Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study

• Published in: The Lancet (British edition) 2024-04, Vol.403 (10436), p.1563-1573
• Main Authors: Campochiaro, Peter A, Avery, Robert, Brown, David M, Heier, Jeffrey S, Ho, Allen C, Huddleston, Stephen M, Jaffe, Glenn J, Khanani, Arshad M, Pakola, Stephen, Pieramici, Dante J, Wykoff, Charles C, Van Everen, Sherri
• Format: Article
• Language: English
• Subjects: Acuity; Age; Age related diseases; Angiogenesis Inhibitors - therapeutic use; Antibodies; Antigens; Aqueous humour; Cataracts; Clinical medicine; Clinical trials; Exudation; Eye; Eye diseases; Gene therapy; Genetic Therapy - methods; Genomes; Growth factors; Humans; Immune response; Injection; Macular degeneration; Observational studies; Proteins; Ranibizumab; Retina; Risk reduction; Safety; Treatment Outcome; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vision; Visual acuity; Wet Macular Degeneration - drug therapy
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(24)00310-6

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. 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. 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