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

  • Lancet. 2017 Aug 26;390(10097):849-860. doi: 10.1016/S0140-6736(17)31868-8.
Stephen Russell  1 ,  Jean Bennett  2 ,  Jennifer A Wellman  3 ,  Daniel C Chung  3 ,  Zi-Fan Yu  4 ,  Amy Tillman  4 ,  Janet Wittes  4 ,  Julie Pappas  5 ,  Okan Elci  5 ,  Sarah McCague  6 ,  Dominique Cross  6 ,  Kathleen A Marshall  6 ,  Jean Walshire  7 ,  Taylor L Kehoe  7 ,  Hannah Reichert  7 ,  Maria Davis  7 ,  Leslie Raffini  8 ,  Lindsey A George  8 ,  F Parker Hudson  9 ,  Laura Dingfield  10 ,  Xiaosong Zhu  8 ,  Julia A Haller  11 ,  Elliott H Sohn  12 ,  Vinit B Mahajan  12 ,  Wanda Pfeifer  7 ,  Michelle Weckmann  13 ,  Chris Johnson  12 ,  Dina Gewaily  14 ,  Arlene Drack  12 ,  Edwin Stone  15 ,  Katie Wachtel  3 ,  Francesca Simonelli  16 ,  Bart P Leroy  17 ,  J Fraser Wright  3 ,  Katherine A High  3 ,  Albert M Maguire  2
Affiliations
  • 1. Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA. Electronic address: [email protected].
  • 2. Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 3. Spark Therapeutics, Philadelphia, PA, USA.
  • 4. Statistics Collaborative, Washington, DC, USA.
  • 5. Westat Biostatistics and Data Management Core, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 6. Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 7. University of Iowa Health Care, Iowa City, Iowa, USA.
  • 8. Department of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 9. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 10. Division of General Internal Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 11. Wills Eye Hospital and Department of Ophthalmology, Jefferson Medical College, Thomas Jefferson University and Thomas Jefferson University Hospitals, Philadelphia, PA, USA.
  • 12. Department of Ophthalmology and Visual Sciences, University of Iowa, Carver College of Medicine, Iowa City, IA, USA.
  • 13. Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, IA, USA.
  • 14. Philadelphia Retina Associates, Philadelphia, PA, USA.
  • 15. Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA.
  • 16. Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy.
  • 17. Division of Ophthalmology and Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Ophthalmology, Ghent University Hospital, Ghent, Belgium.
PMID: 28712537 DOI: 10.1016/S0140-6736(17)31868-8
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.