Title | Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Russell, Stephen, Bennett Jean, Wellman Jennifer A., Chung Daniel C., Yu Zi-Fan, Tillman Amy, Wittes Janet, Pappas Julie, Elci Okan, McCague Sarah, Cross Dominique, Marshall Kathleen A., Walshire Jean, Kehoe Taylor L., Reichert Hannah, Davis Maria, Raffini Leslie, George Lindsey A., F Hudson Parker, Dingfield Laura, Zhu Xiaosong, Haller Julia A., Sohn Elliott H., Mahajan Vinit B., Pfeifer Wanda, Weckmann Michelle, Johnson Chris, Gewaily Dina, Drack Arlene, Stone Edwin, Wachtel Katie, Simonelli Francesca, Leroy Bart P., J Wright Fraser, High Katherine A., and Maguire Albert M. |
Journal | Lancet |
Volume | 390 |
Issue | 10097 |
Pagination | 849-860 |
Date Published | 2017 Aug 26 |
ISSN | 1474-547X |
Abstract | BACKGROUND: Phase 1 studies have shown potential benefit of gene replacement in RPE65-mediated inherited retinal dystrophy. This phase 3 study assessed the efficacy and safety of voretigene neparvovec in participants whose inherited retinal dystrophy would otherwise progress to complete blindness. METHODS: In this open-label, randomised, controlled phase 3 trial done at two sites in the USA, individuals aged 3 years or older with, in each eye, best corrected visual acuity of 20/60 or worse, or visual field less than 20 degrees in any meridian, or both, with confirmed genetic diagnosis of biallelic RPE65 mutations, sufficient viable retina, and ability to perform standardised multi-luminance mobility testing (MLMT) within the luminance range evaluated, were eligible. Participants were randomly assigned (2:1) to intervention or control using a permuted block design, stratified by age ( FINDINGS: Between Nov 15, 2012, and Nov 21, 2013, 31 individuals were enrolled and randomly assigned to intervention (n=21) or control (n=10). One participant from each group withdrew after consent, before intervention, leaving an mITT population of 20 intervention and nine control participants. At 1 year, mean bilateral MLMT change score was 1·8 (SD 1·1) light levels in the intervention group versus 0·2 (1·0) in the control group (difference of 1·6, 95% CI 0·72-2·41, p=0·0013). 13 (65%) of 20 intervention participants, but no control participants, passed MLMT at the lowest luminance level tested (1 lux), demonstrating maximum possible improvement. No product-related serious adverse events or deleterious immune responses occurred. Two intervention participants, one with a pre-existing complex seizure disorder and another who experienced oral surgery complications, had serious adverse events unrelated to study participation. Most ocular events were mild in severity. INTERPRETATION: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable. FUNDING: Spark Therapeutics. |
DOI | 10.1016/S0140-6736(17)31868-8 |
Alternate Journal | Lancet |
PubMed ID | 28712537 |
PubMed Central ID | PMC5726391 |
Grant List | DP1 EY023177 / EY / NEI NIH HHS / United States T32 HL007150 / HL / NHLBI NIH HHS / United States |