Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Cellular and Molecular Therapeutics, Inc., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Department of Ophthalmology and Visual Sciences, University of Iowa Institute for Vision Research, University of Iowa, Iowa City, Iowa.
Ophthalmology. 2019 Sep;126(9):1273-1285. doi: 10.1016/j.ophtha.2019.06.017. Epub 2019 Jun 22.
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.
Open-label phase 1 follow-on clinical trial and open-label, randomized, controlled phase 3 clinical trial.
Forty subjects who received 1.5×10 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]).
Subretinal injection of VN in the second eye of phase 1 follow-on subjects and in both eyes of phase 3 subjects.
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.
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(cd.s/m) 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.
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.
报告 voretigene neparvovec-rzyl（VN）腺相关病毒载体基因治疗 RPE65 突变相关遗传性视网膜营养不良（IRD）的持久性，包括第 1 年的 1 期后续研究和第 2 年的 3 期研究结果。
开放标签 1 期后续临床研究和开放标签、随机、对照 3 期临床研究。
40 名受试者在至少 1 只眼接受了每只眼 1.5×10 个载体基因组（vg）的 VN，其中包括 11 名 1 期后续研究受试者和 29 名 3 期研究受试者（20 名原始干预 [OI]和 9 名对照/干预 [CI]）。
在第 1 期后续研究受试者的第二只眼和第 3 期研究受试者的双眼进行 VN 的视网膜下注射。
第 1 期和第 3 期研究共有的终点包括评估照度范围内多亮度移动测试（MLMT）的性能变化、全视野光敏感度阈值（FST）测试和最佳矫正视力（BCVA）。安全性终点包括不良事件报告、眼科检查、体检和实验室检查。
第 1 期后续研究 8 名受试者（n=8）在给药后 4 年的平均（标准差）MLMT 勒克斯评分变化为 2.4（1.3），1 年为 2.6（1.6）；OI 受试者（n=20）在 2 年时为 1.9（1.1），在 1 年时为 1.9（1.0）；CI 受试者（n=9）在 1 年时为 2.1（1.6）。所有 3 组均保持 FST 的平均改善，反映出在 1 年和随后的可随访访问时，光敏感度提高了超过 2 个对数（cd.s/m）。安全性特征与玻璃体切除术和视网膜下注射程序一致，并且没有发生有害的免疫反应。
在 VN 基因增强治疗后，3 组 RPE65 突变相关 IRD 患者的导航能力和光敏感性均有类似的改善，提示获益风险比良好，IRDD 是一种进行性致盲退行性疾病。安全性特征与给药程序一致。这些数据表明，这种效应在 VN 给药后 30 天内几乎达到最大值，并且在 4 年内具有持久性，目前仍在观察中。
