Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease: Phase 3 Results at 3 Years and 4 Years.

Objective To determine whether functional vision and visual function improvements after voretigene neparvovec (VN; LUXTURNA®, Spark Therapeutics, Inc.) administration in subjects with biallelic RPE65 mutation-associated inherited retinal disease are maintained at 3-4 years, and to review safety outcomes. Design Open-label, randomized, controlled phase 3 trial. Subjects Thirty-one individuals were enrolled and randomized 2:1 to intervention (n=21) or control (n=10). One subject from each group withdrew before, or at, randomization. Methods Subjects in the original intervention (OI) group received bilateral subretinal VN injections. Delayed intervention (DI) subjects served as controls for 1 year, then received VN. Main outcome measures Change from injection baseline in bilateral performance on the multi-luminance mobility test (MLMT), a measure of ambulatory navigation, and change from injection baseline in full-field light sensitivity threshold (FST) white light, visual field (VF), and visual acuity (VA). Results Mean bilateral MLMT change scores at Year 4 for OI subjects and at Year 3 for DI subjects were 1.7 and 2.4 respectively, with 71% of subjects with a Year 3 visit able to pass MLMT at the lowest light level. Mean change in FST white light, averaged over both eyes at Year 4 for OI subjects, and at Year 3 for DI subjects, was -1.90 log10(cd.s/m2) and -2.91 log10(cd.s/m2), respectively. Mean change in Goldmann kinetic VF III4e sum total degrees, averaged across both eyes, was 197.7 at Year 4 for OI subjects and 157.9 at Year 3 for DI subjects. Mean change in VA (Holladay scale), averaged across both eyes, was -0.003 logMAR at Year 4 for OI subjects and -0.06 logMAR at Year 3 for DI subjects. One OI subject had a retinal detachment around Year 4, which impacted VA for the OI group. No product-related serious adverse events (SAEs) occurred, and there were no deleterious immune responses. Conclusions Improvements in ambulatory navigation, light sensitivity, and VF were consistent in both intervention groups. Overall, improvements were maintained up to 3-4 years, with ongoing observation. The safety profile of VN was consistent with vitrectomy and the subretinal injection procedure, and was similar between intervention groups, with no product-related SAEs reported.