Efficacy and Safety of Voretigene Neparvovec in RPE65-Retinopathy: Results of a Phase III Trial in Japan

Abstract

Purpose: We report the efficacy and safety of voretigene neparvovec (VN) as an adeno-associated viral vector-based gene therapy for Japanese patients with inherited retinal dystrophy caused by biallelic pathogenic RPE65 variants (RPE65-retinopathy).

Design: Open-label, single arm, phase III clinical trial.

Participants: Four subjects were recruited based on the following criteria: (1) a clinical and molecular genetic diagnosis of RPE65-retinopathy; (2) age ≥4 years; (3) a best-corrected VA (BCVA) worse than 20/60 or a visual field (VF) <20° by a III4e isopter or equivalent; and (4) sufficient viable retinal cells by OCT or ophthalmoscopy.

Methods: All subjects received subretinal injections of VN (1.5 × 10¹¹ vg in 0.3 mL) after vitrectomy in both eyes.

Main outcome measures: The primary efficacy end point was a change from baseline in full-field light sensitivity threshold (FST) (white light, averaged over both eyes) at days 30, 90, 180, 270, and year 1. The secondary efficacy end points included changes from baseline in VF testing by Goldmann kinetic perimetry (GP) and BCVA in the logarithm of the minimum angle of resolution (LogMAR) unit. Safety was evaluated by adverse events (AEs), laboratory evaluations, and opthalmic examinations.

Results: The mean baseline age of 4 subjects was 31.3 years (10, 17, 49, and 49 years). The homozygous pathogenic variants (c.1543C>T, p.Arg515Trp) were identified in 3 subjects. The mean (range) FST averaged over both eyes improved by -1.831 (-3.54 to -0.56) log₁₀(cd.s/m²) from baseline to year 1 after treatment. The mean changes in VF as measured by (GP III4e) and LogMAR BCVA, averaged across both eyes, were 427.8 (-11 to 1014) sum total degrees and -0.033 (-0.15 to 0.17) LogMAR from baseline to year 1, respectively. None of the AEs, including one serious AE (ovarian cyst torsion), were judged to be related to VN.

Conclusions: Overall, these data from a phase III trial showed improvements in FST and VF and well-tolerated safety profiles of VN for 1 year, with ongoing follow-up of up to 5 years in Japanese patients with RPE65-retinopathy. These results support the further applicability of VN to the Japanese population.

Financial disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Electrophysiology; Full-field stimulus test; Gene therapy; RPE65; Voretigene neparvovec.

Figure 1

Study design of the phase III trial in Japan. An open-label phase III clinical trial (NCT04516369) was approved by the PMDA in Japan. Target sample size: ≥1 and up to 4 participants. Observation period: 5 years in total; 1-year interim analysis to evaluate the efficacy and safety of voretigene neparvovec in Japanese participants. PMDA = Pharmaceuticals and Medical Devices Agency.

Figure 2

Full-field light sensitivity thresholds or full-field stimulus test, kinetic visual fields, and best-corrected visual acuity. The mean full-field light sensitivity threshold (FST) (white light, averaged of both eyes), mean VF detected by Goldmann kinetic perimetry (averaged over both eyes), and best-corrected visual acuity in the LogMAR unit, mean Intervals are ± 1 SE. BL = baseline; D = day; LogMAR = logarithm of the minimum angle of resolution; SE = standard error; VF = visual field; Y = year.