Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial

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

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 1·5 × 1011 vector genomes of voretigene neparvovec in 0·3 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 1·8 (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.

Conflict of interest statement

Declaration of interests

SR’s institution has received grants from Spark Therapeutics and he has provided presentations on behalf of Spark Therapeutics. DC and AD have received grants from Spark Therapeutics. JB has received grants from the Foundation Fighting Blindness, the National Institutes of Health, and Spark Therapeutics; non-financial support from the Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania, and the FM Kirby Foundation; has a provisional patent pending and a US patent licensed to Spark Therapeutics for which she has waived financial interest; and is a coauthor on a copyrighted visual function questionnaire used in the present study. JAW is an employee of and has equity/options in Spark Therapeutics; has received grants from the National Institutes of Health (specifically for Clinical and Translational Research Centre services); and has a patent pending pertaining to the primary endpoint measure licensed to Spark Therapeutics. DCC is an employee of Spark Therapeutics and has a patent pending pertaining to the primary endpoint measure licensed to Spark Therapeutics. Z-FY, AT, and JWi are employees of Statistics Collaborative, which provides statistical and regulatory consulting to Spark Therapeutics. JP is an employee of Westat, which was contracted by Spark Therapeutics. SM is a clinical coordinator of a study sponsored by Spark Therapeutics, receives salary support from the Center for Cellular and Molecular Therapeutics (CCMT) at The Children’s Hospital of Philadelphia, and has a patent pending licensed to Spark Therapeutics. KAM is a clinical coordinator of a study sponsored by Spark Therapeutics and received salary support from CCMT at Children’s Hospital of Philadelphia. JWa, TLK, and MD have received salary support from Spark Therapeutics and grants from the Carver Center for Macular Degeneration and Children’s Hospital of Philadelphia; TLK has received travel support from Spark Therapeutics. JAH has received consulting fees from Merck and Kalvista, grants from ThromboGenics, and serves on boards for Janssen and Celgene. ES’s institution has received grants from Children’s Hospital of Philadelphia and Spark Therapeutics. EHS has received grants from Oxford Biomedica. KW is an employee of and has equity/options with Spark Therapeutics and has received grants from the National Institutes of Health. FS has received grants from Regione Campania and serves on boards for Sanofi, Dompe Farmaceutici, and Spark Therapeutics. JFW has a patent and a patent pending, both licensed to Spark Therapeutics. KAH is an employee of Spark Therapeutics and has a patent pending pertaining to the primary endpoint measure. AMM has received grants from Spark Therapeutics, the National Institutes of Health, and the Foundation Fighting Blindness; non-financial support from the Center for Advanced Retinal and Ocular Therapeutics, University of Pennsylvania, and the FM Kirby Foundation; and has a provisional patent pending and a US patent licensed to Spark Therapeutics for which he has waived financial interest. OE, HR, LR, LAG, FPH, LD, XZ, VBM, WP, MW, CJ, DG, and BPL declare no competing interests.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Phase 3 trial design
Figure 1. Phase 3 trial design
Visual field and a visual function questionnaire were additional, protocol-specified efficacy endpoints. vg=vector genomes. MLMT=multi-luminance mobility test. BCVA=best-corrected visual acuity. FST=full-field light sensitivity threshold.
Figure 2. Trial profile
Figure 2. Trial profile
*Baseline optical coherence tomography findings included severe retinal atrophy or degeneration, with an almost complete absence of the photoreceptor layer in the macular area. The discontinuation decision was made before either the participant or the physician had been informed of the treatment assignment. †The participant discontinued due to personal reasons, and this decision was made before either the participant or the physician had been informed of the treatment assignment.
Figure 3. Mean bilateral MLMT lux score…
Figure 3. Mean bilateral MLMT lux score and white light FST for mITT population
(A) Mean bilateral MLMT lux score (p=0·0038) and (B) mean white light FST (both eyes; p=0·0004) by treatment arm and study visit for the mITT population. Bars denote SEs. FST=full-field light sensitivity threshold. mITT=modified intention-to-treat. MLMT=multi-luminance mobility test.
Figure 4. Mean change in BCVA in…
Figure 4. Mean change in BCVA in mITT population
Mean change (LogMAR; baseline minus each study visit) in BCVA (both eyes) by treatment arm and study visit using (A) Holladay (post-hoc p=0·27) and (B) Lange (post-hoc p=0·0469) for off-chart acuities in the mITT population. Bars denote SEs. BCVA=best-corrected visual acuity. mITT=modified intention-to-treat.

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