UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
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FORM 8-K
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CURRENT REPORT
Pursuant to Section 13 OR 15 (d)
of The Securities Exchange Act of 1934
Date of Report (Date of Earliest Event Reported): November 1, 2022
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(Exact Name of Registrant as Specified in its Charter)
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| (State or Other Jurisdiction of Incorporation) | (Commission File Number) | (I.R.S. Employer Identification Number) | ||||||||||||
(484 ) 328-4701
(Address, including zip code, and telephone number, including area code, of principal executive office)
N/A
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8–K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
Securities registered pursuant to Section 12(b) of the Act:
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(The Nasdaq Capital Market) | ||||||||||||||
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
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. ☐
Item 7.01 Regulation FD Disclosure.
Attached as Exhibits 99.1 and 99.2 hereto and furnished herewith are presentations that Ocugen, Inc. (the "Company") intends to present at its in-person Research & Development Day on November 1, 2022 ("R&D Day").
In addition, attached as Exhibits 99.3, 99.4, 99.5, 99.6, 99.7, and 99.8 hereto and furnished herewith are copies of the poster presentations and displays that the Company intends to use and display throughout R&D Day.
The information disclosed under Item 7.01 of this Current Report on Form 8-K, including Exhibits 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, and 99.8, is being furnished and shall not be deemed "filed" for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the "Exchange Act"), or otherwise subject to the liabilities of that section, and shall not be deemed to be incorporated by reference in any Company filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
Item 9.01 Financial Statements and Exhibits.
The following exhibits are being furnished herewith:
(d) Exhibits
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SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
Date: November 1, 2022
| OCUGEN, INC. | ||||||||
| By: | /s/ Shankar Musunuri | |||||||
| Name: Shankar Musunuri | ||||||||
| Title: Chief Executive Officer and Chairman | ||||||||
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Long-Term Outlook Shankar Musunuri, PhD, MBA Chairman of the Board, CEO & Co-founder R&D Day November 1, 2022
Forward Looking Statements 2 This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, which are based on the beliefs and assumptions of Ocugen, Inc. and on information currently available to management. All statements contained in this presentation other than statements of historical fact are forward-looking statements. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “proposed,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should,” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such statements are subject to numerous important factors, risks, and uncertainties that may cause actual events or results to differ materially from our current expectations. These and other risks and uncertainties are more fully described in our periodic filings with the Securities and Exchange Commission (SEC), including the risk factors described in the section entitled “Risk Factors” in the quarterly and annual reports that we file with the SEC. In addition, this presentation contains estimates, projections and other information concerning market, industry and other data. We obtained this data from our own internal estimates and research and from academic and industry research, publications, surveys, and studies conducted by third parties, including governmental agencies. These data involve a number of assumptions and limitations, are subject to risks and uncertainties, and are subject to change based on various factors, including those discussed in our filings with the SEC. These and other factors could cause results to differ materially from those expressed in the estimates made by the independent parties and by us. While we believe such information is generally reliable, we have not independently verified any third-party information. Forward-looking statements that we make in this presentation are based on a combination of facts and factors currently known to us and speak only as of the date of this presentation. Except as required by law, we assume no obligation to update forward-looking statements contained in this presentation whether as a result of new information, future events, or otherwise, after the date of this presentation.
We’re Here to Make an Impact Through Courageous Innovation 3 Mission: Developing cutting-edge innovations for people facing serious disease and conditions with a commitment to ensuring global market access Pioneering modifier gene therapy for inherited retinal diseases, as well as larger blindness diseases with unmet need Innovating a novel biologic to treat eye diseases that can lead to vision loss for millions of people Developing vaccines to provide choice to Americans in the fight against COVID-19 Pursuing Regenerative Cell Therapy to treat serious conditions like articular cartilage lesions
4 Pipeline Overview Asset/Program Indication Current Status Vaccines COVAXIN™ (BBV152) SARS-CoV-2 virus COVID-19 • EUA for adults in Mexico; EUA for 5 to 18-year-olds submitted • Recruitment completed for U.S. Phase 2/3 Immuno-bridging and broadening clinical trial OCU500 Mucosal vaccine COVID-19 • License secured from Washington University • Phase 1/2 pending FDA discussions Cell therapies (Regenerative Medicine) NeoCart® (Autologous chondrocyte-derived neocartilage) Treatment of Articular Cartilage Defects in the Knee U.S. Regenerative Medicine Advanced Therapy (RMAT) designation; Phase 3 clinical trial under development and subject to finalization with FDA Gene therapies OCU400 ** AAV-hNR2E3 Gene mutation-associated retinal degeneration* NR2E3 Mutation (RP) Phase 1/2 RHO Mutation (RP) Phase 1/2 CEP290 Mutation (LCA) Phase 1/2 OCU410 AAV-hRORA Dry Age-Related Macular Degeneration (Dry AMD)** IND planned for Q2 OCU410ST AAV-hRORA Stargardt (orphan disease) IND planned for Q2 Biologicals OCU200 Transferrin – Tumstatin Diabetic Macular Edema IND planned for Q1 Diabetic Retinopathy IND enabling Wet Age-Related Macular Degeneration (Wet AMD) IND enabling *No approved therapies exist https://www.aao.org/eye-health/diseases/retinitis-pigmentosa-treatment | https://www.aao.org/eye-health/diseases/amd-treatment **ORPHAN DRUG DESIGNATION in the US; Broad ORPHAN MEDICINAL PRODUCT DESIGNATION by the EC for the treatment of retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA)
Corporate Executive Summary Ocugen has an exciting and unique portfolio spanning ocular gene therapies, a novel biologic, an orthopedic regenerative cell therapy, and COVID-19 vaccines. We believe the modifier gene therapy platform assets (OCU400 and OCU410) are the most significant drivers of value. We believe each asset has the potential to be significant if clinical data and commercial assumptions are positive— more conservative estimates still offer a meaningful valuation upside. Ocugen will need to carefully manage available capital in the near-term to maximize value for the ocular gene therapies. Additional capital raises and partnerships will be required to extend the runway and accelerate the portfolio. Investments through business development in capability building and portfolio diversification will be important to enable the current portfolio and scale the portfolio in the longer-term. 1 2 3 4 5
Modifier Gene Therapy Platform—Compelling Value Proposition with Potential to Meaningfully Disrupt the Market Traditional single-gene augmentation transfers a functional version of a non-functional gene into target cells – This approach is limited by its ability to address one gene mutation at a time, meaning ability to address large populations is significantly constrained Ocugen’s modifier gene therapy platform is designed to introduce a functional gene to modify the expression of many genes/gene networks – This approach has the potential to address significantly larger patient populations in a much shorter period, given streamlined clinical development and regulatory filings We believe clinical success of the Modifier Gene Therapy platform will unlock the revenue potential of OCU400 and OCU410 and provide significant valuation upside to Ocugen GENE X GENE X GENE M GENE X 6
Potential Market Opportunity for Ocugen Gene Therapies— Revenue Potential of up to ~$40B in 2032 # Doses (in Thousands)* OCU400 6.0 18.6 19.8 25.5 29.4 34.1 39.5 OCU410 - 11.7 24.1 32.1 50.2 71.5 79.3 Forecasted Net-Revenue (OCU400, OCU410) Key Assumptions – 90% Ability-To-Pay (adjusting for affordability, including uninsured patient population) – 25% standard GTN discount (as observed for high-priced GTs) $0 $5 $10 $15 $20 $25 2026 2027 2028 2029 2030 2031 2032 Bi llio ns ~$23B ~$17B Launch in Broad Spectrum (US) Launch in Late dAMD (US) Launch in Late dAMD (EU) Launch in Moderate dAMD and Mild dAMD (EU) Launch in Moderate dAMD and Mild dAMD (US) Launch in Mutation Specific (US)* Launch in Broad Spectrum (EU) *Not risk-adjusted ** Disease prevalence: U.S./EU/UK RP/LCA > 250,000. U.S./EU/UK dAMD (Geographic Atrophy) > 2 million . 7
Key Potential Milestones for Portfolio Assets C UR RE N T PO RT FO LI O M IIL ES TO N ES CA PI TA L AV AI LA BL E 2022 2023 2024 2025 2026 2027 OCU500 (mucosal) Ph I/II (Potential EUA Path) COVAXIN Ph 3 Safety US BLA Filing US BLA FilingNeoCart® Phase III BLA Filing BLA FilingOCU400 Ph I/II Global Ph III Global Ph IIIOCU410* Ph I/II Phase III (DME)OCU200 Ph I Phase II US US MX Launch “EXTEND THE RUNWAY” In the near-term: Efficiently manage capital, including seeking USG support for COVID-19 vaccines development “RAISE & ACCELERATE” In the medium-term “SCALE THE PORTFOLIO” In the longer-termST RA TE GI C IM PE RA TI VE S 6-mth reviewCOVAXIN Immuno. Ph 2/3 OCU500 Booster BLA Filing 8
9 Ocugen™ Vision Fully integrated, patient-centric biotech company focused on vaccines in support of public health and gene and cell therapies targeting unmet medical needs through Courageous Innovation
Modifier Gene Therapy Technology For Retinal Diseases Arun Upadhyay, PhD CSO
2Modifier Gene Therapy and OCU400 Forward Looking Statement This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995, which are based on the beliefs and assumptions of Ocugen, Inc. and on information currently available to management. All statements contained in this presentation other than statements of historical fact are forward-looking statements. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “proposed,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should,” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. Such statements are subject to numerous important factors, risks, and uncertainties that may cause actual events or results to differ materially from our current expectations. These and other risks and uncertainties are more fully described in our periodic filings with the Securities and Exchange Commission (SEC), including the risk factors described in the section entitled “Risk Factors” in the quarterly and annual reports that we file with the SEC. In addition, this presentation contains estimates, projections and other information concerning market, industry and other data. We obtained this data from our own internal estimates and research and from academic and industry research, publications, surveys, and studies conducted by third parties, including governmental agencies. These data involve a number of assumptions and limitations, are subject to risks and uncertainties, and are subject to change based on various factors, including those discussed in our filings with the SEC. These and other factors could cause results to differ materially from those expressed in the estimates made by the independent parties and by us. While we believe such information is generally reliable, we have not independently verified any third-party information. Forward-looking statements that we make in this presentation are based on a combination of facts and factors currently known to us and speak only as of the date of this presentation. Except as required by law, we assume no obligation to update forward-looking statements contained in this presentation whether as a result of new information, future events, or otherwise, after the date of this presentation.
3Modifier Gene Therapy and OCU400 We’re Here to Make an Impact Through Courageous Innovation Mission: Developing cutting-edge innovations for people facing serious disease and conditions with a commitment to ensuring global market access Pioneering modifier gene therapy for inherited retinal diseases, as well as larger blindness diseases with unmet need Innovating a novel biologic to treat eye diseases that can lead to vision loss for millions of people Developing vaccines to provide choice to Americans in the fight against COVID-19 Pursuing Regenerative Cell Therapy to treat serious conditions like articular cartilage lesions
4Modifier Gene Therapy and OCU400 Why is Modifier Gene Therapy Needed? Modifier Gene Therapy Retinal Diseases > IRDs and AMD are most common cause of vision impairment and blindness > Can be broadly categorized into monogenic and complex (multifactorial) forms > High genetic heterogeneity significantly limits gene- specific therapeutic strategy - Monogenic inherited retinal diseases—Retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), and others > Gene specific strategy may not be applicable for multifactorial diseases, such as dry age-related macular degeneration > Need for mutation-independent approach - Modulating key retinal gene-network involved in retinal damage Retinal Diseases Multifactorial Environmental Genetic / Inherited Retinitis Pigmentosa & LCA Age-related Macular Degeneration Monogenic Multigenic Monogenic Multivariant Gene augmentation/ Editing
5Modifier Gene Therapy and OCU400 Nuclear Hormone Receptors as Modifier Genes RORA alone regulates expression of several hundred homeostasis genes Nejati Moharrami et al, PLOS ONE 2018
6Modifier Gene Therapy and OCU400 Why Target Nuclear Hormone Receptor Genes? > Nuclear hormone receptors (NHRs) are intracellular receptors that regulate gene expression - NHRs act as “Master Genes” inside the cell > NHRs can regulate diverse physiological functions - Homeostasis - Cellular and tissue development - Cellular and tissue metabolism > The human genome contains 48 NHRs - Many have tissue-specific expression patterns - NHR dysregulation often leads to disease ∘ Therefore, NHRs are common drug discovery targets N H R DEVELOPMENT HOMEOSTASIS METABOLISM N H R ∆ G E N E E X P R E S S I O N
7Modifier Gene Therapy and OCU400 * No approved therapies exist https://www.aao.org/eye-health/diseases/retinitis-pigmentosa-treatment | https://www.aao.org/eye-health/diseases/amd-treatment A S S E T/ P R O G R A M I N D I C AT I O N S TAT U S Modifier Gene Therapy Platform OCU400 ** *Inherited retinal degeneration* NR2E3 Mutation Phase 1/2 RHO Mutation Phase 1/2 CEP290 Mutation Phase1/2 to be initiated OCU410 Dry Age-related Macular Degeneration (Dry AMD)* IND Enabling OCU410-ST Stargardt Disease IND Enabling **Orphan drug designation in the US; Broad orphan medicinal product designation by the EC for the treatment of retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) Pipeline Overview: Modifier Gene Therapy Technology
Modifier Gene Therapy Platform: OCU400 ( A AV 5 - h N R 2 E 3 ) fo r R P a n d L C A D i s e a s e s
9Modifier Gene Therapy and OCU400 2 million >300 genes IRD 1.5 million >100 genes RP ~100,000 >25 genes LCA ~100,000 ~8,200~400,000 Go ng e t a l, 20 21 Inherited Retinal Diseases: Prevalence and Associated Genes IRDs: Diverse disease class with large phenotypic and genetic heterogeneity > A common cause of irreversible blindness due to retinal cell degeneration > Symptom onset can range from birth to adulthood > Varying rate of progression and severity > Limited information on disease natural history and windows of opportunities for therapeutic intervention > RP and LCA are the most common IRDs involving photoreceptors and the retinal pigment epithelium (RPE) > RP alone is associated with mutations in >100 genes
10Modifier Gene Therapy and OCU400 > Only one approved gene therapy for LCA associated with RPE65 mutation: Luxturna® (Voretigene Neparvovec-rzyl) > Electronic Smart glasses as a low vision aid in patients with RP—IrisVision is a Class I medical device > No disease-modifying therapy options are available for broader IRD-associated mutations Inherited Retinal Degeneration: A Broader Reach For OCU400 Gene augmentation or editing can only treat a small fraction of the IRD population, but OCU400 has the potential to treat a large group of patients with IRDs EyesOnGenes.com
11Modifier Gene Therapy and OCU400 Current Limitations of Conventional Gene Therapy Gene Augmentation: Transfer functional version of a non-functional gene into the target cells. ONE Disease Regulatory pathway focused on specific product for one disease GENE X cell GENE X Cell with mutated/nonfunctioning gene X GENE X GENE X cell GENE X GENE X cell N O R M A L G E N E X > Two patients with the same disease but arising from mutations in different genes cannot benefit from the same gene therapy - Example: ∘ RP affects 1.5 million people worldwide ∘ Associated # of genes exceeds 100 ∘ Up to 40% of patients cannot be genetically diagnosed → Difficult to Individualize Treatment > Limited by the capacity of the vehicle > Significant costs and effort required to develop and manufactureTraditional approach that targets one individual gene mutation at a time Longer time to recoup development costs
12Modifier Gene Therapy and OCU400 Modifier Gene Therapy: An Innovative Potential Treatment for IRDs Gene Augmentation: Transfer functional version of a non-functional gene into the target cells. ONE Disease Regulatory pathway focused on specific product for one disease GENE X cell GENE X Cell with mutated/nonfunctioning gene X GENE X GENE X cell GENE X GENE X cell N O R M A L G E N E X Modifier Gene Therapy: Designed to introduce a functional gene to modify the expression of many genes, gene-networks and regulate basic biological processes in retina. OCU400 NR2E3 Mutation-Associated Retinal Disease Rhodopsin Mutation-Associated Retinal Disease CEP290 Mutation-Associated Retinal Disease PDE6B Mutation-Associated Retinal Disease Broad Spectrum Therapy for RP Novel approach that targets nuclear hormone genes (NHRs), which regulate multiple functions within the retina Potentially smoother regulatory pathway due to ability to target multiple gene mutations with one product Ability to recoup development costs over multiple therapeutic indications GENE X cell GENE M Cell with mutated/nonfunctioning gene(s) other than modifier gene Cell with normal function cell We plan to address several gene mutations associated diseases using the same Modifier Gene product. GENE X GENE M cell Longer time to recoup development costs Traditional approach that targets one individual gene mutation at a time
13Modifier Gene Therapy and OCU400 Modifier Gene Therapy: An Innovative Potential Treatment for IRDs Modifier Gene Therapy: Designed to introduce a functional gene to modify the expression of many genes, gene-networks and regulate basic biological processes in retina. OCU400 NR2E3 Mutation-Associated Retinal Disease Rhodopsin Mutation-Associated Retinal Disease CEP290 Mutation-Associated Retinal Disease PDE6B Mutation-Associated Retinal Disease Broad Spectrum Therapy for RP Novel approach that targets nuclear hormone genes (NHRs), which regulate multiple functions within the retina Potentially smoother regulatory pathway due to ability to target multiple gene mutations with one product Ability to recoup development costs over multiple therapeutic indications GENE X cell GENE M Cell with mutated/nonfunctioning gene(s) other than modifier gene Cell with normal function cell We plan to address several gene mutations associated diseases using the same Modifier Gene product. GENE X GENE M cell > Modifier gene therapy: Expression of an upstream “master gene” to affect expression of wide gene-networks downstream - The OCU400 platform delivers a nuclear hormone receptor (NHR) “master gene” NR2E3 via viral vector > A gene agnostic approach: Potential for restoring retinal integrity and function across a range of IRD-related genotypes Potential to address multiple genetic defects in patients with IRDs using a single product
14Modifier Gene Therapy and OCU400 OCU400 Targets the Retina-specific NHR Gene NR2E3 to Potentially Treat IRDs > Why target the NHR gene NR2E3? - NR2E3 is a retina-specific NHR ∘ Act as a retinal “master gene” ∘ Regulates: ∘ Retinal cell homeostasis (eg, cell maintenance and survival) ∘ Metabolism ∘ Visual cycle function INFLAMMATION & CELL SURVIVAL PHOTOTRANSDUCTION METABOLISM PHOTORECEPTOR DEVELOPMENT CONE CELL DEVELOPMENT Key Mutations: RGR, RHO, PDE6 Key Mutations: PRP16, OTX Key Mutations: GNB3, RP78, GNAT Key Mutations: PEX7 Key Mutations: NR2E3, RP68 N R 2 E 3
15Modifier Gene Therapy and OCU400 Gene modifier therapy can potentially address multiple genetic defects with a single product. In patients with IRDs, this could mean: Modifier Gene Therapy: A Broader Reach Improved visual outcomes and quality of life GENE X GENE M cell NR2E3 Delivery “Molecular reset” of health & survival gene networks Cell with normal function cell Restored retinal cell homeostasis ONL ONL/photoreceptor survival GENE X cell GENE M Cell with mutated/ nonfunctioning gene(s) other than modifier gene M O D I F I E R G E N E M
16Modifier Gene Therapy and OCU400 OCU400 Pre-clinical Data: Efficacy Across Multiple RP Mouse Models rd16 (Leber Congenital Amaurosis) 5 RP mouse models treated subretinally with OCU400 rd1 (PDE6β- associated RP) Rho-/- and RhoP23H (both rhodopsin- associated RPs) rd7 (Enhanced S-cone Syndrome) 1 2&3 4 5
17Modifier Gene Therapy and OCU400 OCU400 Pre-clinical Data: NR2E3 Overexpression Restores Expression of Key Retinal Transcription Factors > Restoration of pro-survival and pro-maintenance genes > Recruitment of transcription factors NR2E3 overexpression results in a “molecular reset” Control Untreated Mutant Treated Mutant Untreated rd1 mutant mice were assessed at P7; untreated RhoP23H mutant mice were assessed at 1M Treated mutant mice were assessed at 1M. Li S. Gene Ther. 2021;28(5):223-241. -5 Lo g 2 fo ld c ha ng e in ge ne e xp re ss io n 15 10 5 0 Nr2e3 Nrl Rora Thrb Nr1d1 Crx 30 20 10 0 -10 Nr2e3 Nrl Rora Thrb Nr1d1 Crx rd1 RhoP23H
18Modifier Gene Therapy and OCU400 OCU400 Pre-clinical Data: Rescue of Retinal Cell Counts in Early and Advanced Stage Disease *rd1 evaluated one month post-injection ONL, outer nuclear layer; P, postnatal day Li S. Gene Ther. 2021;28(5):223-241. * E A R LY S TA G E R E S C U E Injection: P0 ONL Cell Count: 3-4 months A D VA N C E D S TA G E R E S C U E O U T E R N U C L E A R L AY E R ( O N L ) S TA I N I N G OCU400 helps preserve retinal cells, such as photoreceptors, which could translate to improved retinal health in patients with IRDs Injection: P21 ONL Cell Count: 2-3 months
19Modifier Gene Therapy and OCU400 OCU400 Pre-clinical Data: Improved ERG Signals ERG response: P0 single subretinal injection, evaluation 3-4 months post injection Li S. Gene Ther. 2021;28(5):223-241. OCU400 enhances the retina’s electrical activity, which could mean improved vision for patients with IRDs E R G B - WAV E A M P L I T U D E E R G B - WAV E A M P L I T U D E S C O T O P I C : R O D - F O C U S E D P H O T O P I C : C O N E - F O C U S E D
20Modifier Gene Therapy and OCU400 OCU400: Clinical Opportunities Backed by Pre-clinical Science ERG, electroretinogram; IRD, inherited retinal degeneration; NHR, nuclear hormone receptor; ONL, outer nuclear layer; RP, retinitis pigmentosa Li S. Gene Ther. 2021;28(5):223-241. > OCU400 causes overexpression of the retina-specific “master gene” (ie, NHR) NR2E3 - Viral vector-mediated delivery of functional NR2E3 to the retina > In IRDs like RP, mutations can disrupt gene expression homeostasis - NR2E3 regulates the expression of whole gene networks involved in retinal maintenance, resulting in ∘ Increased expression of pro-cell health and maintenance transcription factors ∘ Improved ONL morphology in early and advanced disease ∘ Rescued retina function (ERG response) NR2E3 overexpression can benefit RP disease state across multiple genotypes O U T E R N U C L E A R L AY E R ( O N L ) S TA I N I N G
21Modifier Gene Therapy and OCU400 Our pre-clinical data show that OCU400 could produce important anatomical and clinical benefits for patients with IRDs Modifier Gene Therapy: A Broader Reach POTENTIAL PATIENT OUTCOMES Maintained retinal health to delay or prevent disease progression Patient anatomical and potentially functional benefit in both early or advanced disease stage Prolonged visual function for • Keeping an independent lifestyle • Improved quality of life
22Modifier Gene Therapy and OCU400 > Orphan Drug Designations for NR2E3, RHO, PDE6B and CEP290 mutations associated IRDs (FDA) - Ocugen is also considering broader use of the platform > Orphan Medicinal Product Designation from EMA for the treatment of RP and LCA OCU400 Developmental Stage and Regulatory Milestones Expansion to include CEP290 patientsDose escalation in NR2E3 and RHO patientsP H A S E 1 / 2
Modifier Gene Therapy Platform: OCU410 & OCU410-ST A AV 5 - h R O R A fo r D r y A M D a n d S t a rga rd t D i s e a s e s
24Modifier Gene Therapy and OCU400 Age-related Macular Degeneration (AMD) and Stargardt Disease: Prevalence Leading cause of irreversible sight loss in the elderly population • First manifests in macula with appearance of pigment changes and subretinal deposits (drusen) 90% of AMD cases • Non-neovascular • Leads to geographic atrophy of RPE, choriocapillaries, and photoreceptors • Risk factor for Wet AMD 196 million 11 million AMD AMD Dry AMD Macula Geographic Atrophy Drusen Global AMD potential treatment market – 2022 www.grandviewresearch.com USD 10.52 billion ~800,000 ~35,000 STGD >1200 gene variants
25Modifier Gene Therapy and OCU400 Age-related Macular Degeneration(AMD) Stargardt Disease (STGD) Acquired Age-related Inherited Macular Degeneration AMD starts as a “dry,” non- neovascular form Progresses to geographic atrophy Most prevalent (≈90%) form Can progress to a more rapid “wet,” neovascular form Wet AMD may cause vascular leakage, hemorrhage, and fibrovascular growth Stargardt Disease (STGD1) • Dysfunction of ABCA4, • >1,200 ABCA4 variants are associated with STGD • Important for detoxifying oxidized retinol compounds in visual cycle
26Modifier Gene Therapy and OCU400 AMD Pathogenesis and Limited Treatment Approaches • Several environmental factors are associated with AMD • Certain polymorphisms in several genes are associated with AMD • A strong role of inflammation, complement, and oxidative pathways in AMD
27Modifier Gene Therapy and OCU400 RORA regulated gene networks are relevant in AMD and Stargardt disease ABCA4 RORA CD59 Inflammatory response Ingenuity Pathway Analysis of Canonical Stargardt Gene Networks show significant overlap with • RORA gene network • Inflammatory response pathway • Complement machinery
28Modifier Gene Therapy and OCU400 OCU410 (RORA): A Potential Modifier Therapeutic for Dry-AMD OCU410 is an adeno-associated virus-based vector containing Human RORA (isoform 1) The Retinoic Acid Related (RAR) Orphan Receptor Alpha (RORA) regulates several gene networks • Reduce oxidative stress • Limit lipofuscin deposits • Reduce chronic inflammation • Improve choroidal blood flow insufficiency
29Modifier Gene Therapy and OCU400 OCU410: Anti-Inflammatory Response OCU410 suppresses inflammatory response in multiple cell lines
30Modifier Gene Therapy and OCU400 OCU410 Protects Against Oxidative Stress 50 55 60 65 70 75 80 85 N or m al ize d Ce ll Su rv iv al RORA NR2E3 NR1D1 OCU410 Rescues NaIO3 mediated oxidative death in ARPE19 cells Cells 1E2 1E3 1E4 1E5 1E6 Multiple doses of OCU410 (MOI/cell)
31Modifier Gene Therapy and OCU400 OCU410 Restores CD59 Expression in ABCA4 -/- Mice ONL RPE INL • ABCA4 transports oxidized retinol compounds from photoreceptors to RPE cells for detoxification • Gene variants of ABCA4 are associated with both Stargardt disease and AMD. ABCA4 -/- mice show very low CD59 expression in their retinas • OCU410 CD59 expression in the RPE cells • CD59 prevents the formation of the complement membrane attack complex (MAC) Ab ca -/ -m ic e CD59 prevents the formation of the complement membrane attack complex
32Modifier Gene Therapy and OCU400 OCU410: Restoring Retinal Function in ABCA4 -/- Mice
33Modifier Gene Therapy and OCU400 • Significant global unmet medical need—more than 176 million of individuals affected with dry AMD with no approved therapy • Stargardt disease involves >1200 gene variants of ABCA4 gene. Large gene size and number of variants makes gene augmentation/editing therapy difficult • OCU410 reduced inflammation mediated by suppressing complement and other proinflammatory pathways • OCU410 plays a role in regulating genes associated with Dry-AMD and Stargardt disease • OCU410 in vitro and in vivo studies demonstrate its potential favorable role in Dry AMD and Stargardt disease treatment OCU410: Summary Target IND submission Q2 2023 to initiate Phase 1/2 clinical studies for GA and STGD
34Modifier Gene Therapy and OCU400 34 Ocugen™ Vision Fully integrated, patient-centric biotech company focused on vaccines in support of public health and gene and cell therapies targeting unmet medical needs through Courageous Innovation
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Ocugen Clinical Studies Immuno-bridging and Broadening Study (OCU002) Safety Study (OCU003) Interim Analysis NCT: 05258669 → A Phase 2/3, Immuno-bridging, and Broadening Study of a Whole, Inactivated SARS-CoV-2 Vaccine (BBV152) in Healthy Adults 18 to 65 years of age with no prior history of COVID-19 Interim Blinded Safety Summary: No incidence of myocarditis, pericarditis, thrombocytopenia & Guillain Barre syndrome COVAXIN a safe and effective whole virus vaccine against SARS-CoV-2 Ocugen Inc. Malvern, PA, United States COVAXIN development The COVAXIN Edge: Multiple antigen targets and IMDG adjuvant Study Type Placebo-Controlled Estimated Enrollment 400 participants Allocation Randomized Intervention Model Parallel assignment Intervention Model Description 1:1 randomization ratio Serious Adverse Event (SAE) 0 AE of Special Interest (AESI) 0 Medically Attended AE (MAAE) None related to IP Potential Immune Mediated Medical Conditions (PIMMC) 0 Age Group Participants 18 - <65 380 (90%) >=65 42 (10%) Gender Participants Female 230 (54.5%) Male 192 (45.5%) COVID-19 Vaccine Challenges ➢ Emergence of multiple mutations in Variants of Concern decreases efficacy of existing vaccines ➢ Immunological: Global SARS-CoV-2 pervasiveness due to viral reservoirs in unvaccinated ➢ Logistics: Ultra-cold chain storage, lack of community coordination & inaccurate vaccine demand forecast ➢ Safety: More adverse events after multiple mRNA boosters and insufficient long-term mRNA vaccine data ➢ Equitable Distribution: Vaccine hesitancy, manufacturing/distribution capacity & vaccine nationalism ➢ Heterologous Prime-Boost: No safety & efficacy data & clinical trial disparities make comparison difficult ➢ Neglected Groups: Patients with cancer, kidney disorders, HIV, pregnancy, transplants & children Whole virus inactivated vaccine: Strain NIV-2020-770 Strong Th1 immune response due to TLR7/8 agonist adjuvant IMDG 98.4% Seroconversion, 77.8% protection from symptomatic COVID-19 & 93.4% protection from severe symptoms Booster dose provides robust neutralizing antibody titers against Omicron and Delta variants The vaccine is stable for 2 years at 2 - 8 ͦC and 6 months at room temperature Strong safety and immunogenicity in adult and pediatric age groups EUL in 28 countries and over 350 million doses administered COVAXIN: Rising to the Challenge Complete List COVAXIN HIGHLIGHTS Phase 1 & 2 data for safety & persistent immunogenic responses Nonclinical data supports vaccine effectiveness & safety Meets all safety data expectations (2 months after the second dose for 25,800 participants) Efficacy against cases of severe COVID-19 Final efficacy with a point estimate over 50% Neutralization data published against Alpha, Beta, Delta & Omicron Consistent manufacturing (lot to lot consistency) Robust AEFI system in-place Post marketing safety underway Trials in HIV infected, pregnant individuals are being planned Vaccine benefits outweigh its risks based on Phase 3 clinical trial Pre-clinical Studies Neutralizing, binding, and cell mediated responses detected in all animal models Th1-biased responses observed in mice NHPs and hamsters show better viral clearance No eosinophile infiltration from NHP lungs DART studies: No detrimental effects in NZW Rabbits Phase I / II Vaccine induced neutralizing antibody titres equal to those found in convalescent patients Strong T-cell memory generated Th1 biased response, no Th2 cytokines observed. No immediate or solicited adverse events due to the vaccine Low reactogenicity relative to other vaccines Algel-IMDG T-cell activity greater than Alum alone Strong helper CD4 & effector CD8 T-cell response Vaccine-induced neutralizing antibodies persisted for 3 months Phase III & Pediatric Trial Solicited adverse events (9.5% vs. 8.2%) Serious Adverse events (0.3% vs. 0.47%) similar between both groups Safety compared to placebo Efficacy Immunogenicity responses across 3 consecutive GMP lots was equivalent. Immunogenicity Kappa: 90.1% Delta: 65.2% Efficacy against Variants Overall efficacy of 78% Severe = 93% Asymptomatic = 63.6% All 95%CI were above the 50% success criteria Alpha, Beta, Delta & Omicron Neutralizing Antibodies Children (2-18 y) generated 1.7X higher Nab responses compared to adults Pediatric study Covaxin Booster Studies
Recombinant Adenoviral-Vectored Mucosal Vaccine against SARS-CoV-2 Ocugen Inc. Malvern, PA, United States Emerging Variants of Concern challenge all approved vaccines ❖ All licensed COVID-19 vaccines are designed for intramuscular (IM) immunization ❖ IM vaccines do not induce mucosal immunity, crucial for preventing upper respiratory tract infection ❖ Mutations in the Omicron BA.5 Spike protein grant substantial, population-level, evasion of immunity from prior infection and immunity induced by vaccines. ❖ IM Vaccination with ancestral spike fails to prevent infection with BA.4 and BA.5 ChAd-SARS-CoV-2S Adenoviral Vectored Mucosal Vaccine ➢ COVID-19 vaccine include Adenoviral vectored vaccine expressing pre-fusion stabilized S-protein ➢ The mucosal vaccination method has demonstrated potent induction of both mucosal and systemic immune responses ➢ Currently 4 candidates in the U.S. are under investigation at different clinical trial phases Mice immunized with single-dose intranasal ChAd- SARS-CoV-2-S protected from SARS-CoV-2 pneumonia Adapted from Hassan et al, Cell 2020 Hamsters immunized with single-dose intranasal ChAd-SARS-CoV-2-S protected from SARS-CoV-2 infection Publication List A single intranasal dose of ChAd-SARS-CoV-2-S promotes systemic and mucosal immunity and induces high levels of IgG and IgA (mucosal) neutralizing antibodies Intranasal ChAd-SARS-CoV-2-S significantly lowers local and systemic viral load MUCOSAL VACCINE PRODUCT DEVELOPMENT PLAN Potential EUA Approval IND Enabling Studies GMP Manufacturing Process Development Phase I / II Phase III Manufacturing Scale up and Process Validation
• NeoCart: bio-engineering breakthroughs enhance the autologous cartilage repair • Accelerated healing and reduced pain using patient’s own cells in a 3D scaffold • Patients receive functional cartilage at the time of treatment Current treatment options are sub- optimal with variable outcomes due to variable cellular response Patients and physicians seeking alternatives that offer a more rapid and durable recovery Cartilage Injury Focal Chondral Defect NeoCart®: The Cutting-Edge Treatment for Knee Articular Cartilage Defects. List of Authors Ocugen Inc. Malvern, PA, United States Knee Cartilage Damage: A Complex Problem Cartilage: • A complex shock absorber • Withstands significant pressure • Allows for rolling & sliding Immediate Problems: • Damage from acute injury or repetitive trauma • Debilitating pain and loss of function Long term Problems: • Limited regeneration - lack of vascularity • Strong correlation with Osteoarthritis 9% 41% 43% 8%Extremely likely Likely Neutral Unlikely Willingness to prescribe NeoCart (N=79 surgeons) Annual procedures for knee cartilage defects Large market opportunity to treat knee cartilage damage approximately 1.2M defects identified each year Clinically meaningful Phase 3 top-line results reported in Q3:18 Planned expansion of NeoCart platform into additional markets and indications Powerful, proprietary platform that provides restorative cell therapies (RCTs) for active living NeoCart®, is a proprietary RCT that rebuilds patients’ own knee cartilage, reducing pain at the source and potentially prevents progression to osteoarthritis (OA) Follow-up Arthroscopy Demonstrates NeoCart Integration Initial Lesion Implantation 8 Weeks 6 Months Reduces pain Improves function Promotes repair of damaged cartilage Short rehabilitation / rapid return to daily activities Durable response No specialized surgical techniques and less operating room time Non-opioid approach Attributes of an Optimal Treatment for Knee Cartilage Damage Assessment of defect & biopsy Implantation into defect with CT3 bioadhesive Su rg ic al S te ps 6-8 Week Process M an uf ac tu rin g St ep s Cell isolation expansion, & seeding of 3D scaffold Quality control: histology & biomarkers Implant processing Continued growth in static culture • Patient Satisfaction: pain relief, better QoL, improved productivity • Physician Satisfaction: robust clinical data – 1-year superiority endpoint • Payer Cost Effectiveness Potential Benefits of NeoCart®Economics & Unmet Needs of Knee Repair: The NeoCart Advantage The NeoCart® Breakthrough Phase I Study parameters: • Treatment group – 8 patients • Cartilage injury – 1-2 cm Evaluations: • Through 60 months post-op • International Knee Documentation Committee (IKDC) questionnaire • Visual analog scale • Range of motion • Cartilage-sensitive MRI Results: • Lowered pain and improved functions after NeoCart • Six patients had substantial defect fill at 24 months • Improved IKDC score in 7 out of 8 patients Safety: • No adverse events reported • No patient developed arthrofibrosis or implant hypertrophy • Sagittal MRI and arthroscopic image of the NeoCart implant (blue arrow) at 12 weeks with meniscal tear (red arrow). • The NeoCart (blue arrow) is flush & integrated to repaired region (border shown by black line) (Crawford et al., AJSM 2009) Phase II Coronal MRI shows good fill of the cartilage defect 10 days to 6 months after NeoCart Implantation (Crawford et al., AJSM 2009). Clinical Trials: NeoCart Publications Phase III Ocugen Phase III Study parameters: • 30 patients at 6 U.S. centers • 2:1 randomization (NeoCart v. Microfracture) • Lesion size – 1-3 cm Evaluations: 60 months post-op • IKDC questionnaire • Knee Injury and Osteoarthritis Outcome Score (KOOS) for pain, symptoms, activities of daily living (ADL), quality of life (QOL), sports scales, Visual analog scale and Short Form-36 (SF-36) questionnaire Results: • More patients responded to NeoCart than microfracture – at 6 months (43% Vs 25%) – at 12 months (76% Vs 22%) • Improvement with NeoCart was significantly greater – at 6, 12 and 24 months for IKDC, SF-36 & KOOS-ADL / pain – at 6 months for KOOS-symp – at 12 & 24 months for KOOS sports & VAS Safety: • No serious adverse events reported • None of the AE were related to either treatments Responders Non-Responders +12 points +20 points IK DC Su bj ec tiv e KOOS PainBaseline N on -R es po nd er s Superiority Endpoint: % of NeoCart “Responders” vs Mfx “Responders” Change in Patient-Reported Outcomes From Baseline to Final Follow-up Parameter Baseline Final Follow-up Change From Baseline P -Value n IKDC subjective 47.9 ± 17.4 75.5 ± 22.1 27.6 ± 19.1 <0.0001 29 VAS mean 34.6 ± 22.5 14.3 ± 18.4 –20.3 ± 24.6 <0.0001 29 VAS highest 60.1 ± 20.6 23.5 ± 27.0 –36.6 ± 29.7 <0.0001 21 KOOS-Pain 64.8 ± 12.1 86.1 ± 17.3 21.4 ± 10.7 <0.0001 21 KOOS-ADL 75.5 ± 14.8 91.6 ± 13.8 16.1 ± 11.0 <0.0001 21 KOOS-QoL 28.6 ± 15.5 69.4 ± 28.0 40.8 ± 27.5 <0.0001 21 KOOS-Symptoms 65.8 ± 13.8 86.6 ± 13.4 20.8 ± 15.4 <0.0001 21 KOOS-Sports 41.4 ± 24.3 72.4 ± 28.8 31.0 ± 26.4 <0.0001 21 SF-36 physical 40.5 ± 7.2 51.4 ± 8.1 11.0 ± 7.1 <0.0001 21 SF-36 mental 55.1 ± 9.2 54.8 ± 6.7 –0.3 ± 9.5 0.8858 21 Active ROM 131.5 ± 7.9 140.7 ± 6.3 9.2 ± 9.6 <0.0001 29 Data are reported as mean ± SD unless otherwise indicated. Anderson et al AJSM 2017 *76% 89% 69% 22% 44% 29% 1 YR 2 YR 3 YR 21 9 18 9 16 7Evaluable Patients: NeoCart Microfracture *p < 0.05 1 year primary superiority endpoint Phase 3 requires only ~15-20% difference between NeoCart and microfracture HIGHLIGHTS FROM HISTOGENICS PHASE III STUDY —A prospective randomized trial comparing NeoCart to the microfracture in the treatment of cartilage defects in the knee —NeoCart narrowly missed the primary endpoint of a statistically significant improvement in pain and function —Both NeoCart & microfracture were well tolerated with strong safety profiles —Improvements in KOOS subscales (p≤ 0.050) and IKDC subscales (P=0.0126) favoring NeoCart® at 1 year —Secondary outcomes met their target goals Primary endpoint narrowly missed NeoCart Micro- fracture ACI & other Products • Accelerated recovery and improved clinical efficacy • Shorter recovery times • Excellent safety profile • Long term performance • Fewer complications and re-operations • Tissue quality and competence at implantation • Biomechanical competence after 1 year • Earlier weight-bearing and return to activity NeoCart Highlights: Improved Outcomes Versus Established Suboptimal Alternatives COMBATING CONFOUNDERS: PROPOSED ALTERATIONS IN STUDY DESIGN A dynamic randomization design should result in equipoise in the baseline confounders. Ad hoc analyses demonstrated improvement in pain and function for the NeoCart group vs. microfracture for the following factors: • Larger lesion sizes • Younger patients • Larger BMI (Body Mass Index) These confounding factors will be controlled for using dynamic randomization in addition to: • Baseline KOOS (Knee Injury and Osteoarthritis Outcome Score) pain • Baseline KOOS ADL (Activities of Daily Living) • Maximum ICRS (International Cartilage Repair Society) Score on MRI PRIMARY OUTCOMES EFFICACY: To demonstrate that NeoCart®, improves pain and function in the repair of knee cartilage defects and is superior to the comparator. SAFETY: To evaluate NeoCart® safety up to 5 years post-implantation CO-PRIMARY EFFICACY ENDPOINT Mean change from baseline to 2 years for the Patients’ Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain and Function Activities of Daily Living (ADL) subscale scores. SECONDARY SAFETY OBJECTIVE To evaluate NeoCart® safety in the repair of cartilage defects of the femoral condyles and/or trochlea. A PROPOSED RANDOMIZED COMPARISON OF NEOCART® TO A COMPARATOR ARM FOR THE KNEE ARTICULAR CARTILAGE REPAIR Screening n = 249 Endpoints at 1 Year Key Inclusion Criteria • Age: 18-59 • Severe and symptomatic cartilage lesions (0.5-6cm2) • Femoral condyle and/or trochlear lesions Ra nd om iz at io n Primary • Knee pain/function improvement: ‒ ≥12 pts KOOS pain ‒ ≥20 pts IKDC Subjective Key Exclusion Criteria • Prior lesion treatment • High BMI • Significant arthritis • Concomitant surgeries Secondary • Time to full weight-bearing • Failure: Reop or deterioration • Collagen layering via MRI Arm 1: NeoCart (n = 169) Arm 2: Microfracture (n = 80) Study parameters: