Year 2 results for a phase 3 trial of voretigene neparvovec in biallelic RPE65-mediated inherited retinal disease

Abstract

Purpose : At year 1, subjects with biallelic RPE65-mediated inherited retinal disease (IRD) receiving voretigene neparvovec (VN) in a phase 3 gene therapy trial showed improved ambulatory navigation, light sensitivity, and visual field. We report year 2 results for the original intervention group (OI) as well as year 1 results for the original control group who received delayed intervention (DI).

Methods : Twenty-nine subjects with biallelic RPE65 gene mutations received bilateral, subretinal injections of VN. At Baseline, subjects were randomized 2:1, stratified for age and multi-luminance mobility test (MLMT) performance, and enrolled to an intervention or control group; after 1 year, the control group received VN. Endpoints included change in performance on MLMT at 7 standardized illumination levels, full-field light threshold sensitivity (FST), visual acuity (VA), Goldmann kinetic visual field (GVF), and Humphrey static visual field (HVF).

Results : MLMT mean (SD) bilateral change score was 1.9 levels (1.1) for OI subjects (n=20) at 2 years and 2.1 (1.6) for DI subjects (n=9) at 1 year, with 89% of DI subjects able to pass MLMT at the lowest light level. Change in white light FST averaged over both eyes was -2.27 log₁₀ (cd.s/m²) (1.65) at 2 years for OI subjects and -2.86 (1.49) at 1 year for DI subjects, nearly a 180% increase in light sensitivity for DI subjects. A trend toward improved Holladay VA averaged over both eyes was seen, with a 7.8-letter gain (-0.16 logMAR, SD 0.36) at 2 years for OI subjects and a 4.5-letter gain (-0.09 logMAR, SD 0.22) at 1 year for DI subjects. Mean change in sum total degrees on GVF III4e averaged over both eyes was 311.6 (SD 295.3) for OI subjects at 2 years and 194.3 (SD 244.7) for DI subjects at 1 year. Change in HVF macula threshold averaged over both eyes was a 6.45 db (SD 7.35) gain for OI subjects at 2 years and a 5.23 db (SD 9.92) gain for DI subjects at 1 year (Fig. 1).

Conclusions : Improvement in MLMT, FST, and visual field in DI subjects confirms the statistically significant 1-year results in OI subjects. Furthermore, improvement was maintained at 2 years in OI subjects. VN gene replacement improved ambulatory navigation, light sensitivity, and visual field size in subjects with biallelic RPE65-mediated IRD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.