Slide 1: Modifier Gene Therapy Technology For Retinal Diseases
Modifier Gene Therapy Technology For Retinal Diseases Arun Upadhyay, PhD CSO
Slide 2: Forward Looking Statement
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 manag
Slide 3: We're Here to Make an Impact Through Courageous Innovation
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 disease
Slide 4: Why is Modifier Gene Therapy Needed?
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 significan
Slide 5: Nuclear Hormone Receptors as Modifier Genes
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
Slide 6: Why Target Nuclear Hormone Receptor Genes?
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 tiss
Slide 7: Pipeline Overview: Modifier Gene Therapy Technology
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 ret
Slide 8: Modifier Gene Therapy Platform: OCU400 (AAV-hNR2E3) for RP and LCA Diseases
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
Slide 9: Inherited Retinal Diseases: Prevalence and Associated Genes
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
Slide 10: Inherited Retinal Degeneration: A Broader Reach For OCU400
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 avai
Slide 11: Current Limitations of Conventional Gene Therapy
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/nonfuncti
Slide 12: Modifier Gene Therapy: An Innovative Potential Treatment for IRDs
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
Slide 13: Modifier Gene Therapy: An Innovative Potential Treatment for IRDs
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-Associate
Slide 14: OCU400 Targets the Retina-specific NHR Gene NR2E3
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 ∘
Slide 15: Modifier Gene Therapy: A Broader Reach
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 re
Slide 16: OCU400 Pre-clinical Data: Efficacy Across Multiple RP Mouse Models
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
Slide 17: OCU400 Pre-clinical Data: NR2E3 Overexpression Restores Key Transcription Factors
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 Untrea
Slide 18: OCU400 Pre-clinical Data: Rescue of Retinal Cell Counts
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 Cel
Slide 19: OCU400 Pre-clinical Data: Improved ERG Signals
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 wi
Slide 20: OCU400: Clinical Opportunities Backed by Pre-clinical Science
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 overexp
Slide 21: Modifier Gene Therapy: A Broader Reach
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 anatom
Slide 22: OCU400 Developmental Stage and Regulatory Milestones
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 Regul
Slide 23: Modifier Gene Therapy Platform: OCU410 & OCU410-ST for Dry AMD and Stargardt Diseases
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
Slide 24: AMD and Stargardt Disease: Prevalence
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-neovas
Slide 25: Age-related Macular Degeneration and Stargardt Disease
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,” ne
Slide 26: AMD Pathogenesis and Limited Treatment Approaches
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
Slide 27: RORA regulated gene networks are relevant in AMD and Stargardt disease
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 • Compleme
Slide 28: OCU410 (RORA): A Potential Modifier Therapeutic for Dry-AMD
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 • L
Slide 29: OCU410: Anti-Inflammatory Response
29Modifier Gene Therapy and OCU400 OCU410: Anti-Inflammatory Response OCU410 suppresses inflammatory response in multiple cell lines
Slide 30: OCU410 Protects Against Oxidative Stress
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)
Slide 31: OCU410 Restores CD59 Expression in ABCA4-/- Mice
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
Slide 32: OCU410: Restoring Retinal Function in ABCA4-/- Mice
32Modifier Gene Therapy and OCU400 OCU410: Restoring Retinal Function in ABCA4 -/- Mice
Slide 33: OCU410: Summary
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 therap
Slide 34: Ocugen Vision
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
Slide 35: Thank you!
Thank you!