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Lancet. 2017 Aug 26;390(10097):849-860. doi: 10.1016/S0140-6736(17)31868-8. Epub 2017 Jul 14.

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

Author information

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.

Erratum in

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.

PMID:
28712537
PMCID:
PMC5726391
DOI:
10.1016/S0140-6736(17)31868-8
[Indexed for MEDLINE]
Free PMC Article

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