6-K
Opthea Ltd (CKDXF)
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 6-K
REPORT OF FOREIGN ISSUER
PURSUANT TO RULE 13a-16 OR 15d-16
OF THE SECURITIES EXCHANGE ACT OF 1934
For the month of September 2024
Commission File No. 001-39621
OPTHEA LIMITED
(Translation of registrant’s name into English)
Level 4
650 Chapel Street
South Yarra, Victoria, 3141
Australia
(Address of registrant’s principal executive office)
Indicate by check mark whether the registrant files or will file annual reports under cover Form 20-F or Form 40-F.
Form 20-F ☒ Form 40-F ☐
EXHIBIT INDEX
| Exhibit | Description |
|---|---|
| 99.1 | Press Release - Euretina Symposium |
SIGNATURES
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, thereto duly authorized.
| OPTHEA LIMITED | |
|---|---|
| (Registrant) | |
| By: | /s/ Frederic Guerard |
| Name: | Frederic Guerard |
| Title: | Chief Executive Officer |
Date: 09/26/2024
Improving on the Standard of Care in nAMD: Sponsored by Addressing the VEGF-C and -D Pathways EURetina Symposium 2024 Exhibit 99.1
Introduction and Objectives Speaker: Arshad Khanani, MD, MA, FASRS
Consultant: AbbVie, Adverum, Alcon, Amgen, Annexin, Annexon, Apellis Pharmaceuticals, Aviceda Therapeutics, Beacon Therapeutics, Clearside Biomedical, Complement Therapeutics, 4DMT, Exegenesis, EyePoint Pharmaceuticals, Frontera Therapeutics, Genentech, Gyroscope Therapeutics, i-Lumen Scientific, Iveric Bio, Janssen Pharmaceuticals, Kodiak Sciences, Kriya Therapeutics, Nanoscope, Novartis, Ocular Therapeutix, Oculis, Ocuphire, OcuTerra, Olive BioPharma, Opthea, Oxular, Oxurion, Perfuse, Ray Therapeutics, Recens Medical, Regeneron Pharmaceuticals, Regenxbio, Revive, RevOpsis, Roche, Sanofi, Stealth BioTherapeutics, Thea Pharma, Unity Biotechnology, Vanotech, and Vial Research support: Aviceda, Adverum, Alexion, Annexon, Apellis Pharmaceuticals, Aviceda Therapeutics, 4DMT, EyePoint, Exegenesis, Genentech, Gyroscope Therapeutics, Iveric Bio, Janssen, Kodiak, Neurotech, Ocular Therapeutix, Oxular, Regenxbio Stock options: Aviceda Therapeutics, Oculis, Opthea, PolyPhotonix, Recens Medical, Perfuse, RevOpsis, and Vial Dr. Arshad Khanani’s Disclosures
Agenda Time Topic Presenter/Moderator 1:00-1:05 pm Introduction and Objectives Chair: Arshad Khanani, MD, MA, FASRS 1:05-1:20 pm nAMD: Where Are We Today? Disease overview Adnan Tufail, MD, MBBS, FRCOphth 1:20-1:35 pm Most Recent and Emerging Treatments in nAMD Treatment objectives for innovation in nAMD Review of most recent treatments Review of emerging treatments in phase 3 An introduction to sozinibercept, a novel anti-VEGF-C & -D inhibitor Gemmy Cheung, MD, MBBS, FRCOphth, FAMS, MC 1:35-1:50 pm Sozinibercept (OPT-302): An Emerging Therapy With the Potential to Raise the Standard-of-Care Benchmark in Visual Outcomes Phase 2b trial results Phase 3 trials: COAST and ShORe Anat Loewenstein, MD, MHA 1:50-2:00 pm Panel Discussion, Questions, Summary, and Closing Remarks Anat Loewenstein, MD, MHA
Objectives Understand the role of VEGF-C and VEGF-D in nAMD Establish that emerging therapies are focused primarily on reducing treatment burden (durability) Introduce sozinibercept as the only late-stage emerging therapy that has the potential to improve standard of care in visual outcomes 1 2 3
Featured Speakers Arshad Khanani, MD, MA, FASRS Sierra Eye Associates Managing Partner, Director of Clinical Research, Director of Fellowship University of Nevada, Reno School of Medicine Clinical Professor Adnan Tufail, MD, MBBS, FRCOphth Moorfields Eye Hospital, Medical Retina Service Consultant Ophthalmologist University College London Professor Gemmy Cheung, MD, MBBS, FRCOphth, FAMS, MC DukeNUS Medical School, Centre for Clinician-Scientist Development Professor Anat Loewenstein, MD, MHA Tel Aviv Sourasky Medical Center Deputy Director of Ambulatory Services, Head of Ophthalmology Tel Aviv University, Medical School at the Sackler Faculty of Medicine Professor of Ophthalmology and Vice Dean
Audience Question: What Is Your Initial Treatment for This Patient? Bevacizumab Ranibizumab Aflibercept 2 mg Aflibercept 8 mg Faricimab A B C D E BCVA = 71 letters CST = 316 µm Week 4: Week 24: BCVA = 59 letters CST = 462 µm Day 0 (Baseline):
nAMD: Where Are We Today? Speaker: Adnan Tufail, MD, MBBS, FRCOphth
Consultant: AbbVie, Adverum, Annexon, Apellis Pharmaceuticals, Aviceda Therapeutics, Boehringer Ingelheim, EyePoint Pharmaceuticals, Genentech-Roche, Iveric Bio, Janssen Pharmaceuticals, Nanoscope, Novartis, Ocular Therapeutix, Opthea, Oxurion, Regenxbio, Thea Pharma Dr. Adnan Tufail’s Disclosures
Objectives Establish the impact of nAMD on quality of life Review the evolution of current nAMD treatments Establish the role of VEGF-C and VEGF-D in nAMD 1 2 3
Vision Impairment Negatively Impacts Independence and Quality of Life 1 in 4 adults with vision loss report depression or anxiety6 *Instrumental activity of daily living. 1. Hochberg C, et al. Invest Ophthalmol Vis Sci. 2012;53:3201-3206. 2. Christ SL, et al. JAMA Ophthalmol. 2014;132(12):1400-1406. 3. Remillard ET, et al. Gerontologist. 2024;64(6):gnad169. 4. Sahel J-A, et al. Arch Ophthalmol. 2007;125(7):945-951. 5. Guo HJ, et al. (2022, Nov 14). In StatPearls. StatPearls Publishing. Retrieved Sep 10, 2024 from https://www.ncbi.nlm.nih.gov/books/NBK553126/. 6. Lundeen EA, et al. Ophthalmic Epidemiol. 2022;29(2):171-181. Mobility1 Face Recognition4 Reading4 Phone/ Computer Use1,2* Driving/ Transportation Management1,3,4* Cooking1* Shopping1,3* Rx Management1,3* Finance Management1-3* Housekeeping1-3* Laundry1,2,5*
Loss of Vision Leads to Increased Mortality Risk Hazard for All-Cause Mortality1 Higher in People With Vision Impairment Decrease of 1 ETDRS letter per year increases mortality risk by 16%2 associated exclusively with IADL levels <20/40 vs ≥20/40 <20/60 vs ≥20/60 <20/200 vs ≥20/60 Better Vision Worse Vision ETDRS, Early Treatment Diabetic Retinopathy Study; IADL, instrumental activities of daily living. 1. Erlich JR, et al. Lancet Glob Health. 2021;9:e418-e430. 2. Christ SL, et al. JAMA Ophthalmol. 2014;132(12):1400-1406.
Evolution of nAMD Treatments to Today Early treatments such as veteporfin/PDT used light sensitivity to break down blood vessels in the eye1 Pegaptanib was the first drug to the VEGF pathway by inhibiting the 165 isoform of VEGF4 Since then, developing treatments have all targeted the VEGF pathway, specifically VEGF-A6 Despite attempts at improving treatment results, we are not seeing real-world superiority over previous treatments6 Improved efficacy2,3 Verteporfin1 Targets VEGF-A, VEGF-B, & PlGF6,12,13 Targets VEGF-A & Ang-211 Targets all isoforms of VEGF-A8 Targets VEGF-A, VEGF-B, & PlGF6,7 Targets all isoforms of VEGF-A5,6* Targets isoform-specific VEGF-A165 inhibition4 Photosensitizing agent used in laser treatment 2000 2004 2006 2011 2023 2022 2019 Targets all isoforms of VEGF-A9,10 2021 *Avastin (bevacizumab) used off-label. Ang-2, angiopoietin-2; nAMD, neovascular age-related macular degeneration; PDT, photodynamic therapy; PIGF, placental growth factor; VEGF, vascular endothelial growth factor. 1. VISUDYNE [prescribing information]. Charleston, SC: Bausch & Lomb Incorporated. https://www.bausch.com/globalassets/pdf/packageinserts/pharma/visudyne-prescribing-information.pdf. Revised Feb 2023. 2. Brown DM, et al. N Engl J Med. 2006;355:1432-1444. 3. Nowak MS, et al. Med Sci Monit. 2012;18(6):CR374-380. 4. MACUGEN [prescribing information]. San Dimas, CA: Gilead Sciences, Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021756s018lbl.pdf. Revised Jul 2011. 5. LUCENTIS [prescribing information]. South San Francisco, CA: Genentech, Inc. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/125156s128lbl.pdf. Revised Feb 2024. 6. Khachigian LM, et al. J Transl Med. 2023;21(1):133. 7. EYLEA [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc. https://www.regeneron.com/downloads/eylea_fpi.pdf. Revised Dec 2023. 8. BEOVU [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. https://www.novartis.com/us-en/sites/novartis_us/files/beovu.pdf. Revised Jul 2024. 9. SUSVIMO [prescribing information]. South San Francisco, CA: Genentech, Inc. https://www.gene.com/download/pdf/susvimo_prescribing.pdf. Revised Apr 2022. 10. Genentech: Press Release. Oct 22, 2021. https://www.gene.com/media/press-releases/14935/2021-10-22/fda-approves-genentechs-susvimo-a-first- 11. VABYSMO [prescribing information]. South San Francisco, CA: Genentech, Inc. https://www.gene.com/download/pdf/vabysmo_prescribing.pdf. Revised Jul 2024. 12. EYLEA HD [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc. https://www.regeneron.com/downloads/eyleahd_fpi.pdf. Revised Dec 2023. 13. Regeneron: Press Release. Aug 18, 2023. https://investor.regeneron.com/news-releases/news-release-details/eylea-hd-aflibercept-injection-8-mg-approved-fda-treatment-wet. All websites accessed Sep 11, 2024.
Overview of Current Anti-VEGF Therapies Half of CATT follow-up study patients had visual acuity worse than 20/40 at 5 years CATT, Comparison of Age-Related Macular Degeneration Treatments Trials; PRN, as needed; VEGF, vascular endothelial growth factor. CATT Research Group, et al. Ophthalmology. 2016;123(8):1751-1761. Overall Monthly Switched PRN 20/100 20/80 20/63 20/50 20/40 20/32 20/25 Visual Acuity, Letters Snellen Equivalent
Effect of Treatment Paradigm Change in nAMD on Outcomes Based on results from a 12-year follow-up of 42,161 patients1,2 Group (n) Number of injections (mean ± SD) Number of visits (mean ± SD) Visit/injection ratio (median) 2016–2017 (633) 11.2 ± 6.1 24.2 ± 7.3 2.17 2014–2015 (6,083) 10.4 ± 6.1 22.5 ± 7.9 2.20 2012–2013 (5,432) 7.9 ± 5.1 21.9 ± 8.2 3 2010–2011 (5,017) 9.3 ± 5.6 23.4 ± 9.9 2.6 2008–2009 (2,395) 9.5 ± 5.8 24.4 ± 11.2 2.71 nAMD, neovascular age-related macular degeneration; VA, visual acuity. 1. Schwartz R. Ophthalmol Retina. 2021;5(8):e11-e22. 2. Data on file. Baseline VA improved over the years—patients identified earlier Final VA improved over the years Trend is the same—patients are still losing vision over time despite the move to more “advanced” treatment regimens In a multivariable analysis accounting for baseline VA, which improved over the years, year of treatment initiation was not related to better outcomes Baseline VA remains strongly associated with outcome
Advantages and Limitations of Current Anti-VEGF-A Therapies Advantages Limitations Suboptimal responses with current anti-VEGF therapies in 25–35% of patients with nAMD1 Persistent macular fluid in 60% of patients with nAMD2 Further vision loss at 12+ months for 25% of patients treated with anti-VEGFs4 Frequent treatment required to maintain vision1 Real-world evidence does not match clinical trial data5 Continued limitations on visual outcomes from all current therapies4 Improved quality of life1 Visual gains1 Multiple anti-VEGF drugs available2 Favorable safety profile1,3 Clinical trial evidence2 PCV, polypoidal choroidal vasculopathy with branching vascular network; PDA, persistent disease activity; nAMD, neovascular age-related macular degeneration; VEGF, vascular endothelial growth factor. 1. Khachigian LM, et al. J Transl Med. 2023;21(1):133. 2. Mettu PS, et al. Prog Retin Eye Res. 2021;82:100906. 3. Heier JS, et al. Ophthalmology. 2012;119(12):2537-2548. 4. Garweg JG, et al. Graefes Arch Clin Exp Ophthalmol. 2018;256(4):823-831. 5. Data on file.
Pathophysiology of AMD and the Role of VEGF-A1,2 Intracellular Extracellular Angiogenesis Vascular Permeability Inflammation Lymphangiogenesis AMD, age-related macular degeneration; PIGF, placental growth factor; VEGF(R), vascular endothelial growth factor (receptor). 1. Khachigian LM, et al. J Transl Med. 2023;21(1):133. 2. Heloterä H, et al. Cells. 2022;11:3453.
The Role of Anti-VEGF Inhibitors in nAMD1-3 Intracellular Extracellular Angiogenesis Vascular Permeability Inflammation Lymphangiogenesis Aflibercept Bevacizumab (off-label) Ranibizumab Brolucizumab nAMD, neovascular age-related macular degeneration; PIGF, placental growth factor; VEGF(R), vascular endothelial growth factor (receptor). 1. Khachigian LM, et al. J Transl Med. 2023;21(1):133. 2. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597. 3. Heloterä H, et al. Cells. 2022;11:3453. Current anti-VEGF therapies primarily target VEGF-A but do not target VEGF-C and VEGF-D1 VEGF-C and D promote angiogenesis and vascular leakage2
VEGF-C and VEGF-D Are Upregulated Following VEGF-A Inhibition in nAMD1-3 Intracellular Extracellular Angiogenesis Vascular Permeability Inflammation Lymphangiogenesis nAMD, neovascular age-related macular degeneration; PIGF, placental growth factor; VEGF(R), vascular endothelial growth factor (receptor). 1. Khachigian LM, et al. J Transl Med. 2023;21(1):133. 2. Leitch IM, et al. Ophthalmol Ther. 2024;13:1857-1875. 3. Heloterä H, et al. Cells. 2022;11:3453.
VEGF-A Inhibition Leads to Upregulation of VEGF-C1-4 Intracellular Extracellular Angiogenesis Vascular Permeability Inflammation Lymphangiogenesis Aflibercept Bevacizumab (off label) Ranibizumab Brolucizumab PIGF, placental growth factor; VEGF(R), vascular endothelial growth factor (receptor). 1. Khachigian LM, et al. J Transl Med. 2023;21(1):133. 2. Leitch IM, et al. Ophthalmol Ther. 2024;13:1857-1875. 3. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597. 4. Heloterä H, et al. Cells. 2022;11:3453. VEGF-C VEGF-D
Role of VEGF-C/D in nAMD Published Data Suggest VEGF-C/D May Contribute to Suboptimal Responses to Anti-VEGF-A Therapy VEGF-C Stimulates Retinal Angiogenesis1 VEGF-A and VEGF-C Induce Vascular Leakage/Permeability2 Circulating VEGF-C Levels Significantly Elevated in AMD Patients3 Elevated VEGF-C in Aqueous Humor Following Anti-VEGF-A Therapy in Patients With nAMD3 Aqueous Humor VEGF-C (pg/mL) 10 8 66% 6 5.4 6.9 8.9 Bevacizumab 4 2 0 Baseline 1 month 2 months ** ** Control AMD Plasma Concentrations (pg/mL) 300 200 100 0 VEGF-A VEGF-C VEGF-D Additive Benefit of VEGF-A and VEGF-C/D Inhibition in Mouse nAMD Model3 CNV Area 70% 78% 91% * 0 200000 400000 600000 Control antibody Sozinibercept Aflibercept Aflibercept + sozinibercept (n)AMD, (neovascular) age-related macular degeneration; CNV, choroidal neovascularization; VEGF, vascular endothelial growth factor. 1. Tammela T, et al. Nat Cell Biol. 2011;13(10):1202-1213. 2. Cao R, et al. Circ Res. 2004;94:664-670. 3. Data on file.
Summary and Conclusion Current nAMD therapies primarily target VEGF-A1 nAMD is multifactorial, and targeting only VEGF-A may contribute to suboptimal response1 Conclusion: There is still unmet need for further visual improvements in the treatment of nAMD Elevated levels of VEGF-C/D leads to angiogenesis and vascular leakage2 nAMD, neovascular age-related macular degeneration; VEGF, vascular endothelial growth factor. 1. Khachigian LM, et al. J Transl Med. 2023;21(1):133. 2. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597.
Most Recent and Emerging Treatments in nAMD Speaker: Gemmy Cheung, MD, MBBS, FRCOphth, FAMS, MC
Consultant: Avirmax, Astellas, Bayer, Boehringer Ingelheim, Janssen, Novartis, Opthea, Roche, Topcon, Zeiss Dr. Gemmy Cheung’s Disclosures
Objectives Evaluate treatment objectives for innovation in nAMD Review recently approved treatments in nAMD Explore emerging treatments in nAMD 1 2 3
Improved Vision Is Now the Greatest Unmet Need for nAMD 0 Greater durability Improved vision ASRS PAT SURVEY 20231 20 40 60 80 100 US 78.6% Intl 74.3% US 50.4% Intl 55.2% (n=1,012) What are the greatest unmet needs in treating wet AMD and DME? ASRS, American Society of Retinal Specialists; DME, diabetic macular edema; Intl, international; nAMD, neovascular age-related macular degeneration; PAT, Preferences and Trends; VEGF, vascular endothelial growth factor. 1. Hahn P, ed. ASRS 2023 Preferences and Trends Membership Survey. Chicago, IL. American Society of Retina Specialists; 2023. 2. Data on file. ASRS PAT SURVEY 20242 Greater durability Improved vision US 76.4% Intl 75.3% US 80.6% Intl 77.3% 0 20 40 60 80 100 (n=1,021) Significant increases over 2023 Goals of Anti-VEGF Treatment Maintenance of visual gain Less frequent dosing Fewer follow-up visits Low rate of AEs Optimal visual improvements
Despite Treatment with Standard of Care Anti-VEGF-A Therapies, the Majority of Patients Achieve Suboptimal Vision Outcomes Despite treatment with anti-VEGF-A therapy*: >60% with have persisting macular fluid2 >45% do not achieve significant vision gains1 25% will have further vision loss at 12+ months3 The majority2 of patients fail to achieve 20/40 vision Most patients cannot resume routine daily activities, such as driving or reading4 BCVA, best corrected visual acuity; CST, central subfield thickness; PCV, polypoidal choroidal vasculopathy with branching vascular network; PDA, persistent disease activity; SD-OCT, spectral domain optical coherence tomography; VEGF, vascular endothelial growth factor. *Based on randomized controlled clinical trial data; >45% fail to achieve ≥2 lines improvement in BCVA; persisting fluid: SD-OCT CST ≥300 µM or time-domain OCT CST ≥250 µM. 1. Lux A, et al. Br J Ophthalmol. 2007;91:1318-1322. 2. Mettu PS, et al. Prog Retin Eye Res. 2021;82:100906. 3. Garweg JG, et al. Graefes Arch Clin Exp Ophthalmol. 2018;256(4):823-831. 4. Data on file.
Current State of nAMD Treatments Recently approved treatments reduce treatment burden but do not lead to superior visual gain Emerging therapies are targeting increased durability nAMD, neovascular age-related macular degeneration.
Aflibercept 8 mg, Faricimab 6 mg, and Port Delivery System with Ranibizumab Demonstrate Improved Durability Compared With Other Anti-VEGF Treatments Also targets VEGF-B and PIGF Aflibercept 8 mg1,2 Soluble decoy receptor fusion protein VEGF-A trap Anti-VEGF-A Fab Anti-Ang-2 Fab Fc Faricimab 6 mg3 Bispecific antibody Ranibizumab implant4,5 Port delivery system (not currently approved in EU) Aflibercept 8 mg is marketed as Eylea HD, Faricimab 8 mg is marketed as Vabysmo, Ranibizumab injection is marketed as Susvimo. Ang-2, angiopoietin-2; PIGF, placental growth factor; VEGF, vascular endothelial growth factor.1. EYLEA HD [prescribing information]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc. https://www.regeneron.com/downloads/eyleahd_fpi.pdf. Revised Dec 2023. 2. Heier JS, et al. Ophthalmology. 2012;119(12):2537-2548. 3. VABYSMO [prescribing information]. South San Francisco, CA: Genentech, Inc. https://www.gene.com/download/pdf/vabysmo_prescribing.pdf. Revised Jul 2024. 4. Holekamp NM, et al. Ophthalmology. 2022;129(3):295-307. 5. SUSVIMO [prescribing information]. South San Francisco, CA: Genentech, Inc. https://www.gene.com/download/pdf/susvimo_prescribing.pdf. Revised Apr 2022. 6. Heier JS, et al. Lancet. 2022;399(10326):729-740. Non-inferior in vision gain compared to standard-of-care anti-VEGF therapies Majority of patients maintained on 12- to 16-week dosing intervals6 Non-inferior in vision gain Refillable every 24 weeks4,5
Emerging Therapy: Gene Therapy Shows Promise to Dramatically Reduce Treatment Burden Uses non-integrating viral vector that encodes genetic material to make an anti-VEGF protein Substantial reduction in treatment burden Potential for one-time treatment Prolonged corticosteroid prophylaxis (IVT administration) – cataract, IOP Intraocular inflammation (IOI) Frequent IOI monitoring Potential for chronic uveitis Lack of long-term safety Potential cost Promoter New gene integrated into cellular DNA Gene transcription and translation Therapeutic Protein Adeno-associated viral (AAV) vector IOP, intraocular pressure; IVT, intravitreal; VEGF, vascular endothelial growth factor. 1. Khanani AM, et al. Eye. 2022;36:303-311. 2. Khanani AM, et al. eClinicalMedicine. 2024;67:102394. Advantages1 Limitations1,2 Transgene
Emerging Therapy: Tyrosine Kinase Inhibitors Work Intracellularly to Inhibit Downstream Effects of VEGF and PDGF Intracellular Extracellular OTX-TKI, EYP-1901, and CLS-AX are in clinical trials for treatment of nAMD1-4 Potential for TKI sustained release to provide every-6-months dosing Targeting further reduction in treatment burden PDGF(R), platelet-derived growth factor (receptor); TKI, tyrosine kinase inhibitor; VEGF(R), vascular endothelial growth factor (receptor). 1. Abbey AM, et al. Presented at ARVO 2023. 2. Patel S, et al. Ophthalmol Sci. 2024;4(5):100527. 3. Moshfeghi AA, et al. IOVS. 2022;64:936. 4. Barakat MR, et al. Ophthalmology Science. 2025;5(1):100586. 31 OTX-TKI CLS-AX EYP-1901
Sozinibercept Combination Therapy Achieves Broad Blockade of the Validated Pathway in nAMD1-4 Sozinibercept Fully Human Molecule Intracellular Extracellular Angiogenesis Vascular Permeability Inflammation Lymphangiogenesis Aflibercept Bevacizumab (off label) Ranibizumab Brolucizumab VEGF-C VEGF-D nAMD, neovascular age-related macular degeneration; PIGF, placental growth factor; VEGF(R), vascular endothelial growth factor (receptor). 1. Khachigian LM, et al. J Transl Med. 2023;21(1):133. 2. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597. 3. Heloterä H, et al. Cells. 2022;11:3453. 4. Leitch IM, et al. Ophthalmol Ther. 2024;13:1857-1875.
Sozinibercept has characteristics to match extended dosing regimens and well-tolerated safety profiles of standard-of-care therapies Sozinibercept Is a Novel VEGF-C/D “Trap” Inhibitor1 A “trap” comprising the extracellular domains 1-3 of VEGFR-3 and the Fc fragment of IgG1 Potent inhibitor of VEGF-C and VEGF-D 140 kDa Comparable ocular biodistribution and similar ocular pharmacokinetics to aflibercept 2 mg IgG, immunoglobulin G; VEGF(R), vascular endothelial growth factor (receptor). 1. Data on file. Sozinibercept Fully Human Molecule
Intravitreal Sozinibercept Has Similar Ocular Biodistribution & PK to Aflibercept - Potential for Similar Durability1 Concentration ngEq/mL Sozinibercept (analogue) Aflibercept Retina Vitreous Humor Time (hr) PK, pharmacokinetics. 1. Data on file. Sozinibercept (analogue) Aflibercept
Summary and Conclusion There continues to be great innovation in nAMD development Most potential new treatment are focused on durability, not on improved VISUAL OUTCOMES as standard of care Objective: Better Visual Outcomes1 Objective: Better Durability1,2 Sozinibercept OTX-TKI EYP-1901 Tyrosine kinase inhibitors Sozinibercept is the only late-stage drug in development targeting superior visual gain RGX-314 Gene therapy 4D-150 IXO-VEC CLS-AX nAMD, neovascular age-related macular degeneration. 1. Leitch IM, et al. Ophthalmol Ther. 2024;13:1857-1875. 2. Khanani AM, et al. eClinicalMedicine. 2024;67:102394.
Sozinibercept (OPT-302): An Emerging Therapy With the Potential to Raise the Standard-of-Care Benchmark in Visual Outcomes Speaker: Anat Loewenstein, MD, MHA
Head of Retina, Tel Aviv Medical Center; Vice President Tel Aviv Medical Center Consultant: Abbvie, Bayer Health Care, Beyeonics, Notal Vision, Novartis, Roche, Syneos, Ocular Therapeutics, Apellis, Oxurion, 4DMT, OcuTerra, Annexon, Astellas, J&J, Ocuphire Pharma, Opthea, Oculis, Alkeus, EyePoint Prof. Anat Loewenstein’s Disclosures
Objectives Review Phase 2b Trial Results Present Phase 3 Trials: COAST and ShORe 1 2
Phase 2b Trial Results Speaker: Anat Loewenstein, MD, MHA
Phase 2b nAMD Trial Overview BCVA, best corrected visual acuity; CNV, choroidal neovascularization; IVT, intravitreal; (m)ITT, (modified) intention to treat; nAMD, neovascular age-related macular degeneration; Q4W, once every 4 weeks; VA, visual acuity. ITT population: all participants who were randomized into the study irrespective of whether study medication was administered; safety population: all participants in the ITT but excluding those who did not receive at least one dose of study medication; mITT population: all participants in the safety population but excluding any participant without a baseline VA score and/or any participant who did not return for at least one post-baseline visit. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597. Treatment-naïve patients with neovascular AMD Key exclusion criteria Subfoveal fibrosis or >25% of total lesion Hemorrhage >50% total lesion Other clinically significant ocular disease Key inclusion criteria Active CNV ≥50% lesion, classic/minimally classic/occult BCVA ≥25 and ≤60 letters Follow-up Randomized (n=366) Sozinibercept 0.5 mg + 0.5-mg ranibizumab IVT Q4W x 6 n=122 Sham + 0.5-mg ranibizumab IVT Q4W x 6 n=121 Sozinibercept 2.0 mg + 0.5-mg ranibizumab IVT Q4W x 6 n=123 Completed study n=112 (91.8%) Completed study n=116 (95.9%) Completed study n=120 (97.6%) Analyzed n=122 Analyzed n=119 Analyzed n=121 Screening Allocation ITT population Analysis mITT population
Phase 2b Primary and Secondary Endpoints Primary Endpoint Select Prespecified Subgroups Predominantly classic, minimally classic, & occult lesions (stratification factor) Retinal angiomatous proliferation (RAP) detected/not detected at baseline Idiopathic polypoidal choroidal vasculopathy (PCV) detected/not detected at baseline Mean change from baseline in BCVA at Week 24 Key Secondary Endpoints Proportion of patients gaining ≥15 letters (ETDRS) from baseline at Week 24 Change in CST from baseline at Week 24 Change in intraretinal and subretinal fluid from baseline to Week 24 Safety and tolerability BCVA, best corrected visual acuity; CST, central subfield thickness; EDTRS, Early Treatment Diabetic Retinopathy Study. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597.
Sozinibercept Achieves Primary Clinical Trial Endpoint BCVA, best corrected visual acuity; mITT, modified intention to treat; SEM, standard error of the mean; VA, visual acuity. mITT population: all participants in the safety population but excluding any participant without a baseline VA score and/or any participant who did not return for at least one post-baseline visit. 1. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597. 2. Data on file. Phase 2b primary endpoint achieved1,2 Mean Change in BCVA (SEM) (Letters) Δ = +3.4 (p=0.0107) 20 15 10 5 0 0 4 8 16 20 24 12 Weeks Total Patient Population +14.2 +10.8 Sham + 0.5-mg ranibizumab (n=119) 0.5-mg sozinibercept + 0.5-mg ranibizumab (n=122) 2.0-mg sozinibercept + 0.5-mg ranibizumab (n=121)
Sozinibercept Combination Therapy Demonstrates Superior Vision Gains Vision Gain From Baseline to Week 24 (Overall Population) Modified intent-to-treat population; as observed. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597. Sham + 0.5 mg ranibizumab (n=116) 2.0 mg sozinibercept + 0.5 mg ranibizumab (n=120)
Fewer Patients Lost Vision in the Sozinibercept Combination Group Vision Loss From Baseline to Week 24 (Overall Population) Modified intent-to-treat population; as observed. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597. Sham + 0.5 mg ranibizumab (n=116) 2.0 mg sozinibercept + 0.5 mg ranibizumab (n=120)
Additional Improvement in Visual Acuity Outcomes With Sozinibercept Combination Therapy in Patients With Occult & Minimally Classic Lesions (RAP Absent) Sham + 0.5-mg ranibizumab (n=87) 2.0-mg sozinibercept + 0.5-mg ranibizumab (n=88) +10.3 +16.1 Δ = +5.7 p = 0.0002* Occult & Minimally Classic Lesions (RAP Absent) 0 4 8 12 16 20 24 0 5 10 15 20 Weeks ( l e t t e r s ) Mean Change in BCVA (SEM) (Letters) Phase 2b demonstrated superior efficacy of a +5.7-letter gain over standard of care based on a predetermined analysis This patient population (minimally classic & occult) represents ~75% of patients with nAMD *Unadjusted p-value. BCVA, best corrected visual acuity; nAMD, neovascular age-related macular degeneration; RAP, retinal angiomatous proliferation; SEM, standard error of the mean. Data on file.
Sozinibercept Combination Therapy Demonstrates Superior Vision Gains Vision Gain from Baseline to Week 24 (Min. Classic & Occult, RAP Absent) BCVA, best-corrected visual acuity; ETDRS, Early Treatment of Diabetic Retinopathy Study; RAP, retinal angiomatous proliferation. Modified intention-to-treat (mITT) population; as observed. Data on file. 42% relative increase in % of ≥15-letter gainers compared to ranibizumab control 30% relative increase in % of ≥10-letter gainers compared to ranibizumab control 20% relative increase in % of ≥5-letter gainers compared to ranibizumab control Higher percentage of patients gaining ≥15, ≥10, and ≥5 ETDRS BCVA letters in sozinibercept combination group Sham + 0.5 mg ranibizumab (n=87) 2.0 mg sozinibercept + 0.5 mg ranibizumab (n=88)
Fewer Patients Lost Vision in the Sozinibercept Combination Group Vision Loss from Baseline to Week 24 (Min. Classic & Occult, RAP Absent) RAP, retinal angiomatous proliferation. Modified intention-to-treat (mITT) population; as observed. Data on file. Sham + 0.5 mg ranibizumab (n=87) 2.0 mg sozinibercept + 0.5 mg ranibizumab (n=88)
Reduced Retinal Thickness and Better Retinal Drying With Combination Therapy in Occult & Minimally Classic (RAP Absent) Patients Sham + 0.5-mg ranibizumab (n=87) 2.0-mg sozinibercept + 0.5-mg ranibizumab (n=88) Mean Change in CST Baseline to Week 24 % of Participants With SRF at Week 24 % of Participants with IR Cysts at Week 24 -180 -140 -100 -60 86 -133.5 85 -126.8 Mean Change in CST (SEM) (µm) % Participants 0 20 40 88 14.8 87 18.4 0 20 40 86 19.8 85 28.2 % Participants Modified intention-to-treat (mITT) population; as observed; top of bar – statistic, bottom of bar – n. CST, central subfield thickness; IR, intraretinal; RAP, retinal angiomatous proliferation; SRF, subretinal fluid. Data on file.
Higher Percentage of Patients with 20/40 Vision or Better in Sozinibercept Combination Group (Min. Classic & Occult, RAP Absent) Sham + 0.5-mg ranibizumab (n=87) 2.0-mg sozinibercept + 0.5-mg ranibizumab (n=88) 0 20 40 60 80 48.9 34.5 % Participants ≥70 letters (20/40 Snellen Equivalent) at Week 24 42% relative increase in % of patients with 20/40 vision at Week 24 compared with ranibizumab control RAP, retinal angiomatous proliferation. Data on file.
Greater CNV and Lesion Regression With Combination Therapy in Occult & Minimally Classic (RAP Absent) Patients Mean Change in Total Lesion Area at Week 24 Mean Change in CNV Area at Week 24 -6 -4 -2 0 81 -4.4 80 -3.5 Mean Change in Total Lesion Area (SEM) (mm2) -6 -4 -2 0 81 -5.0 80 -3.9 Mean Change in CNV Area (SEM) (mm2) Sham + 0.5-mg ranibizumab (n=80) 2.0-mg sozinibercept + 0.5-mg ranibizumab (n=81) Modified intention-to-treat (mITT) population; as observed; ; top of bar – statistic, bottom of bar – n. CNV, choroidal neovascularization; RAP, retinal angiomatous proliferation; SEM, standard error of the mean. Data on file.
Phase 2b Safety1,2 Combination Therapy Well Tolerated and Comparable to Standard of Care Safety population analyzed according to medication received. AE, adverse event; APTC, Anti-Platelet Trialists' Collaboration; IP, investigational product; SAE, serious adverse event; TEAE, treatment-emergent adverse event. *Assessed by investigator to be “possibly related,” “probably related,” or “definitely related” to administration of study drug(s); †Assessed by investigator to be National Institutes of Health Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or above, or, if CTCAE grade is unavailable, an AE assessed as “causing an inability to perform normal daily activities”; ‡SAE of endophthalmitis, with AEs of hypopyon and raised IOP and anterior chamber cell (n=1), SAE of vitritis (n=1); §AEs considered to be indicative of intraocular inflammation, defined prior to database lock as: endophthalmitis, iritis, vitritis, iridocyclitis, uveitis, hypopyon, viral iritis, or anterior chamber inflammation; ¶Transient anterior chamber cell (trace 1-4 cells); #Not reported as a TEAE; **Non-Squamous cell carcinoma of the lung diagnosed shortly after baseline visit; ††Non-fatal myocardial infarction; ‡‡Pneumonia (n=1), infective endocarditis (n=1). 1. Jackson TL, et al. Ophthalmology. 2023;130(6):588-597. 2. Data on file. Participants, n (%) Sham + 0.5-mg ranibizumab n=121 0.5-mg sozinibercept + 0.5-mg ranibizumab n=120 2.0-mg sozinibercept + 0.5-mg ranibizumab n=124 TEAEs 84 (69.4) 87 (72.5) 93 (75.0) Ocular AEs, study eye – related to study product(s)* 17 (14.0) 17 (14.2) 19 (15.3) Ocular AEs, study eye – severe† 1 (0.8) 2 (1.7) 1 (0.8) SAEs 10 (8.3) 16 (13.3) 7 (5.6) Ocular SAEs in study eye 0 (0.0) 2‡ (1.7) 0 (0.0) Intraocular inflammation,§ study eye 2¶,# (1.7) 2‡ (1.7) 1¶ (0.8) Participants with AEs leading to study IP discontinuation only 2 (1.7) 3 (2.5) 0 (0.0) Participants with AEs leading to study discontinuation 1** (0.8) 0 (0.0) 0 (0.0) Any APTC event 0 (0.0) 1†† (0.8) 0 (0.0) Deaths 2‡‡ (1.7) 0 (0.0) 0 (0.0)
Pooled Safety for Completed Sozinibercept Trials Combination Therapy Well Tolerated and Comparable to Standard-of-Care Monotherapy AE, adverse event; APTC, Anti-Platelet Trialists' Collaboration; IOP, intraocular pressure; SAE, serious adverse event; TEAE, treatment-emergent adverse event. *Any dose (sozinibercept 0.3 mg, 1 mg, or 2 mg); †Transient anterior chamber cell (trace 1-4 cells); ‡SAE of endophthalmitis, with AEs of hypopyon and anterior chamber cell (n=1; 0.5 mg); §SAE of vitritis (n=1; 0.5 mg); ¶Non-fatal myocardial infarction; #Cerebrovascular accident; **Enteritis; ††Abdominal pain; ‡‡Increased IOP; §§Non-fatal angina pectoris; ¶¶Fatal congestive heart failure/myocardial infarction; ##Non-fatal arterial embolism; ***Embolic stroke; †††Metastatic ovarian cancer; §§§Pneumonia; ###Infective endocarditis. Data on file. Participants, n (%) Sozinibercept any dose* n=399 (n=1,842 injections) Sozinibercept 2.0 mg n=263 (n=1,121 injections) Sham + anti-VEGF-A control n=170 (n=854 injections) Ocular TEAEs, study eye – related to study product(s) 41 (10.2) 22 (8.4) 20 (11.8) Ocular TEAEs, study eye – severe 4 (1.0) 2 (0.8) 2 (1.2) Intraocular inflammation, study eye 7†,‡,§ (1.8) 3† (1.1) 3† (1.8) Participants with AEs leading to treatment discontinuation 4‡, ¶,#,** (1.0) 1¶ (0.4) 2††,‡‡ (1.2) Any APTC event 4¶,#,§§,¶¶ (1.0) 3#,§§,¶¶ (1.1) 2##,*** (1.2) Deaths 2¶¶,††† (0.5) 2¶¶,††† (0.8) 2§§§,### (1.2)
Phase 3 Trials: COAST and ShORe
Ongoing Phase 3 Trials Topline data from both trials anticipated in mid-CY 2025 Near-Term Focus Is on Sozinibercept Phase 3 Execution Pivotal Program Design Informed by Phase 2b and Optimized for Success Standard of care administered according to approved dosing schedule: aflibercept 2.0 mg IVT Q8W after 3 loading doses and ranibizumab, 0.5 mg IVT Q4W after 3 loading doses. Sozinibercept dosed at 2.0 mg. Note that sham administered at visits when sozinibercept is not administered. Maintenance dosing continued through end of the safety follow-up. CY, calendar year; DME, diabetic macular edema; IVT, intravitreal; nAMD, neovascular age-related macular degeneration; Q4W, once every 4 weeks; Q8W, once every 8 weeks. Data on file. Completed Phase 1-2 Trials Phase 1/2a (n=51) Treatment-naïve/prior-treated nAMD Sozinibercept + ranibizumab: 3x monthly dosing Sozinibercept: 3x monthly dosing Comparator: aflibercept (monthly) Phase 1b/2a (n=153) Prior-treated DME Sozinibercept: 6x monthly dosing Comparator: ranibizumab (monthly) Phase 2b (n=366) Treatment-naïve nAMD Standard Dosing Sozinibercept once every month Extended Dosing Sozinibercept once every 2 months after 3 monthly doses Standard Dosing Sozinibercept once every month Extended Dosing Sozinibercept once every 2 months after 3 monthly doses Comparator: Aflibercept (Eylea®) once every 2 months after 3 monthly doses Comparator: Ranibizumab (Lucentis®) once every month COAST Phase 3 - nAMD (treatment naïve) n=~990 ShORe Phase 3 - nAMD (treatment naïve) n=~990
Phase 3 nAMD Trials COAST and ShORe Are Well Advanced Complete Enrollment Anticipated in Q2 CY2024 | Topline Data Mid-CY2025 Multicenter, double-masked, randomized (1:1:1), sham control Treatment-naïve patients with nAMD ~990 per trial ~330 patients per arm: 2-mg sozinibercept Q4W & Q8W, or sham control 2-mg aflibercept Q8W (COAST) & 0.5-mg ranibizumab Q4W (ShORe) ~90% power, 5% type I error rate Design1,2 Sample Size1,2 Comparators1,2 Regulatory Quality3 CY, calendar year; nAMD, neovascular age-related macular degeneration; Q2, second quarter; Q4W, once every 4 weeks; Q8W, once every 8 weeks. 1. ClinicalTrials.gov. ShORe (NCT04757610). https://clinicaltrials.gov/study/NCT04757610. Accessed Sep 12, 2024. 2. ClinicalTrials.gov. COAST (NCT04757636). https://clinicaltrials.gov/study/NCT04757636. Accessed Sep 12, 2024. 3. Data on file.
Phase 3 Trial Design Supports Potential Broad Label for Use With Any Anti-VEGF-A Therapy Standard of care administered according to approved dosing schedule: aflibercept 2.0 mg IVT Q8W after 3 loading doses and ranibizumab, 0.5 mg IVT Q4W after 3 loading doses. Sozinibercept dosed at 2.0 mg. Note that sham administered at visits when sozinibercept is not administered. Maintenance dosing continued through end of the safety follow-up. CY, calendar year; IVT, intravitreal; nAMD, neovascular age-related macular degeneration; Q2, second quarter; Q4W, once every 4 weeks; Q8W, once every 8 weeks; Tx, treatment; VEGF, vascular endothelial growth factor. Data on file. Ranibizumab Q4W + sozinibercept Q4W Ranibizumab Q4W + sham Q4W Ranibizumab Q4W + sozinibercept Q8W Primary Efficacy Endpoint Week 52 Aflibercept Q8W + sozinibercept Q4W Aflibercept Q8W + sham Q4W Aflibercept Q8W + sozinibercept Q8W Safety Follow-up Week 100 Primary Efficacy Endpoint Week 52 Safety Follow-up Week 100 Aflibercept + sozinibercept Q4W Aflibercept + sozinibercept Q4W Aflibercept + sham Q4W Ranibizumab + sozinibercept Q4W Ranibizumab + sozinibercept Q4W Ranibizumab + sham Q4W nAMD Tx-naïve Patients N=~990 Enrollment Complete Enrollment Complete Maintenance Dosage (40 w) Loading Dosage (12 w) Efficacy Phase Maintenance Dosage (40 w) Loading Dosage (12 w) Efficacy Phase nAMD Tx-naïve Patients N=~990
Phase 3 Inclusion and Exclusion Criteria1,2 AMD, age-related macular degeneration; BCVA, best corrected visual acuity; BLA, Biologics License Application; CNV, choroidal neovascularization; EDTRS, Early Treatment Diabetic Retinopathy Study. 1. ClinicalTrials.gov. ShORe (NCT04757610). https://clinicaltrials.gov/study/NCT04757610. Accessed Sep 12, 2024. 2. ClinicalTrials.gov. COAST (NCT04757636). https://clinicaltrials.gov/study/NCT04757636. Accessed Sep 12, 2024 Inclusion Criteria Main Exclusion Criteria Active subfoveal CNV lesion or juxtafoveal CNV lesion with foveal involvement that is secondary to AMD in the study eye Any previous treatment for neovascular AMD Clinically significant ocular disorders (other than neovascular AMD) that may interfere with assessment of BCVA, assessment of safety, or fundus imaging Any current (or history of a) social, psychological, or medical condition that precludes enrollment into the study An ETDRS BCVA score between 60 and 25 (inclusive) letters in the study eye
Phase 3 Primary and Secondary Endpoints1,2 Primary Efficacy Endpoint at Week 52 to Support BLA Submission Primary Endpoint Key Secondary Endpoints (Baseline to Week 52) Proportion of participants gaining ≥15 letters Proportion of participants gaining ≥10 letters Change in choroidal neovascularization area Proportion of participants with absence of both subretinal fluid and intraretinal cysts Mean change from baseline in BCVA at week 52 BCVA, best corrected visual acuity; BLA, Biologics License Application. 1. ClinicalTrials.gov. ShORe (NCT04757610). https://clinicaltrials.gov/study/NCT04757610. Accessed Sep 12, 2024. 2. ClinicalTrials.gov. COAST (NCT04757636). https://clinicaltrials.gov/study/NCT04757636. Accessed Sep 12, 2024.
Potential for combination of sozinibercept and anti-VEGF standard of care to provide superior vision compared to anti-VEGF-A alone Sozinibercept - Novel MOA, potent trap molecule that neutralizes VEGF-C and VEGF-D1 Summary MOA, mechanism of action; VEGF, vascular endothelial growth factor. 1. Leitch IM, et al. Ophthalmol Ther. 2024;13:1857-1875 Sozinibercept Fully Human Molecule
Panel Discussion Speaker: Anat Loewenstein, MD, MHA
Case: Panel Discussion BCVA = 71 letters CST = 316 µm Week 4: Week 24: What is your drug of choice? What is your primary treatment goal? BCVA = 59 letters CST = 462 µm Day 0 (Baseline):
Ph2b Case: Treatment-Naïve nAMD Patient Receiving 2-mg Sozinibercept and Ranibizumab Combination Therapy Baseline Lesion Type: Predominantly Classic BCVA (ETDRS) CST (µm) -169 µm +18 letters Weeks Weeks Final 6-month analysis from phase 2b trial. BCVA, best corrected visual acuity; CST, central subfield thickness; EDTRS, Early Treatment Diabetic Retinopathy Study; nAMD, neovascular age-related macular degeneration. BCVA = 59 letters CST = 462 µm BCVA = 71 letters CST = 316 µm Day 0 (Baseline): Week 4: BCVA = 77 letters CST = 293 µm Week 24:
Audience Question: What Is Your Primary Treatment Goal With Anti-VEGF Therapy at 12 Months? (3-Monthly Loading Dose, Followed by Treat-and-Extend) BCVA Improvement of 5-10 Letters BCVA Improvement of >10 Letters Achieve ≥20/40 Vision Resolution of Fluid Moderate Vision Gain and Reduction of Fluid A B C D E BCVA = 55 letters (~20/80) CST = 363 µm Day 0 (Baseline):
Case: Panel Discussion BCVA = 55 letters (~20/80) CST = 363 µm Day 0 (Baseline): What is your drug of choice? What is your primary treatment goal?
Ph2b Case: Treatment-Naïve Patient With nAMD Receiving 2-mg Sozinibercept and Ranibizumab Combination Therapy Final 6-month analysis from phase 2b trial. BCVA, best corrected visual acuity; CST, central subfield thickness; EDTRS, Early Treatment Diabetic Retinopathy Study; nAMD, neovascular age-related macular degeneration. BCVA = 55 letters (~20/80) CST = 363 µm BCVA = 61 letters (~20/63) CST = 142 µm +22 letters Day 0 (Baseline): Week 4: BCVA = 77 letters (~20/32) CST = 171 µm Week 24: -192 µm BCVA (ETDRS) CST (µm) Weeks Weeks
Questions Speaker: Anat Loewenstein, MD, MHA
Summary/Closing Remarks Speaker: Anat Loewenstein, MD, MHA