Goal To determine whether ambulatory navigation, light sensitivity, and visual field (VF) improvements 1 year after voretigene neparvovec (VN) administration in patients with biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD) are maintained at 5 years and review safety outcomes over the entire period.

Methods This is an open label, randomized, controlled Phase III trial performed at 2 sites in the United States. Patients were randomized to either original intervention (OI: bilateral subretinal VN at baseline; n=20) or delayed intervention (DI: VN after 1 year; n=9). The primary endpoint was bilateral performance on the Multi-Luminance Mobility Test (MLMT) at 7 standard light levels as measured by a change in score. Additional endpoints were full-field light sensitivity threshold (FST) testing, visual acuity (VA), and Goldmann kinetic VF (GVF), each averaged over both eyes. Safety outcomes included adverse event reporting, laboratory testing, and changes in physical and ophthalmic examinations.

Results For OI patients at Year 5 (n=18) and DI patients at Year 4 (n=8), the mean (standard deviation) MLMT bilateral light level score change was 1.6 (1.1) and 2.4 (1.5) levels, respectively, compared with baseline. Subsequent to the 1-year outcomes, a change of 1 light level occurred in 6 patients (none were below pre-treatment performance) and no change in the remaining 20 (N=26). Mean change in white light FST in log10 (cd.s/m2) averaged over both eyes was −2.02 (1.45) log10 at Year 5 for OI patients (n=17) and −2.58 (1.04) log10 at Year 4 for DI patients (n=8). Mean change in VA (Holladay Scale) averaged over both eyes (logMAR was −0.00 (0.64) at Year 5 for OI patients (n=18) and −0.06 (0.26) at Year 4 for DI patients (n=8). Mean change in GVF III4e sum total degrees averaged over both eyes was 166.6 (208.7) at Year 5 for OI patients (n=15) and 178.8 (241.9) at Year 4 for DI patients (n=8). Five years after treatment, the safety profile (N=29) was consistent with vitrectomy and subretinal injection procedure with 2 reports of cataract, 1 of ptosis, and 1 new report of retinal detachment since the last update. No deleterious immune responses were reported.

Conclusion Improvements in ambulatory navigation, light sensitivity, and VF are maintained for at least 5 years after VN administration in most OI patients.

Improvements in DI patients were consistent with those observed in OI patients. The safety profile of VN is consistent with the administration procedure.