德兰地司创莫维帕韦治疗杜氏肌营养不良症的三年随访：长期3期EMBARK试验结果。
摘要
引言：德兰地司创莫维帕韦是一种基于腺相关病毒载体的基因疗法，通过递送优化的微型肌营养不良蛋白转基因，以解决杜氏肌营养不良症（DMD）中的肌营养不良蛋白缺乏问题。EMBARK是一项3期、随机、双盲、安慰剂对照、两部分交叉研究，评估德兰地司创莫维帕韦在年龄≥4至<8岁、可行走的DMD患者中的安全性和有效性。在EMBARK研究完成2年后，患者可选择进入长期随访的开放性EXPEDITION研究。…
正文 待译
INTRODUCTION: Delandistrogene moxeparvovec, an adeno-associated virus vector-based gene therapy, delivers an optimized micro-dystrophin transgene to address dystrophin deficiency in Duchenne muscular dystrophy (DMD). EMBARK was a phase 3, randomized, double-blind, placebo-controlled, two-part crossover study evaluating the safety and effectiveness of delandistrogene moxeparvovec in patients with DMD who are ambulatory aged ≥ 4 to < 8 years. After completion of the EMBARK study at 2 years, patients had the option to enroll into the long-term follow-up open-label EXPEDITION study. METHODS: Three-year functional outcomes from patients treated with delandistrogene moxeparvovec in EMBARK part 1 (single intravenous dose 1.33 × 1014 vg/kg; n = 64) were compared with a matched propensity score weighted external control (EC) cohort (n = 143) derived from randomized controlled clinical trials (patients treated with placebo only) and natural history datasets. Mixed-effects models for repeated measures accounted for missing data and estimated changes from baseline and between-cohort differences. All P values are nominal. RESULTS: At 3 years post-infusion, patients treated in part 1 of EMBARK (aged 7-10 years at 3 years) suggested sustained and statistically significant differences versus the matched EC cohort in change from baseline in North Star Ambulatory Assessment total score (between-cohort least-squares mean difference, 4.39 points; P = 0.0002), Time to Rise (- 6.05 s; P < 0.0001), and 10-m Walk/Run (- 2.70 s; P = 0.0039), suggesting durable slowing of disease progression. No new safety signals were identified through year 3, with no emerging cardiac safety concerns as the left ventricular ejection fraction remained above the normal threshold of 55% in this population over 3 years. There were no treatment-related deaths or discontinuations due to adverse events during follow-up. CONCLUSIONS: The 3-year follow-up of patients with DMD who are ambulatory treated in EMBARK part 1 compared with external comparators suggests durable functional benefit and a consistent safety profile following treatment with delandistrogene moxeparvovec, which may indicate long-term disease trajectory modification and increasing divergence from natural history over time. Graphical abstract available for this article. CLINICAL TRIAL NUMBERS: EMBARK: NCT05096221; EXPEDITION: NCT05967351.
English
INTRODUCTION: Delandistrogene moxeparvovec, an adeno-associated virus vector-based gene therapy, delivers an optimized micro-dystrophin transgene to address dystrophin deficiency in Duchenne muscular dystrophy (DMD). EMBARK was a phase 3, randomized, double-blind, placebo-controlled, two-part crossover study evaluating the safety and effectiveness of delandistrogene moxeparvovec in patients with DMD who are ambulatory aged ≥ 4 to < 8 years. After completion of the EMBARK study at 2 years, patients had the option to enroll into the long-term follow-up open-label EXPEDITION study.…