Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation–Associated Inherited Retinal Dystrophy

Abstract

Purpose: To report the durability of voretigene neparvovec-rzyl (VN) adeno-associated viral vectorebased gene therapy for RPE65 mutationeassociated inherited retinal dystrophy (IRD), including results of a phase 1 follow-on study at year 4 and phase 3 study at year 2.Design: Open-label phase 1 follow-on clinical trial and open-label, randomized, controlled phase 3 clinical trial.Participants: Forty subjects who received 1.5Â10 11 vector genomes (vg) of VN per eye in at least 1 eye during the trials, including 11 phase 1 follow-on subjects and 29 phase 3 subjects (20 original intervention [OI] and 9 control/intervention [CI]).Methods: Subretinal injection of VN in the second eye of phase 1 follow-on subjects and in both eyes of phase 3 subjects.Main Outcome Measures: End points common to the phase 1 and phase 3 studies included change in performance on the Multi-Luminance Mobility Test (MLMT) within the illuminance range evaluated, full-field light sensitivity threshold (FST) testing, and best-corrected visual acuity (BCVA). Safety end points included adverse event reporting, ophthalmic examination, physical examination, and laboratory testing.Results: Mean (standard deviation) MLMT lux score change was 2.4 (1.3) at 4 years compared with 2.6 (1.6) at 1 year after administration in phase 1 follow-on subjects (n ¼ 8), 1.9 (1.1) at 2 years, and 1.9 (1.0) at 1 year postadministration in OI subjects (n ¼ 20), and 2.1 (1.6) at 1 year post-administration in CI subjects (n ¼ 9). All 3 groups maintained an average improvement in FST, reflecting more than a 2 log 10 (cd.s/m 2 ) improvement in light sensitivity at 1 year and subsequent available follow-up visits. The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no deleterious immune responses occurred.Conclusions: After VN gene augmentation therapy, there was a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity among 3 groups of subjects with RPE65 mutationeassociated IRD, a degenerative disease that progresses to complete blindness. The safety profile is consistent with the administration procedure. These data suggest that this effect, which is nearly maximal by 30 days after VN administration, is durable for 4 years, with observation ongoing.

An Economic Evaluation of Voretigene Neparvovec for the Treatment of Biallelic RPE65-Mediated Inherited Retinal Dystrophies in the UK

“…In earlier phase I trials, improvements in vision following treatment were maintained through to the latest published follow-up time points (7.5 and 4 years), providing supporting evidence on the durability of the treatment effect [20,21].…”

Findings from a Genotyping Study of over 1000 People with Inherited Retinal Disorders in Ireland

“…This was subsequently expanded to include a milder, dominant form of retinopathy and more recently, to include less severe autosomal recessive retinopathies [35,37]. Luxturna, the first ocular gene therapy approved by the FDA, is for biallelic RPE65 retinal disease [16]. RPE65 c.1430A>G (p.Asp477Gly) remains the predominant RPE65 genotype observed in the Irish population.…”

“…It is of note that aberrant RNA splicing has been shown to have a major pathogenic effect in a knock-in mouse model with this variant [71]. Given the success of the gene therapy treatment of biallelic RPE65 retinopathies with Luxturna [16], an AAV-based therapy, it is interesting to speculate whether the therapy might have any utility for monoallelic dominant RPE65 cases.…”

Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

“…[5][6][7] Some clinical trials of adeno-associated viral vector-based gene therapy for RPE65-related IRD have reported sustained visual improvements lasting up to at least 4 years after treatment. 24,25 However, other follow-up studies revealed that after 3 years, despite initial improvement in visual function, gene therapy failed to halt or even slow photoreceptor degeneration in these patients. [24][25][26][27][28][29] Three hypotheses have been proposed to explain why the results of gene supplementation during longterm follow up may be disappointing for these chronic conditions.…”

“…24,25 However, other follow-up studies revealed that after 3 years, despite initial improvement in visual function, gene therapy failed to halt or even slow photoreceptor degeneration in these patients. [24][25][26][27][28][29] Three hypotheses have been proposed to explain why the results of gene supplementation during longterm follow up may be disappointing for these chronic conditions. First, expression of the delivered gene may have been too low in humans, perhaps as a result of poor transduction due to inefficient gene delivery and/or transcriptional silencing of the therapeutic transgene despite robust transduction.…”