Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study
- PMID: 38554726
- DOI: 10.1016/S0140-6736(24)00310-6
Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study
Abstract
Background: Frequent anti-vascular endothelial growth factor A (VEGF-A) injections reduce the risk of rapid and severe vision loss in patients with neovascular age-related macular degeneration (nAMD); however, due to undertreatment, many patients lose vision over time. New treatments that provide sustained suppression of VEGF-A are needed. RGX-314 (currently known as ABBV-RGX-314) is an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment, which provides potential for continuous VEGF-A suppression after a single subretinal injection. We report results on the safety and efficacy of subretinal injection of RGX-314 in patients with nAMD.
Methods: For this open-label, multiple-cohort, multicentre, phase 1/2a, dose-escalation study conducted at eight sites in the USA, we enrolled participants with nAMD aged 50-89 years who had previously been treated with anti-VEGF injections into five cohorts (with five different doses of RGX-314). To be eligible, participants had to have macular neovascularisation secondary to nAMD with subretinal or intraretinal fluid in the centre subfield, be pseudophakic (after cataract removal), and have a best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400 for the first participant in each cohort and between 20/40 and 20/400 for others. Subretinal injection of RGX-314 was done without a pre-bleb by a wet-laboratory-trained vitreoretinal surgeon. Cohort 1 received 3 × 109 genome copies per eye, cohort 2 received 1 × 1010, and cohort 3 received 6 × 1010. Two additional dose cohorts (cohort 4: 1·6 × 1011; cohort 5: 2·5 × 1011) were added. Participants were seen 1 day and 1 week after administration of RGX-314, and then monthly for 2 years (up to week 106). The primary outcome was safety of RGX-314 delivered by subretinal injection up to week 26. This analysis includes all 42 patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT03066258.
Findings: Between May 12, 2017, and May 21, 2019, we screened 110 patients for eligibility and enrolled 68. 42 participants demonstrated the required anatomic response to intravitreal ranibizumab and then received a single RGX-314 injection (dose range 3 × 109 to 2·5 × 1011 genome copies per eye) and were followed up for 2 years. There were 20 serious adverse events in 13 participants, of which one was possibly related to RGX-314: pigmentary changes in the macula with severe vision reduction 12 months after injection of RGX-314 at a dose of 2·5 × 1011 genome copies per eye. Asymptomatic pigmentary changes were seen in the inferior retinal periphery several months after subretinal injection of RGX-314 most commonly at doses of 6 × 1010 genome copies per eye or higher. There were no clinically determined immune responses or inflammation beyond that expected following routine vitrectomy. Doses of 6 × 1010 genome copies or higher resulted in sustained concentrations of RGX-314 protein in aqueous humour and stable or improved BCVA and central retinal thickness with few or no supplemental anti-VEGF-A injections in most participants.
Interpretation: Subretinal delivery of RGX-314 was generally well tolerated with no clinically recognised immune responses. RGX-314 gene therapy provides a novel approach for sustained VEGF-A suppression in patients with nAMD that has potential to control exudation, maintain vision, and reduce treatment burden after a single administration. Results from this study informed the pivotal programme to evaluate RGX-314 in patients with nAMD.
Funding: RegenxBio.
Copyright © 2024 Elsevier Ltd. All rights reserved.
Conflict of interest statement
Declaration of interests PAC has received grant funding, paid to the institution, from RegenxBio, Genentech, Mallinckrodt, Sanofi, Cove, and Cellanese; has received consulting fees from Allegro, Asclepix, Ashvattha, Bausch & Lomb, Catawba, Cellanese, Cove, Genentech, Merck, and Perfuse; and has stock or stock options in Allegro and Cove. RA has received grant funding, paid to the institution, from Adverum, Genentech, Ocular Therapeutix, RegenxBio, and Regeneron; has received consulting fees from 4DMT, Adverum, Allergan, Amgen, Cardinal Health, Clearside, Coherus, Eyepoint, Genentech, Ingenia, Kriya, Novartis, NVasc, Ocular Therapeutix, Outlook, RegenxBio, Replenish, and ReVana; has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Genentech; holds a patent from Replenish; has leadership or fiduciary roles in boards, societies, committees, or advocacy groups, paid or unpaid, of the Board of the American Society of Retina Specialists (ASRS); and has stock or stock options in Adverum, Eyepoint, Ingenia, Kodiak, Novartis, Nvasc, Outlook, Regeneron, Replenish, and ReVana. DMB has received grant funding, paid to the institution, from Adverum, Alderya, Alexion, Alkahest, Alimera, Amgen, Annexon, Apellis, Aura, Bayer, Boston Image Reading Center, Boehringer Ingelheim, Clearside Biomedical, Cleveland Clinic Foundation, Eyepoint, Gemini, Genentech/Roche, Graybug, Gyroscope, John Hopkins, Ionis, Irenix, Iveric, Kodiak, Lowery Medical Research Group, Lumithera, Nanoscope, NEI/NH, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire Pharma, OIRRC, ONS, Opthea, Opthotech, OPTOS, Oxurion, Oysterpoint, Regeneron, RegenxBio, Roche, SamChunDang, Samsung, Sandoz, Santen, Senju, Stealth, Unity, Xbrane, and Zeiss; has received consulting fees from 4DMT, AbbVie, Adverum Biotechnologies, AGTC, Alexion Pharmaceuticals, Annexon, Apellis Pharmaceuticals, Bayer, Biogen MA, Boehringer Ingelheim, Celltrion, Chengdu Kanghong Pharmaceutical, Clearside Biomedical, Coherus BioScience, Gemini Therapeutics, Glaukos, Heidelberg Engineering, Iveric Bio, Kodiak Sciences, Lineage Cell Therapeutics, Medscape, Molecular Partners, Novartis Pharma, Ocular Therapeutix, Ocuphire Pharma, OPTOS, Pontifax, PPD, Regeneron Pharmaceuticals, RetinAI Medical, Ray Therapeutics, Samsung Bioepis, Senju Pharmaceuticals, SciNeuro Therapeutics, SIMR Biotech, Smilebiotek Zhuhai, Stealth BioTherapeutics, Verseon, WebMD Global, and XEQUEL BIO; holds leadership or fiduciary roles in other boards, societies, committees, or advocacy groups, paid or unpaid, in the ASRS (board of directors from 2014 to present), ASRS (governmental affairs 2017 to present), the Foundation of the ASRS (board of directors 2014 to present), Macula Society (credentials committee 2013 to present), the Retina Society (finance committee 2018 to present), the American Society of Cataract & Refractive Surgery (retina clinical committee 2015 to present), and the University of Iowa Center for Macular Degeneration (advisory board 2003 to present); and holds stock options in Adverum, Clearside Biomedical, and Ocuphire Pharma. JSH has received grant funding, paid to the institution, from RegenxBio, 4D Molecular Technologies, Annexon, Apellis, AsclepiX Therapeutics, Ashvattha, Bayer, Cognition Therapeutics, Curacle, Genentech/Roche, Gyroscope Therapeutics, Iveric Bio, Janssen R&D, Kodiak, NGM, Novartis, OcuTerra, Perceive Bio, and Regeneron Pharmaceuticals; has received consulting fees from 4D Molecular Technologies, Abpro, Adverum, AffaMed Therapeutics, Applied Genetics Technologies Corporation, Akouos, Annexon, Apellis, AsclepiX Therapeutics, Aviceda, Bausch & Lomb, Biovisics, Clearside, Curacle, DTx Pharma, Exegenesis, Genentech/Roche, Glaukos, Gyroscope Therapeutics, Immunogen, Iveric Bio, Janssen R&D, jCyte, Kodiak, Kriya, Nanoscope, NGM, Notal Vision, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, OliX, ONL Therapeutics, Outlook Therapeutics, Palatin Technologies, Perceive Bio, Ray Therapeutics, Regeneron Pharmaceuticals, RegenxBio, RetinAI, RevOpsis Therapeutics, Stealth BioTherapeutics, Théa Pharmaceuticals, and Vanotech; holds leadership or fiduciary roles in boards, societies, committees, or advocacy groups, paid or unpaid, in ASRS (board of directors), Retina Society (president), and Ocular Therapeutics (board of directors); and holds stock or equity in Adverum, Aldeyra Therapeutics, Allegro, Aviceda, jCyte, Ocuphire, Ocular Therapeutix, RevOpsis, and Vinci Pharmaceuticals. ACH has received grant funding, paid to the institution, and consulting fees from RegenxBio and AbbVie; has received other consultant or grant support from AcuSurgical, Adverum, Aerie, AGTC, Alcon Laboratories, Aldeyra, Allergan, Apellis, Asclepix, Atsena, Beaver-Visitec, International, Clearside, Covalent Medical, Dompe, Exegenesis Bio, EyePoint, Eyevensys, Genentech, Gyroscope, Iveric, Janssen/Johnson&Johnson, Kiora, Lineage, Lumithera, Nanoscope, National Eye Institute, Neurotech, Pharmaceuticals, Notal, Novartis, Ocugen, Ocular Therapeutics, ONL, Orasis, Oxular, ProQR, and Regeneron Pharmaceuticals; and holds stealth stock or equity in Kiora, ONL, Covalent Medical, and Gyroscope. SMH received grant funding, paid to the institution, from RegenxBio, Apellis, Byaer, Boehringer, Chengdu, Origen Biotechnology, EyeBiotech, EyePoint, Genentech, Gyroscope, i_Lumen Scientific, Janssen, Kodia, Novartis, OcuTerra, ONL, and Roche; has received consulting fees from RegenxBio; has received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Novartis, and the Retina World Congress; has received travel support to attend meetings from Genentech and RegenxBio; and has participated on the data safety and monitoring board at Genentech and SUSVIMO. GJJ has received consulting fees from Roche/Genentech, EyePoint, Novartis, Annexon, 4DMT, Regeneron, Adverum, and Outlook. AMK has received grant funding, paid to the institution, from RegenxBio, Adverum, 4DMT, Genentech, Gyroscope, and Janssen; and has received consulting fees from AbbVie, Adverum, 4DMT, Genentech, Gyroscope, Janssen, and Regeneron. SP is an employee of RegenxBio. DJP has received grant funding, paid to the institution, from RegenxBio, Genentech, Regeneron, Adverum, 4DMT, Kodiak, EyePoint, Clearside, Opthea, Annexon, Janseen, and Stealth; has received consulting fees from RegenxBio, Genentech, Adverum, Apellis, Regeneron, Gyroscope, EyePoint, Clearside, Opthea, Annexon, SIMR, Neurotech, Stealth, NGM, and Novartis; and has participated on the data safety and monitoring board of Perceive. CCW has received grant funding, paid to the institution, from RegenxBio, 4D Molecular Technologies, Adverum, AffaMed, Alexion, Alimera, Alkahest, Allergan, Aldeyra, Allgenesis, Amgen, Annexin, Annexon, Apellis, Asclepix, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Curacle, Eyebiotech, EyePoint, Gemini, Genentech, GlaxoSmithKline, Graybug, Gyroscope, IONIS, iRENIX, IVERIC Bio, Janssen, Kodiak, LMRI, McMaster University, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, OliX, Ophthotech, Opthea, Oxurion, Oxular, Oyster Point, PerceiveBio, RecensMedical, Regeneron, Rezolute, Roche, SamChunDang Pharm, Sandoz, Senju, Shanghai Henlius, Taiwan Liposome, UNITY, Verily, and Xbrane; has received consulting fees from 4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Alimera, Allergan, Allgenesis, Alnylam, Annexon, Apellis, Arrowhead, Ascidian, Bausch & Lomb, Bayer, Bionic Vision Technologies, Boehringer Ingelheim, Cholgene, Clearside, Curacle, Eyebiotech, EyePoint, Foresite, Frontera, Genentech, Gyroscope, IACTA, IVERIC Bio, Janssen, Kato, Kiora, Kodiak, Kriya, Merck, Nanoscope, Neurotech, NGM, Notal Vision, Novartis, OccuRx, Ocular Therapeutix, Ocuphire, Ocuterra, OliX, ONL, Opthea, Oxular, Palatin, PerceiveBio, Perfuse, PolyPhotonix, Ray, RecensMedical, Regeneron, RegenxBio, Resonance, Roche, Sandoz, Sanofi, SciNeuro, Stealth, Surrozen, Suzhou Raymon, Takeda, THEA, Therini, TissueGen, Valo, and Verana; has participated on the data safety and monitoring board of Kato and Aerie; holds leadership or fiduciary roles in other boards, societies, committees, or advocacy groups, paid or unpaid, at ASRS (board member); and holds stock options at ONL, PolyPhotonix, RecensMedical, TissueGen, Visgenx, and Vitranu. SVE is an employee at RegenxBio.
Comment in
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The promise of long-term treatment for neovascular age-related macular degeneration.Lancet. 2024 Apr 20;403(10436):1517-1519. doi: 10.1016/S0140-6736(24)00428-8. Epub 2024 Mar 27. Lancet. 2024. PMID: 38554724 No abstract available.
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