Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy Results of Phase 1 and 3 Trials
Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy Results of Phase 1 and 3 Trials
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DOI：
10.1016/j.ophtha.2019.06.017
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发表时间：
2019-09-01
期刊：
影响因子：
13.7
通讯作者：
Bennett, Jean
中科院分区：
文献类型：
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作者：
Maguire, Albert M.;Russell, Stephen;Bennett, Jean
目的：报告基于voretigene neparvovec-rzyl（VN）腺相关病毒载体的基因疗法治疗RPE 65突变相关遗传性视网膜营养不良（IRD）的持久性，包括第4年的1期随访研究和第2年的3期研究的结果。设计：开放标签1期随访临床试验和开放标签、随机、对照3期临床试验。在试验期间，40例受试者至少1只眼睛接受了1.5 x 10（11）个VN载体基因组（vg），包括11例I期随访受试者和29例III期受试者（20例原始干预[OI]和9例对照/干预[CI]）。在第1阶段随访受试者的第二只眼睛和第3阶段受试者的两只眼睛中视网膜下注射VN。1期和3期研究的共同终点包括在评价的照度范围内多亮度迁移率测试（MLMT）的性能变化、全场光敏度阈值（FST）测试，最佳矫正视力（BCVA）安全性终点包括不良事件报告、眼科检查、体格检查和实验室检查。是说（标准差）MLMT lux评分变化为2.4（4年时为1.3，相比之下为2.6）（1.6）在1期随访受试者（n = 8）中给药后1年，1.9 OI受试者（n = 20）给药后2年和1年分别为1.1（1.1）和1.9（1.0），CI受试者（n = 9）给药后1年分别为2.1（1.6）。所有3组的FST均保持了平均改善，反映了1年和随后可用的随访访视时光敏感性改善超过2 log（10）（cd.s/m（2））。的安全性是一致的玻璃体切除术和视网膜下注射程序，并没有有害的免疫反应occurrency.Conclusions：VN基因增强治疗后，有一个有利的利益与风险的配置文件与类似的改善表现在导航能力和光敏感性3组的主题与RPE 65突变相关的IRD，退行性疾病，进展到完全失明。安全性特征与给药程序一致。这些数据表明，这种作用在VN给药后30天几乎达到最大，持续4年，观察仍在进行中。(C)2019年美国眼科学会。
Purpose: To report the durability of voretigene neparvovec-rzyl (VN) adeno-associated viral vector-based gene therapy for RPE65 mutation-associated 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 1.5 x 10(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 = 8), 1.9 (1.1) at 2 years, and 1.9 (1.0) at 1 year post-administration in OI subjects (n = 20), and 2.1 (1.6) at 1 year post-administration in CI subjects (n = 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 mutation-associated 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. (C) 2019 by the American Academy of Ophthalmology.