@article {625, 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.}, journal = {Lancet}, volume = {390}, year = {2017}, month = {2017 Aug 26}, pages = {849-860}, 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 (<10 years and >=10 years) and baseline mobility testing passing level (pass at >=125 lux vs <125 lux). Graders assessing primary outcome were masked to treatment group. Intervention was bilateral, subretinal injection of 1{\textperiodcentered}5 {\texttimes} 10vector genomes of voretigene neparvovec in 0{\textperiodcentered}3 mL total volume. The primary efficacy endpoint was 1-year change in MLMT performance, measuring functional vision at specified light levels. The intention-to-treat (ITT) and modified ITT populations were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00999609, and enrolment is complete.

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{\textperiodcentered}8 (SD 1{\textperiodcentered}1) light levels in the intervention group versus 0{\textperiodcentered}2 (1{\textperiodcentered}0) in the control group (difference of 1{\textperiodcentered}6, 95\% CI 0{\textperiodcentered}72-2{\textperiodcentered}41, p=0{\textperiodcentered}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.

}, issn = {1474-547X}, doi = {10.1016/S0140-6736(17)31868-8}, author = {Russell, Stephen and Bennett, Jean and Wellman, Jennifer A and Chung, Daniel C and Yu, Zi-Fan and Tillman, Amy and Wittes, Janet and Pappas, Julie and Elci, Okan and McCague, Sarah and Cross, Dominique and Marshall, Kathleen A and Walshire, Jean and Kehoe, Taylor L and Reichert, Hannah and Davis, Maria and Raffini, Leslie and George, Lindsey A and Hudson, F Parker and Dingfield, Laura and Zhu, Xiaosong and Haller, Julia A and Sohn, Elliott H and Mahajan, Vinit B and Pfeifer, Wanda and Weckmann, Michelle and Johnson, Chris and Gewaily, Dina and Drack, Arlene and Stone, Edwin and Wachtel, Katie and Simonelli, Francesca and Leroy, Bart P and Wright, J Fraser and High, Katherine A and Maguire, Albert M} }