Five-Year Update for the Phase III Voretigene Neparvovec Study in Biallelic RPE65 Mutation–Associated Inherited Retinal Disease - EAP 2021 Virtual Congress and MasterCourse

Bart Leroy ^1,2 Stephen R. Russell ³ Jean Bennett ^2,4 Katherine A. High ⁵ Arlene V. Drack ⁶ Zi-Fan Yu ⁷ Amy Tillman ⁷ Daniel Chung ⁵ Kathleen Z. Reape ⁵ Albert M. Maguire ^3,4

¹Department of Ophthalmology & Center for Medical Genetics Ghent, Ghent University & Ghent University Hospital, Ghent, Belgium
²Department of Ophthalmology, Children’s Hospital of Philadelphia, Philadelphia, USA
³Institute for Vision Research, University of Iowa, Iowa City, USA
⁴Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
⁵Spark Therapeutics, Inc., Ophthalmology, Philadelphia, USA
⁶Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, USA
⁷Statistics Collaborative, Inc., Biostatistics, Washington, DC, USA

Background: Voretigene neparvovec (VN) is the first ocular gene therapy approved for the treatment of patients with visual impairment due to confirmed biallelic RPE65 mutation-associated retinal dystrophy.

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

Methods: Patients were randomized to either original intervention (OI: bilateral subretinal VN at baseline; n=20) or delayed intervention (DI: VN after 1Y; n=9). The primary endpoint was bilateral performance on the Multi-Luminance Mobility Test (MLMT) at 7 standard light levels measured by change score. Additional endpoints were full-field light sensitivity threshold (FST) testing, visual acuity (VA), Goldmann kinetic VF (GVF), each averaged over both eyes, and safety outcomes.

Results: Mean (standard deviation [SD]) MLMT bilateral light level change scores were 1.6 (1.1) and 2.4 (1.5) at Y5 (OI; n=18) and Y4 (DI; n=8), respectively, compared with baseline. Subsequent to Y1 outcomes, a change of 1 light level occurred in 6 patients with no change in others (N=26). Mean (SD) white light FST change (in log10 [cd.s/m2]) was −2.02 (1.45) at Y5 (OI; n=17) and −2.58 (1.04) atY4 (DI; n=8). Mean (SD) VA (Holladay Scale) change (in logMAR) was −0.00 (0.64) at Y5 (OI; n=18) and −0.06 (0.26) at Y4 (DI; n=8). Mean (SD) GVF III4e change (in sum total degrees) was 166.6 (208.7) at Y5 (OI; n=15) and 178.8 (241.9) at Y4 (DI; n=8). Five years post-treatment, safety profile (N=29) was consistent with surgical administration procedures with no deleterious immune responses.

Conclusion: Improvements in MLMT, FST, and GVF were maintained at Y5 post-VN administration. Improvements in DI group were consistent with those observed in OI. The safety profile of VN is consistent with the administration procedure.