Efficacy and Safety of Voretigene Neparvovec in RPE65 -Retinopathy: Results of a Phase III Trial in Japan.
Fujinami Kaoru, Akiyama Kunihiko, Tsunoda Kazushige, Ito Saori, Seko Noriko, Yamamoto Shuichi
AI Summary
Voretigene neparvovec gene therapy improved light sensitivity and visual fields in Japanese RPE65-retinopathy patients over one year, with a good safety profile, supporting its broader clinical use.
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 × 10 11 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) log 10 (cd.s/m 2 ) 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.
Shields Classification
Key Concepts4
Voretigene neparvovec (VN) gene therapy resulted in a mean improvement in full-field light sensitivity threshold (FST) of -1.831 (-3.54 to -0.56) log10 (cd.s/m2) from baseline to year 1 after treatment in 4 Japanese patients with RPE65-retinopathy.
Voretigene neparvovec (VN) gene therapy resulted in a mean change in visual field (VF) as measured by Goldmann kinetic perimetry (GP III4e) of 427.8 (-11 to 1014) sum total degrees from baseline to year 1 in 4 Japanese patients with RPE65-retinopathy.
No adverse events, including one serious adverse event (ovarian cyst torsion), were judged to be related to voretigene neparvovec (VN) gene therapy in 4 Japanese patients with RPE65-retinopathy.
The mean change in best-corrected visual acuity (BCVA) in logarithm of the minimum angle of resolution (LogMAR) unit after voretigene neparvovec (VN) gene therapy was -0.033 (-0.15 to 0.17) LogMAR from baseline to year 1 in 4 Japanese patients with RPE65-retinopathy.
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