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Braydon, RDH12 patient Key Opinion Leader Event Phase 1/2 6-month Safety and Efficacy Data of OPGx-LCA5, an Adeno-Associated Virus (AAV)-Based Gene Therapy December 11, 2024
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Introductions and Agenda Ash Jayagopal, PhD, MBA Chief Scientific and Development Officer, Opus Genetics KOL Event | December 2024
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This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements include, but are not limited to, statements concerning expectations regarding our cash runway, data from and future enrollment for our clinical trials, our pipeline of additional indications, expectations of potential growth, and our expectations regarding our recent acquisition of former Opus Genetics Inc. These forward-looking statements relate to us, our business prospects and our results of operations and are subject to certain risks and uncertainties posed by many factors and events that could cause our actual business, prospects and results of operations to differ materially from those anticipated by such forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to, those described under the heading “Risk Factors” included in our Quarterly Report on Form 10-Q for the quarter ended September 30, 2024 filed with the U.S. Securities and Exchange Commission (the “SEC”) and in our other filings with the SEC. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this presentation. In some cases, you can identify forward-looking statements by the following words: “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “ongoing,” “plan,” “potential,” “predict,” “project,” “should,” “will,” “would,” or the negative of these terms, or other comparable terminology, although not all forward-looking statements contain these words. We undertake no obligation to revise any forward-looking statements in order to reflect events or circumstances that might subsequently arise. These forward-looking statements are based upon our current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, including, without limitation: our ability to successfully integrate the business of former Opus Genetics Inc. and manage our expanded combined product pipeline; our ability to develop and obtain regulatory approval for newly acquired gene therapies to treat inherited retinal diseases; our ability to obtain and maintain orphan drug designation or rare pediatric disease designation for our current and future product candidates; the success and timing of regulatory submissions and pre-clinical and clinical trials, including enrollment and data readouts; regulatory requirements or developments; changes to or unanticipated events in connection with clinical trial designs and regulatory pathways; delays or difficulties in the enrollment of patients in clinical trials; substantial competition; rapid technological change; our development of sales and marketing infrastructure; future revenue losses and profitability; changes in capital resource requirements; risks related to our inability to obtain sufficient additional capital to continue to advance our product candidates and preclinical programs; domestic and worldwide legislative, regulatory, political and economic developments; our dependency on key personnel; changes in market opportunities and acceptance; reliance on third parties to conduct our clinical trials and supply and manufacture drug supplies; future potential product liability and securities litigation; system failures, unplanned events, or cyber incidents; the substantial number of shares subject to potential issuance associated with our share purchase facility; risks that our licensing or partnership arrangements may not facilitate the commercialization or market acceptance of our product candidates; future fluctuations in the market price of our common stock; the success and timing of commercialization of any of our product candidates; obtaining and maintaining our intellectual property rights; and the success of mergers and acquisitions. The foregoing review of important factors that could cause actual events to differ from expectations should not be construed as exhaustive. Readers are urged to carefully review and consider the various disclosures made by us in this presentation and in our reports filed with the SEC that advise interested parties of the risks and factors that may affect our business. All forward-looking statements contained in this presentation speak only as of the date on which they were made. We undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Disclosures and Forward-Looking Statements 3 KOL Event | December 2024
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4 Today’s Agenda Welcome, Introductions, and Opus Genetics Updates Ash Jayagopal, PhD, MBA Overview of LCA5-IRD and Multi-Luminance orientation and Mobility Test Jean Bennett, MD, PhD 6 Month Results of Phase 1/2 Study of OPGx-LCA5 Tomas S. Aleman, MD Panel Discussion and Q&A Moderator: Arshad M. Khanani, MD, MA, FACS Panelists: Christine Kay, MD; Jean Bennett, MD, PhD; Tomas S. Aleman, MD; Ash Jayagopal, PhD, MBA 1 2 3 4 T o p i c S p e a k e r KOL Event | December 2024LCA5, Leber congenital amaurosis 5; IRD, inherited retinal disease.
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5 Meet Our Speakers Ash Jayagopal, PhD, MBA Chief Scientific & Development Officer, Opus Genetics Christine Kay, MD Vitreo Retinal Associates Affiliate Assistant Professor, University of South Florida Jean Bennett, MD, PhD F.M. Kirby Emeritus Professor of Ophthalmology, University of Pennsylvania Arshad M. Khanani, MD, MA, FASRS Managing Partner, Sierra Eye Associates Clinical Professor, University of Nevada Tomas S. Aleman, MD Irene Heinz-Given and John LaPorte Research Professor, University of Pennsylvania KOL Event | December 2024
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6 Limited Treatment Options Despite Key Advances in Gene Therapy • Over 300 genes are known to cause inherited retinal diseases (IRDs), which severely affect vision in more than 180,000 people in the U nited States* 1,2 • Almost all IRDs lack treatment to halt progression and rescue vision 2 • Luxturna ® is the only FDA -approved IRD gene therapy and targets the RPE65 gene mutation 2 *Based on 2019 estimates Luxturna® is a registered trademark of Spark Therapeutics, Inc. FDA, Food andDrug Administration; IRD, inherited retinal disease; RPE65, retinal pigment epithelium 65 kDa protein. 1. RetNet Retinal Information Network. 2024. Accessed on November 25, 2024. https://retnet.org/summaries#a-genes 2. Gong J, et al. Clin Ophthalmol. 2021;15:2855-2866. 3 0 0 + G e n e s Adapted from Leroy, et al. AAO EyeNet. July 2018. KOL Event | December 2024
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7 There are Multiple Barriers to the Clinical Translation of IRD Gene Therapies IRD, inherited retinal disease. Small addressable market: Cost/benefit justification is challenging for low prevalence IRDs Small patient population poses challenges for patient recruitment Manufacturing geared to high volume production, not IRD gene therapies Clinical, scientific, and regulatory excellence is requiredto have success in treating IRDs $ $ $ KOL Event | December 2024
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$ $ $ 8 The Opus Approach Overcomes These Challenges COGS, cost of goods sold; IRD, inherited retinal disease. Building a robust IRD -focused gene therapy pipeline • Multiple assets for unaddressed IRDs to balance risk across programs • Favorable competitive landscape Partnering with patient networks and advocacy organizations • Significant relationships with key patient advocacy groups • Strategic partnerships to access global IRD patient registries and natural history studies Focusing on small-scale, high-quality production • Favorable COGS with high -quality gene therapy vectors • Dedicated production lines tailored for IRDs (100s to 10,000s of patients) Establishing strong partnerships and leveraging synergies between programs enables: • Natural history and interventional trials at IRD centers of excellence with high -resolution readouts of safety and efficacy • Harmonization across programs to streamline manufacturing and regulatory processes • Development of shared biomarkers/endpoints across multiple IRD indications KOL Event | December 2024
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9 One of the Largest Dedicated IRD Portfolios and an Established Blueprint for Development AAV, adeno-associated virus; IRD, inherited retinal disease. Future gene targets Gene targets selected based on clinical derisking and commercial value O u r F o u n d a t i o n a l R o a d m a p • Clinically derisked AAV technology • Rigorous prioritization of two clinical -stage gene therapies • Strategic optionality to advance new candidates into development in additional IRD indications Current gene targets Adapted from Leroy, et al. AAO EyeNet. July 2018. KOL Event | December 2024
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10 Efficient IRD Pipeline with Multiple Near-Term Value Inflection Points Anticipated adRP, autosomal dominant retinitis pigmentosa; BEST1, bestrophin 1; CNGB1, cyclic nucleotide-gated channel β1; FDA, Food and Drug Administration; GLP, Good Laboratory Practice; IND, Investigational New Drug; IRD, inherited retinal disease; LCA, Leber congenital amaurosis; MERTK, MER proto-oncogene tyrosine kinase; NHP, nonhuman primate; NMNAT1, nicotinamide mononucleotide adenylyltransferase 1; ODD, Orphan Drug Designation; RDH12, retinol dehydrogenase 12; RHO, rhodopsin; RP, retinitis pigmentosa; RPDD, Rare Pediatric Disease Designation. U.S. Prevalence Preclinical IND-enabling Phase 1/2 Phase 2/3 RPDD / ODD From FDA Status OPGx-LCA5 LCA ~200 patients1,2 Granted • Ph 1/2 pediatric data expected in 2025 OPGx-BEST1 Bestrophinopathies ~9,000 patients1,2 Eligible • Ph 1/2 data expected in 2025 F u t u r e I R D P r o g r a m s OPGx-RHO adRP ~5,600 patients2 Eligible • IND-enabling studies OPGx-RDH12 LCA ~1,100 patients1,2 Eligible • NHP GLP toxicology study OPGx-MERTK RP ~600 patients1 Eligible OPGx-NMNAT1 LCA ~800 patients1 Eligible OPGx-CNGB1 RP ~400 patients1 Granted 1. Stone et al. Ophthalmology. 2017;124:1314-1331. 2. Triangle Insights Groupmarket research (compilation of prevalence studies), conducted August 2023. L e a d C a n d i d a t e s KOL Event | December 2024
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Overview of LCA5-LCA and Multi-Luminance orientation and Mobility Test (MLoMT) Jean Bennett, MD, PhD F.M. Kirby Emeritus Professor of Ophthalmology University of Pennsylvania LCA, Leber congenital amaurosis; LCA5, Leber congenital amaurosis 5. KOL Event | December 2024
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12 LCA5 is an Early-Onset, Severe Hereditary Retinal Degeneration SEVERITY M/31yrs, 20/300 VA F/21yrs, light perception LCA5 patients exhibit preserved photoreceptors in the central retina in adulthood despite disease severity and early onset AAV, adeno-associated virus; LCA5, Leber congenital amaurosis 5; OCT, optical coherence tomography; ONL, outer nerve layer; RPE, retinal pigment epithelium; VA, visual acuity. 1. Uyhazi KE, et al. Invest Ophthalmol Vis Sci. 2020;61:30. 2. Boldt K, et al. J Clin Invest. 2011;121(6):2169-2180. Structure-function disassociation creates favorable pathobiology for AAV gene replacement • Presentation in 1st year of life with nystagmus and vision loss1,2 • Severe and early photoreceptor loss results in severely abnormal or non-detectable visual fields1,2 • Visual acuity often limited to hand motions or light perception1,2 • Fundus photography exhibits pigmentary retinopathy with areas of RPE and photoreceptors1 • OCT demonstrates spared photoreceptors (ONL) and inner/outer segments (P5), even at a severe disease stage (P3)1 KOL Event | December 2024
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• Lebercilin is a ciliary protein critical for the function of photoreceptor inner and outer segments 1 • In LCA5-LCA patients, photoreceptor function is severely impaired due to a lack of functioning lebercilin 1 − However, photoreceptors can survive through the third decade of life, suggestive of a broad window for therapeutic intervention 2 13 OPGx-LCA5 Restores Structure and Function in Photoreceptors AAV, adeno-associated virus; LCA, Leber congenital amaurosis; LCA5, Leber congenital amaurosis 5. 1. Uyhazi KE, et al. Invest Ophthalmol Vis Sci. 2020;61:30. 2. Song JY, et al. Mol Ther. 2018;26:1581-1593. • OPGx-LCA5 is designed to address mutations in the LCA5 gene, which encodes for the lebercilin protein − Clinically derisked AAV8 vector delivers a functional LCA5 gene directly to photoreceptor cells − Same promoter technology as Luxturna − Validated surgical delivery method via subretinal injection KOL Event | December 2024
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• MLoMT utilizes a readily available VR headset with body trackers to navigate a virtual course • Household objects are presented at increasing illumination while the subject follows a path of red arrows • Subject identifies and “touches” obstacles while following the path • Establishes a "threshold" of functional vision that may be used to assess impact of disease and treatments • Enormous amount of data automatically collected • Relates well with clinical readouts (visual acuity, visual fields, and visual sensitivity) 14 Easing the Answer to a Regulatory Need: Functional Vision Assessment with a Multi-Luminance orientation and Mobility Test (MLoMT) VR, virtual reality. Bennett J, et al. Transl Vis Sci Technol. 2023;12:28. KOL Event | December 2024
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15 MLoMT Builds Upon the Success of MLMT ® MLMT® and Multi-Luminance Mobility Test® are registered trademarks of Spark Therapeutics, Inc. MLoMT, Multi-luminance orientation and Mobility Test; MLMT, Multi-Luminance Mobility Test. 1. Bennett J, et al. Transl Vis Sci Technol. 2023;12:28; 2. Aleman et al. Clin Ophthalmol. 2021;15:939 • Allows automatic randomization of dozens of configurations • Extends operating range (>3 log units) • Can be tailored to different diseases by altering variables (light intensities, wavelength, contrast, color, motion, etc.) • Delivers test in a relatively short time (20 mins) • Equipment/space affordable • Easy to deploy and duplicate at multiple sites • No physical obstacles that could cause harm in a collision • Can test one eye at a time or both eyes • Can adjust to subject’s height • Attractive to digital-savvy pediatric population • Quantitative information (timing, direction of gaze, acceleration, deceleration, collisions) captured automatically as digital data • Data obtained instantaneously and analyzed objectively (no need for reading center) • No personal identifiers MLMT Physical Course KOL Event | December 2024 MLoMT Virtual Course
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6 Month Results of Phase 1/2 Study of OPGx-LCA5 Tomas S. Aleman, MD Irene Heinz-Given and John LaPorte Professor Scheie Eye Institute, University of Pennsylvania
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OPGx-LCA5-1001 Study to Treat a Severe Photoreceptor Disease Design • Phase 1b/2a, open-label of uniocular subretinal injection of OPGx-LCA5 • Nonrandomized, single ascending, dose escalation (1E10 vg/eye, 3E10 vg/eye, and 1E11 vg/eye) unilaterally injected • Minimum of 3 evaluable patients are treated at each dose level • Preliminary results to Day 180 in three patients 17 LCA5, Leber congenital amaurosis 5.
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Study ID Age*/ Gender Date IP Administration Study Eye LCA5 Variants † Allele 1/Allele 2 Visual Acuity ‡ Refraction § Foveal Thickness [µm] BL 3MO OD OS OD OS OD OS OD OS 0103 26/M 07Aug2023 OS Gln279*/Gln279* HM HM +3.00 +3.00 121 NA 136 133.5 0101 34/F 11Sep2023 OS Arg255Gln/del. Exon 1 20/300 20/400 -1.50 -2.50 123.5 127.1 127.1 119.3 0104 19/F 13Nov2023 OD Arg255*/Arg255* 20/200 20/200 +2.25 +2.00 232.2 226.5 170.8 205.1 Characteristics of Patients • Null or non-functional proteins • Poor VA • Severe photoreceptor loss (thin retinas/foveas) 18 BL, baseline; HM, hand motion; IP, investigational product; LCA5, Leber congenital amaurosis 5; OD, right eye; OS, left eye; VA, visual acuity.
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Uneventful Subretinal Injections • 300 µl volume • Multiple SR injections extending near the fovea 19 SR, subretinal. 01-03 01-01 01-04A B
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Safety: Central Retinal Structure • Retina reattached • No major changes post-treatment 20 BL, baseline.
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Subject Date of onset Date of Resolution Diagnosis (if known) or Sign/ Symptoms (list one per AE) Ocular AE? Specify eye(s) Severity Unexpected Serious Frequency Outcome Relationship to Investigational Product Action taken (Add all that apply): 0101 11-SEP- 2023 12-SEP- 2023 Eye Pain Yes Study Grade 1 - Mild No No Intermittent Recovered/ Resolved Unrelated 2 = Con Med (enter on Con Meds Page) 0101 18-SEP- 2023 18-SEP- 2023 Corneal Abrasion Yes Study Grade 1 - Mild No No Single Episode Recovered/ Resolved Unrelated 2 = Con Med (enter on Con Meds Page) 3 = Other 0103 07-AUG- 2023 08-AUG- 2023 Eye Pain Yes Study Grade 1 - Mild No No Intermittent Recovered/ Resolved Unrelated 2 = Con Med (enter on Con Meds Page) 0104 08-AUG- 2023 14-NOV- 2023 Eye Pain Yes Grade 1 - Mild No No Continuous Recovered/ Resolved Unrelated 2 = Con Med (enter on Con Meds Page) • No dose limiting toxicities • AEs were anticipated, mild, and not related to OPGx-LCA5 • All resolved Safety and Tolerability 21 AE, adverse event; LCA5, Leber congenital amaurosis.
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• Formed vision possible for the first time in most affected • On average, better VAs in treated compared to baseline (BL) and untreated eye Visual Acuity Gains 22 VA, visual acuity.
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Large Sensitivity Gains Full-field Stimulus Testing • Significant gain (>1.5 log u) in sensitivity compared to contralateral control eye and baseline (BL) • Results similar for both red (red bars) and blue (blue outlined bars) stimuli in 01-03 and 01-04 • Mechanistically plausible = restoration of function of the cilia 01-03 01-01 01-04 LARGE GAINS IN SENSITIVITIES 23
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Gains are Mediated by Cones • Gains in cone-mediated sensitivity (light adapted in 01-01) in all three patients compared to baseline (BL) and contralateral control eye 24
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Pupillometry Objectively Confirms Efficacy PUPILLOMETRY OBJECTIVELY CONFIRMS EFFICACY/BIOLOGIC ACTIVITY • Pupil responses are more sensitive (left shifted green symbols) compared to baseline (gray curves) and the contralateral control eye • Comparable sensitivity change compared to FSTs 01-03 01-01 01-04 25 FST, full-field stimulus test.
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Functional Vision by MLoMT • Improved orientation and mobility (green up triangles) detected from earliest time point after treatment reproducible to 6 months post -treatment MLoMT, Multi-Luminance orientation and Mobility Test.26
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Restoration of the Fovea Fundus Tracking Perimetry [01-04] STUDY EYE M1 M1 M3M3Control Treated BL 6mo1mo BL 6mo1mo SensitivityFixation MICROPERIMETRY CONFIRMS FOVEAL IMPROVEMENT • Microperimetry, possible in one patient, demonstrates sensitivity gain • Movement of a more stable fixation to the foveal center BL, baseline.27
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Conclusions • Gene augmentation demonstrated robust biologic efficacy in LCA5 • Efficacy corroborated through multiple, mechanistically-driven readouts • Treatment efficacy is possible in a severe neurodegeneration • Approach may be used as a template for other severe IRDs • Inclusion of earlier disease stages in clinical trials is needed Approved to dose 1st pediatric patient with rolling data readout expected in 2025 IRD, inherited retinal disease; LCA5, Leber congenital amaurosis 5.28
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Panel Discussion and Q&A KOL Event | December 2024
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30 Meet Our Panel Ash Jayagopal, PhD, MBA Chief Scientific & Development Officer, Opus Genetics Jean Bennett, MD, PhD F.M. Kirby Emeritus Professor of Ophthalmology, University of Pennsylvania Arshad M. Khanani, MD, MA, FASRS Managing Partner, Sierra Eye Associates Clinical Professor, University of Nevada Tomas S. Aleman, MD Irene Heinz-Given and John LaPorte Research Professor, University of Pennsylvania M o d e r a t o r KOL Event | December 2024 Christine Kay, MD Vitreo Retinal Associates Affiliate Assistant Professor, University of South Florida
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Closing Remarks Ash Jayagopal, PhD, MBA Chief Scientific and Development Officer, Opus Genetics KOL Event | December 2024
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Images of real patients with IRDs. Thank You