Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, open-label, unilateral dose escalation study.

IF 98.4 1区医学 Q1 MEDICINE, GENERAL & INTERNAL The Lancet Pub Date : 2024-09-07 DOI:10.1016/S0140-6736(24)01447-8

Paul Yang, Laura P Pardon, Allen C Ho, Andreas K Lauer, Dan Yoon, Shannon E Boye, Sanford L Boye, Alejandro J Roman, Vivian Wu, Alexandra V Garafalo, Alexander Sumaroka, Malgorzata Swider, Iryna Viarbitskaya, Tomas S Aleman, Mark E Pennesi, Christine N Kay, Kenji P Fujita, Artur V Cideciyan

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Abstract

Background: Leber congenital amaurosis 1 (LCA1), caused by mutations in GUCY2D, is a rare inherited retinal disease that typically causes blindness in early childhood. The aim of this study was to evaluate the safety and preliminary efficacy of ascending doses of ATSN-101, a subretinal AAV5 gene therapy for LCA1.

Methods: 15 patients with genetically confirmed biallelic mutations in GUCY2D were included in this phase 1/2 study. All patients received unilateral subretinal injections of ATSN-101. In the dose-escalation phase, three adult cohorts (n=3 each) were treated with three ascending doses: 1·0 × 10¹⁰ vg/eye (low dose), 3·0 × 10¹⁰ vg/eye (middle dose), and 1·0 × 10¹¹ vg/eye (high dose). In the dose-expansion phase, one adult cohort (n=3) and one paediatric cohort (n=3) were treated at the high dose. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs), and secondary endpoints included full-field stimulus test (FST) and best-corrected visual acuity (BCVA). A multi-luminance mobility test (MLMT) was also done. Data through the 12-month main study period are reported.

Findings: Patients were enrolled between Sept 12, 2019, and May 5, 2022. A total of 68 TEAEs were observed, 56 of which were related to the surgical procedure. No serious TEAE was related to the study drug. Ocular inflammation was mild and reversible with steroid treatment. For patients who received the high dose, mean change in dark-adapted FST was 20·3 decibels (dB; 95% CI 6·6 to 34·0) for treated eyes and 1·1 dB (-3·7 to 5·9) for untreated eyes at month 12 (white stimulus); improvements were first observed at day 28 and persisted over 12 months (p=0·012). Modest improvements in BCVA were also observed (p=0·10). Three of six patients who received the high dose and did the MLMT achieved the maximum score in the treated eye.

Interpretation: ATSN-101 is well tolerated 12 months after treatment, with no drug-related serious adverse events. Clinically significant improvements in retinal sensitivity were sustained in patients receiving the high dose.

Funding: Atsena Therapeutics.

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ATSN-101 对 GUCY2D 双重突变导致的 Leber 先天性羊角疯患者的安全性和疗效：1/2 期、多中心、开放标签、单侧剂量递增研究。

背景：由 GUCY2D 基因突变引起的 Leber 先天性无视力症 1 (LCA1)是一种罕见的遗传性视网膜疾病，通常会在儿童早期导致失明。本研究旨在评估ATSN-101（一种治疗LCA1的视网膜下AAV5基因疗法）递增剂量的安全性和初步疗效。所有患者均接受了单侧视网膜下注射 ATSN-101。在剂量递增阶段，三组成人患者（每组 3 人）接受了三个递增剂量的治疗：1-0 × 1010 vg/眼（低剂量）、3-0 × 1010 vg/眼（中剂量）和 1-0 × 1011 vg/眼（高剂量）。在剂量扩展阶段，一组成人（3 人）和一组儿童（3 人）接受了高剂量治疗。主要终点是治疗突发不良事件（TEAEs）的发生率，次要终点包括全视野刺激测试（FST）和最佳矫正视力（BCVA）。此外，还进行了多亮度移动性测试（MLMT）。报告了为期12个月的主要研究期间的数据：患者于2019年9月12日至2022年5月5日期间入组。共观察到 68 例 TEAE，其中 56 例与手术过程有关。没有严重的TEAE与研究药物有关。眼部炎症轻微，经类固醇治疗后可逆转。对于接受高剂量治疗的患者，在第12个月时（白色刺激），治疗眼的暗适应FST平均变化为20-3分贝（dB；95% CI为6-6至34-0），未治疗眼为1-1分贝（-3-7至5-9）；第28天时首次观察到改善，并持续12个月（P=0-012）。BCVA 也有轻微改善（p=0-10）。在接受高剂量治疗并进行MLMT的六名患者中，有三名患者的治疗眼达到了最高分：ATSN-101在治疗12个月后耐受性良好，未出现与药物相关的严重不良事件。接受高剂量治疗的患者视网膜灵敏度持续得到临床显着改善：Atsena Therapeutics。

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来源期刊

The Lancet 医学-医学：内科

CiteScore

148.10

自引率

0.70%

发文量

2220

审稿时长

3 months

期刊介绍： The Lancet is a world-leading source of clinical, public health, and global health knowledge. It was founded in 1823 by Thomas Wakley and has been an independent, international weekly general medical journal since then. The journal has an Impact Factor of 168.9, ranking first among 167 general and internal medicine journals globally. It also has a Scopus CiteScore of 133·2, ranking it second among 830 general medicine journals. The Lancet's mission is to make science widely available to serve and transform society, positively impacting people's lives. Throughout its history, The Lancet has been dedicated to addressing urgent topics, initiating debate, providing context for scientific research, and influencing decision makers worldwide.

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