简介:Delandistrogenemoxeparvovec(SRP-9001)是一种研究性基因转移疗法,旨在靶向表达SRP-9001肌营养不良蛋白,缩短的肌营养不良蛋白保留野生型蛋白的关键功能域。方法:本阶段2,双盲,两部分(每个部分48周)交叉研究(SRP-9001-102[研究102];NCT03769116)评估了患者的delandistrogenemoxeparvovovec,年龄≥4至<8岁的Duchenne型肌营养不良。主要终点(第1部分)是SRP-9001肌营养不良蛋白表达(第12周)相对于基线(CFBL)的变化,通过蛋白质印迹,和北星门诊评估(NSAA)得分(第48周)。安全性评估包括治疗相关不良事件(TRAEs)。将患者随机分组,并按年龄分层为安慰剂(n=21)或delandistrogenemoxeparvovec(n=20),并交叉进行第2部分。结果:在所有患者中实现SRP-9001肌营养不良蛋白表达:第1部分和第2部分中,第12周的平均CFBL分别为23.82%和39.64%正常。在第1部分中,CFBL到第48周的NSAA评分(最小二乘平均值,LSM[标准误差])为+1.7(0.6),而安慰剂为+0.9(0.6);p=0.37。组间基线运动功能的差异可能混淆了这些结果。在基线运动功能匹配的4至5岁儿童中,CFBL到第48周的NSAA评分显着不同(+2.5分;p=0.0172),但在基线运动功能不平衡的6至7岁儿童中没有显着差异(-0.7分;p=0.5384)。对于第2部分中接受DelandistrogeneMoxeparvovec治疗的患者,NSAA评分至第48周的CFBL为+1.3(2.7),而对于第1部分治疗的患者,NSAA评分得以维持.由于第2部分的所有患者都接受了治疗,结果与倾向评分加权外部对照(EC)队列进行比较.第2部分治疗组和EC组之间的NSAA评分的LSM差异具有统计学意义(+2.0分;p=0.0009)。最常见的TRAEs是呕吐,食欲下降,和恶心。大多数发生在前90天内,并全部解决。讨论:结果表明SRP-9001肌营养不良蛋白的稳健表达和NSAA在治疗后长达2年的总体稳定。第1部分中两组之间的NSAA差异在总体人群中并不显着,可能是因为队列只按年龄分层,和其他关键预后因素在基线时不匹配。
Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2. Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (-0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90 days and all resolved. Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2 years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline.