022 • First patient dosed with XCUR-FXN • 2nd neuro program to enter IND-enabling studies • Final cavro P1b/2 results H2 2022 • Potential for first biomarker readouts from XCUR-FXN P1b 41
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