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

IF 4.6 Q1 OPHTHALMOLOGY

Ophthalmology science Pub Date : 2025-07-07 DOI:10.1016/j.xops.2025.100876

Kaoru Fujinami MD, PhD , Kunihiko Akiyama MD, PhD , Kazushige Tsunoda MD, PhD , Saori Ito , Noriko Seko PhD , Shuichi Yamamoto MD, PhD

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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 Disclosure(s)

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

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Voretigene Neparvovec治疗rpe65视网膜病变的疗效和安全性：日本一项III期试验的结果

目的研究voretigene neparvovec （VN）作为一种腺相关病毒载体基因疗法治疗由双等位基因致病性RPE65变异引起的遗传性视网膜营养不良（RPE65-retinopathy）的有效性和安全性。设计：pen-label，单组，III期临床试验。参与者根据以下标准招募4名受试者：(1)临床和分子遗传学诊断为rpe65 -视网膜病变；(2)年龄≥4岁；(3)经最佳矫正的视差（BCVA）小于20/60，或视场（VF）小于20°，由III4e等视差器或同等视差器矫正；(4)通过OCT或眼科检查发现足够的活视网膜细胞。方法所有患者均在玻璃体切除术后接受视网膜下注射VN （1.5 × 1011vg, 0.3 mL）。主要结局指标：主要疗效终点是在第30天、90天、180天、270天和第1年的全视野光敏阈值（白光，双眼平均）较基线的变化。次要疗效终点包括Goldmann动力学视野（GP）和BCVA最小分辨角（LogMAR）单位对数的VF测试与基线的变化。通过不良事件（ae）、实验室评估和眼科检查来评估安全性。结果4例患者的平均基线年龄为31.3岁（10岁、17岁、49岁和49岁）。在3名受试者中发现纯合致病变异（c.1543C>；T, p.Arg515Trp）。双眼平均FST（范围）提高了- 1.831(- 3.54至- 0.56)log10（cd）。S /m2)，从基线到治疗后1年。通过（GP iii - 4e）和LogMAR BCVA测量的双眼VF平均变化，从基线到第1年分别为427.8（- 11至1014）和- 0.033(- 0.15至0.17)LogMAR总度。所有AE（包括1例严重AE（卵巢囊肿扭转））均未被判断为与VN有关。总的来说，这些来自III期试验的数据显示，日本rpe65视网膜病变患者的FST和VF得到改善，VN的耐受性良好，持续1年，随访时间长达5年。这些结果支持VN进一步适用于日本人口。财务披露专有或商业披露可在本文末尾的脚注和披露中找到。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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