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Initial Results from Cohort 1 of a Phase 1b/2a Clinical Study of OPGx-BEST1 Gene Therapy for the Treatment of BVMD and ARB Due to BEST1 Mutations Mark E Pennesi, MD, PhD, FARVO Chief Medical Officer Steve and Debbie Gray Inherited Retinal Degeneration Endowed Chair Director, Inherited Retinal Degeneration Center Retina Foundation: Dallas, Texas Adjunct Professor of Ophthalmology Paul H. Casey Ophthalmic Genetics Division Casey Eye Institute Oregon Health & Science University Co-authors: Kaylie Jones, BS1 Rajiv Anand, MD2 Aaron Nagiel, MD, PhD3 Charles Wykoff, MD/PhD4 Robert Sisk, MD5 Christine Kay, MD6 1Retina Foundation, Dallas, TX; 2Texas Retina Associates, Dallas, TX; 3Children’s Hospital Los Angeles, Los Angeles, CA; 4Retinal Consultants of America, Houston, TX,4; 5Cincinnati Eye Institute, Cincinnati, OH; 6Vitreoretinal Associates, Gainesville, FL.
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Disclosures • MP: Consultant & Research Support, Opus Genetics, Inc. • KJ: None • RA: None • AN: Consultant & Research Support, Opus Genetics, Inc. • CW: Consultant & Research Support, Opus Genetics, Inc. • RS: Research Support, Opus Genetics, Inc. • CK: Consultant & Research Support, Opus Genetics, Inc. 2
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BEST1 Mutations are Associated with Retinal Degeneration • BEST1 mutations are associated with at least five clinically distinct retinal degenerative diseases1 • Characterized by retinal lesions, with symptoms including dimness of vision, metamorphopsia, or scotoma2 • Mutations, depending on impact on BEST1 function, may lead to serous retinal detachment, vitelliform lesions, macular atrophy, and loss of central vision 1 • Exhibits slow rate of decline and central photoreceptors usually remain viable for decades, providing a wide therapeutic window ARB, autosomal recessive bestrophinopathy; AMD, age-related macular degeneration; BCVA, best-corrected visual acuity; BEST1; bestrophin-1; BVMD, best vitelliform macular dystrophy; CNV, choroidal neovascularization. 1. Johnson AA, et al. Prog Retin Eye Res. 2017;58:45-69. 2. Tripathy K, et al. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. ARB • Prevalence ~ 1:1,000,000 • Recessive – Loss of Function • Severe, multifocal degeneration beginning in childhood Three Main BEST1 Phenotypes 3 BVMD • Prevalence – 1:15,000 • Dominant Inheritance • Haploinsuffiency • Dominant Negative • Macular dystrophy • Occult MNV within Vitelliform Material ADVIRC • Very rare < 1:1,000,000 • Dominant – Gain of Function • Short Axial Length • Peripheral Pigmentation with distinct boundary
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BIRD-1: Ongoing Phase 1/2 Study of OPGx-BEST1 Subretinal Gene Therapy ARB, autosomal-recessive bestrophinopathy; BVMD, best vitelliform macular dystrophy; IDMC, Independent Data Monitoring Committee. Adaptive, open-label, dose-escalation, safety and tolerability study of a subretinal injection of OPGx-BEST1 gene therapy in adult (≥18 years old) participants with autosomal dominant BVMD or autosomal recessive ARB Cohort 2: high dose 4.5E9 vg/eye Cohort 1: low dose 1.5E9 vg/eye Sentinel Participant 4 Further Participants +Day 35 IDMC Safety Eval Sentinel Participant 4 Further Participants +Day 35 IDMC Safety EvalConvert to pivotal Phase 3 study using low dose (1.5E9 vg/eye) Not Achieved Achieved Efficacy signal at 3 months with no safety concerns as determined by IDMC Convert to pivotal Phase 3 study using high dose (4.5E9 vg/eye) Achieved Efficacy signal at 3 months with no safety concerns as determined by IDMC 3-month results from Cohort 1 (N=5) presented here 4
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Participant Demographics: Cohort 1, Low-dose (1.5x109 vg/eye) *ETDRS letters equivalent calculated from logMAR. †Worse eye deemed study eye. ARB, autosomal recessive bestrophinopathy; BEST, bestrophin; BVMD, best vitelliform macular dystrophy; ETDRS, Early Treatment Diabetic Retinopathy Study; RPE, retinal pigment epithelium; VA, visual acuity. 101-101 101-104 102-101 102-102 101-106 Age 63 59 50 45 31 Sex Female Female Male Male Male BEST phenotype ARB ARB BVMD BVMD BVMD Severity of disease End-stage with significant atrophy End-stage with significant atrophy End-stage with sub-foveal, sub-RPE scar Advanced stage vitello-eruptive with some scarring Earlier stage without significant atrophy or scarring ETDRS VA* (study eye †) 1 50 49 61 47 ETDRS VA* (fellow eye) 43 65 68 72 56 Follow -up duration 6 months 6 months 3 months 3 months 3 months 5
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OPGx-BEST1 Demonstrated a Favorable Safety Profile OPGx-BEST1 was well-tolerated in all 5 participants: • No anterior chamber or vitreous cells • No serious AEs • No dose-limiting toxicities • No treatment-related systemic AEs • All ocular treatment-related AEs were mild/moderate in severity • No vital sign issues or safety lab findings of note *Based on the SUN Working Group Grading Scheme. AE, adverse event; ARB, autosomal recessive bestrophinopathy; BVMD, best vitelliform macular dystrophy; . No anterior chamber or vitreous cells observed in any patient at any study visit 101-101 (ARB) 101-104 (ARB) 102-101 (BVMD) 102-102 (BVMD) 101-106 (BVMD) (Grade: cells in field)* 0 1+ 2+ 3+ 4+ 6
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Summary of 3-month Safety and Efficacy Results from Low-Dose Cohort 1 Safety • OPGx-BEST1 was well-tolerated in 5/5 participants, with no SAEs or DLTs Structural Endpoints • 80% of participants (4/5) had structural improvements: • BVMD: 67% of participants (2/3) had a decrease in vitelliform material • ARB: 100% of participants (2/2) had a decrease in intraretinal fluid Functional Endpoints • 100% of participants (5/5) had improvements* in at least one functional measure: • Microperimetry – 75% of participants (3/4) improved • BCVA – 60% of participants (3/5) improved • LLVA – 40% of participants (2/5) improved • Contrast Sensitivity – 40% of participants (2/5) improved • Earlier-stage participant (101-106)† showed the biggest functional gains, suggesting a potential benefit from earlier treatment *Improvements defined as: ≥5 letters of improvement from baseline and ≥5 letter improvement from fellow eye in BCVA or LLVA, 0.2 logMAR improvement from baseline in contrast sensitivity, and ≥5 loci cluster improvement by ≥3 decibels in RPE Transitional Zone on microperimetry. †101-106 was the youngest participant with most recent onset of disease and less progressive disease than other participants. ARB, autosomal recessive bestrophinopathy; BCVA, best-corrected visual acuity; BVMD, best vitelliform macular dystrophy; DLT, dose-limiting toxicity; LLVA, low-luminance visual acuity; logMAR, logarithm of the minimum angle of resolution; RPE, retinal pigment epithelium; SAE, serious adverse event. 7
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Baseline Month 3 Participant 101-106 (BVMD): Vitelliform Material Reduction Co-localized with Microperimetry Improvements BVMD, best vitelliform macular dystrophy; RPE, retinal pigment epithelium. Vitelliform lesions reduced Baseline Month 3 Lesion reduction was consistent with improved function of RPE cells and treatment activity as indicated in microperimetry improvements 8
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Baseline Month 3 Participant 102-102 (BVMD): Microperimetry Improved in the Treated RPE Transitional Zone Baseline Month 3 Yellow box represents treated transitional zone. BVMD, best vitelliform macular dystrophy; RPE, retinal pigment epithelium. Fixation moved to a more natural location in the fovea 9 Baseline Month 3
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Participant 101-104 (ARB): IRF Improvement Co-localized with Microperimetry Improvement Baseline Month 6 Yellow circles denote pockets of intraretinal fluid. Total macular intraretinal fluid volume: Baseline = 19.06 µl, Month 6 = 7.55 µl. ARB, autosomal recessive bestrophinopathy; IRF, intraretinal fluid. Fixation moved to a more natural location in the fovea Two areas of baseline intraretinal fluid 10
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Summary and Next Steps • 3-month results in the ongoing, low-dose Cohort 1 (N=5) demonstrated: • OPGx-BEST1 was well-tolerated with with no SAEs, no DLTs, and no intraocular inflammation; • Signs of efficacy observed on both functional and structural endpoints • IDMC recommended the Phase 1/2 trial advance to Cohort 2 at the higher dose • Over-enrollment of 8 participants with dosing completion expected Q4 2026 and topline 3-month data expected Q2 2027 • Positive FDA Type C meeting aligned on potential pivotal endpoints, including use of ≥3 dB microperimetry improvement in ≥5 prespecified loci area and anchored to a PRO BVMD, best vitelliform macular dystrophy; dB, decibel; DLT, dose-limiting toxicity; FDA, Food and Drug Administration; IDMC, Independent Data Monitoring Committee; SAE, serious adverse events. 11