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

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

Affiliations

  • 1 Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA. Electronic address: steve-russell@uiowa.edu.
  • 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.

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