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Interim Results From a Multicenter Observational Safety Study of Patients Treated With Voretigene Neparvovec-rzyl in the United States
Journal article   Peer reviewed

Interim Results From a Multicenter Observational Safety Study of Patients Treated With Voretigene Neparvovec-rzyl in the United States

Aaron Nagiel, Stephen R Russell, Byron L Lam, Jason I Comander, Tomas S Aleman, Cagri G Besirli, Robert A Sisk, Paul Yang, Christina Y Weng, Daniel C Chung, …
Ophthalmology (Rochester, Minn.)
07/22/2026
DOI: 10.1016/j.ophtha.2026.07.007
PMID: 42486371

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Abstract

To assess long-term safety and exploratory ophthalmic outcomes in patients treated with voretigene neparvovec-rzyl (VN) in US clinical practice. Prospective, multicenter, observational post-authorization safety study. Eighty-seven patients (169 eyes) receiving VN at 10 ocular gene therapy treatment centers. Eligible patients were ≥12 months old with viable retinal photoreceptors and received VN in ≥1 eye. Subretinal delivery followed a 3-port pars plana vitrectomy modified at surgeons' discretion (e.g., automated foot pedal delivery, pre-bleb injection, cannula cut, use of dye for visualization). Safety outcomes included treatment-emergent adverse events (TEAEs) and occurrence of chorioretinal atrophy (CRA). Exploratory assessments included changes in best-corrected visual acuity (BCVA) and full-field stimulus threshold (FST). Outcomes were analyzed descriptively; relative risk (RR) was estimated for subgroup comparisons. With a median 3.7 years of follow-up (range, 2.9-4.9), most patients (95%) reported ≥1 TEAE (387 events); 67% were procedure related, 9% were attributed to VN, and 82% were mild. CRA, including related terms retinal degeneration and retinal depigmentation, occurred in 24 patients (28%; 45 eyes), typically within 1 year, and was mild (80%) or moderate (20%). The area of CRA mostly localized to the retinotomy or bleb area, with 40% of eyes with CRA having atrophy outside the bleb area and highly correlated between fellow eyes (r=0.97; P<0.0001). CRA risk was higher with automated foot pedal administration of VN (RR, 5.33; 95% CI, 1.27-22.40) and in patients with myopia (RR, 8.40; 95% CI, 1.16-60.69). At 3 years, treated eyes showed sustained improvements in BCVA (-0.13 logMAR) and FST (-1.68 log cd·s/m ). BCVA and FST were comparable between CRA and non-CRA eyes, although a subset of CRA eyes showed greater FST improvement at most time points up to Year 3. This interim analysis supports the long-term safety of VN in a real-world US cohort, consistent with clinical trial results. CRA did not appear to diminish sustained functional and anatomical benefits with a minimum follow-up of nearly 3 years. Ongoing data collection will further clarify the occurrence, impact, and risk factors for CRA while continuing to monitor VN safety in clinical practice.
 Gene Therapy Voretigene neparvovec-rzyl Retinal dystrophy RPE65 Inherited retinal disease

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