Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Department of Pediatrics and Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada.
Muscle Nerve. 2022 Jul;66(1):50-62. doi: 10.1002/mus.27558. Epub 2022 May 9.
INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD.
Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated.
Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions.
Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.
介绍/目的：面肩肱型肌营养不良症（FSHD）是一种进展缓慢的肌肉疾病，目前尚无获批的治疗方法。在这项研究中，我们评估了局部作用的 ACE-083 是否能安全地增加肌肉量并改善 FSHD 成人的功能结局。
参与者年龄至少 18 岁，且患有 FSHD1/FSHD2。第 1 部分为开放标签、递增剂量，评估安全性和耐受性（主要目标）。第 2 部分为随机、双盲 6 个月，评估 ACE-083240mg/肌肉双侧肱二头肌（BB）或胫骨前肌（TA）每 3 周注射一次，与安慰剂相比，随后进行 6 个月的开放标签治疗。磁共振成像测量包括总肌肉量（TMV；主要目标）、脂肪分数（FF）和收缩肌肉量（CMV）。功能测量包括 6 分钟步行测试、10 米步行/跑和 4 级爬楼梯（TA 组），以及上肢中水平/肘评分（BB 组）。还评估了力量、患者报告的结局（PROs）和安全性。
第 1 部分和第 2 部分分别招募了 37 名和 58 名参与者。在第 2 部分的 55 名可评估参与者中，BB 组 TMV 的最小二乘均值（90%置信区间，协方差分析）治疗差异为 16.4%（9.8%-23.0%）（P<.0001），TA 组为 9.5%（3.2%-15.9%）（P=0.01）。BB 和 TA 组的 CMV 均显著增加，TA 组的 FF 降低。两组的功能或 PRO 测量均无一致改善。最常见的不良事件为轻度或中度注射部位反应。
ACE-083 与安慰剂相比，TMV 显著增加，但治疗 12 个月后，功能或 PRO 改善并不一致。
