PMID- 33798654 OWN - NLM STAT- MEDLINE DCOM- 20211123 LR - 20211123 IS - 1549-4713 (Electronic) IS - 0161-6420 (Linking) VI - 128 IP - 10 DP - 2021 Oct TI - Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease: Phase 3 Results at 3 and 4 Years. PG - 1460-1468 LID - S0161-6420(21)00236-0 [pii] LID - 10.1016/j.ophtha.2021.03.031 [doi] AB - PURPOSE: To determine whether functional vision and visual function improvements after voretigene neparvovec (VN; Luxturna [Spark Therapeutics, Inc]) administration in patients with biallelic RPE65 mutation-associated inherited retinal disease are maintained at 3 to 4 years and to review safety outcomes. DESIGN: Open-label, randomized, controlled phase 3 trial. PARTICIPANTS: Thirty-one individuals were enrolled and randomized 2:1 to intervention (n = 21) or control (n = 10). One participant from each group withdrew before, or at, randomization. METHODS: Patients in the original intervention (OI) group received bilateral subretinal VN injections. Delayed intervention (DI) patients served as control participants for 1 year then received VN. MAIN OUTCOME MEASURES: Change from injection baseline in bilateral performance on the multiluminance mobility test (MLMT), a measure of ambulatory navigation, and change from injection baseline in full-field light sensitivity threshold white light, visual field (VF), and visual acuity (VA). RESULTS: Mean bilateral MLMT change scores at year 4 for OI patients and year 3 for DI patients were 1.7 and 2.4, respectively, with 71% of patients with a year 3 visit able to pass MLMT at the lowest light level. Mean change in full-field light sensitivity threshold white light, averaged over both eyes at year 4 for OI patients and year 3 for DI patients, was -1.90 log(10)(cd.s/m(2)) and -2.91 log(10)(cd.s/m(2)), respectively. Mean change in Goldmann kinetic VF III4e sum total degrees, averaged across both eyes, was 197.7 at year 4 for OI patients and 157.9 at year 3 for DI patients. Mean change in VA (Holladay scale), averaged across both eyes, was -0.003 logarithm of the minimum angle of resolution (logMAR) at year 4 for OI patients and -0.06 logMAR at year 3 for DI patients. One OI patient experienced retinal detachment at approximately year 4 that impacted VA for the OI group. No product-related serious adverse events (AEs) occurred, nor did any 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 to 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 serious AEs reported. CI - Copyright (c) 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. FAU - Maguire, Albert M AU - Maguire AM AD - Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular and Molecular Therapeutics, Inc., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Electronic address: amaguire@pennmedicine.upenn.edu. FAU - Russell, Stephen AU - Russell S AD - Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, University of Iowa, Iowa City, Iowa. FAU - Chung, Daniel C AU - Chung DC AD - Spark Therapeutics, Inc., Philadelphia, Pennsylvania. FAU - Yu, Zi-Fan AU - Yu ZF AD - SparingVision, Philadelphia, Pennsylvania. FAU - Tillman, Amy AU - Tillman A AD - SparingVision, Philadelphia, Pennsylvania. FAU - Drack, Arlene V AU - Drack AV AD - Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, University of Iowa, Iowa City, Iowa. FAU - Simonelli, Francesca AU - Simonelli F AD - Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy. FAU - Leroy, Bart P AU - Leroy BP AD - Division of Ophthalmology and Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Ophthalmology and Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium. FAU - Reape, Kathleen Z AU - Reape KZ AD - Spark Therapeutics, Inc., Philadelphia, Pennsylvania. FAU - High, Katherine A AU - High KA AD - Spark Therapeutics, Inc., Philadelphia, Pennsylvania. FAU - Bennett, Jean AU - Bennett J AD - Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular and Molecular Therapeutics, Inc., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. LA - eng PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial DEP - 20210330 PL - United States TA - Ophthalmology JT - Ophthalmology JID - 7802443 RN - EC 3.1.1.64 (retinoid isomerohydrolase) RN - EC 5.2.- (cis-trans-Isomerases) SB - IM MH - Adolescent MH - Adult MH - Child MH - Child, Preschool MH - Female MH - Follow-Up Studies MH - Genetic Therapy/*methods MH - Genetic Vectors/*administration & dosage MH - Humans MH - Injections, Intraocular MH - Male MH - *Mutation MH - Retina MH - Retinal Dystrophies/*drug therapy/genetics/metabolism MH - Time Factors MH - Treatment Outcome MH - *Visual Acuity MH - Visual Fields MH - Young Adult MH - cis-trans-Isomerases/*administration & dosage/genetics/metabolism OTO - NOTNLM OT - RPE65 OT - gene augmentation OT - inherited retinal disease OT - voretigene neparvovec EDAT- 2021/04/03 06:00 MHDA- 2021/11/24 06:00 CRDT- 2021/04/02 20:13 PHST- 2020/11/18 00:00 [received] PHST- 2021/03/12 00:00 [revised] PHST- 2021/03/25 00:00 [accepted] PHST- 2021/04/03 06:00 [pubmed] PHST- 2021/11/24 06:00 [medline] PHST- 2021/04/02 20:13 [entrez] AID - S0161-6420(21)00236-0 [pii] AID - 10.1016/j.ophtha.2021.03.031 [doi] PST - ppublish SO - Ophthalmology. 2021 Oct;128(10):1460-1468. doi: 10.1016/j.ophtha.2021.03.031. Epub 2021 Mar 30.