Background

Pompe disease is a rare disorder characterised by progressive loss of muscle and respiratory function due to acid α-glucosidase deficiency. Enzyme replacement therapy with recombinant human acid α-glucosidase, alglucosidase alfa, is the first approved treatment for the disease, but some patients do not respond, and many do not show a sustained benefit. We aimed to assess the safety and efficacy of an investigational two-component therapy (cipaglucosidase alfa, a novel recombinant human acid α-glucosidase, plus miglustat, an enzyme stabiliser) for late-onset Pompe disease.

Methods

We did a randomised, double-blind, parallel-group, phase 3 trial at 62 neuromuscular and metabolic medical centres in 24 countries in the Americas, Asia-Pacific, and Europe. Eligible participants were aged 18 years or older with late-onset Pompe disease, and had either been receiving alglucosidase alfa for at least 2 years or were enzyme replacement therapy-naive. Participants were randomly assigned (2:1) using interactive response technology software, stratified by 6-min walk distance and previous enzyme replacement therapy status, to intravenous cipaglucosidase alfa (20 mg/kg) plus oral miglustat or to intravenous alglucosidase alfa (20 mg/kg) plus oral placebo once every 2 weeks for 52 weeks. Patients, investigators, and outcome assessors were masked to treatment assignment. The primary endpoint was change from baseline to week 52 in 6-min walk distance, assessed using a mixed-effect model for repeated measures analysis for comparison of superiority in the intention-to-treat population (all patients who received at least one dose of study drug). This study is now complete and is registered with ClinicalTrials.gov, NCT03729362.

Findings

Between Dec 3, 2018, and Nov 26, 2019, 130 patients were screened for eligibility and 125 were enrolled and randomly assigned to receive cipaglucosidase alfa plus miglustat (n=85) or alglucosidase alfa plus placebo (n=40). Two patients in the alglucosidase alfa plus placebo group did not receive any dose due to absence of genotype confirmation of late-onset Pompe disease and were excluded from analysis. Six patients discontinued (one in the alglucosidase alfa plus placebo group, five in the cipaglucosidase alfa plus miglustat group), and 117 completed the study. At week 52, mean change from baseline in 6-min walk distance was 20·8 m (SE 4·6) in the cipaglucosidase alfa plus miglustat group versus 7·2 m (6·6) in the alglucosidase alfa plus placebo group using last observation carried forward (between-group difference 13·6 m [95% CI −2·8 to 29·9]). 118 (96%) of 123 patients experienced at least one treatment-emergent adverse event during the study; the incidence was similar between the cipaglucosidase alfa plus miglustat group (n=81 [95%]) and the alglucosidase alfa plus placebo group (n=37 [97%]). The most frequently reported treatment-emergent adverse events were fall (25 [29%] patients in the cipaglucosidase alfa plus miglustat group vs 15 [39%] in the alglucosidase alfa plus placebo group), headache (20 [24%] vs 9 [24%]), nasopharyngitis (19 [22%] vs 3 [8%]), myalgia (14 [16%] vs 5 [13%]), and arthralgia (13 [15%]) vs 5 [13%]). 12 serious adverse events occurred in eight patients in the cipaglucosidase alfa plus miglustat group; only one event (anaphylaxis) was deemed related to study drug. One serious adverse event (stroke) occurred in the alglucosidase alfa plus placebo group, which was deemed unrelated to study drug. There were no deaths.

Interpretation

Cipaglucosidase alfa plus miglustat did not achieve statistical superiority to alglucosidase alfa plus placebo for improving 6-min walk distance in our overall population of patients with late-onset Pompe disease. Further studies should investigate the longer-term safety and efficacy of cipaglucosidase alfa plus miglustat and whether this investigational two-component therapy might provide benefits, particularly in respiratory function and in patients who have been receiving enzyme replacement therapy for more than 2 years, as suggested by our secondary and subgroup analyses.

Funding

Amicus Therapeutics.

中文翻译：

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cipaglucosidase alfa 加 miglustat 与 alglucosidase alfa 加安慰剂治疗晚发性庞贝病 (PROPEL) 的安全性和有效性：一项国际、随机、双盲、平行组 3 期试验

背景

庞贝病是一种罕见疾病，其特征是由于酸性 α-葡萄糖苷酶缺乏而导致肌肉和呼吸功能进行性丧失。使用重组人酸性α-葡萄糖苷酶（alglucosidase alfa）的酶替代疗法是第一个被批准用于该疾病的治疗方法，但一些患者没有反应，并且许多患者没有表现出持续的获益。我们的目的是评估研究性双组分疗法（cipaglucosidase alfa，一种新型重组人酸性 α-葡萄糖苷酶，加上 miglustat，一种酶稳定剂）治疗晚发性庞贝病的安全性和有效性。

方法

我们在美洲、亚太和欧洲 24 个国家的 62 个神经肌肉和代谢医疗中心进行了一项随机、双盲、平行组 3 期试验。符合资格的参与者年龄在 18 岁或以上，患有迟发性庞贝氏症，并且已经接受阿葡萄糖苷酶 alfa 至少 2 年，或者从未接受过酶替代疗法。使用交互式响应技术软件将参与者随机分配 (2:1)，按 6 分钟步行距离和既往酶替代治疗状态分层，静脉注射西帕葡萄糖苷酶 alfa (20 mg/kg) 加口服米格司他或静脉注射阿葡萄糖苷酶 alfa (20 mg) /kg）加上口服安慰剂，每 2 周一次，持续 52 周。患者、研究者和结果评估者对治疗分配情况不知情。主要终点是 6 分钟步行距离从基线到第 52 周的变化，使用混合效应模型进行评估，进行重复测量分析，以比较意向治疗人群（所有接受至少一剂研究药物）。这项研究现已完成，并已在 ClinicalTrials.gov 注册，NCT03729362。

发现

2018年12月3日至2019年11月26日期间，对130名患者进行了资格筛查，其中125名患者被登记并随机分配接受西帕葡萄糖苷酶α加米格司他（n = 85）或阿葡萄糖苷酶α加安慰剂（n = 40）。阿葡萄糖苷酶α加安慰剂组中的两名患者由于缺乏晚发庞贝病的基因型确认而未接受任何剂量，因此被排除在分析之外。6 名患者中止治疗（阿葡萄糖苷酶 alfa 加安慰剂组 1 名，西帕葡萄糖苷酶 alfa 加 miglustat 组 5 名），117 名患者完成了研究。第 52 周时，cipaglucosidase alfa 加 miglustat 组的 6 分钟步行距离相对于基线的平均变化为 20·8 m (SE 4·6)，而 alglucosidase alfa 加安慰剂组的平均变化为 7·2 m (6·6)。继续最后一次观察（组间差异 13·6 m [95% CI -2·8 至 29·9]）。123 名患者中有 118 名 (96%) 在研究期间经历了至少一种治疗引起的不良事件；cipaglucosidase alfa 加 miglustat 组 (n=81 [95%]) 和 alglucosidase alfa 加安慰剂组 (n=37 [97%]) 的发生率相似。最常报告的治疗中出现的不良事件是跌倒（西帕葡萄糖苷酶α加米格司他组为25例[29%]，阿葡萄糖苷酶α加安慰剂组为15例[39%]）、头痛（20例[24%] vs 9例）。 24%]）、鼻咽炎（19 [22%] vs 3 [8%]）、肌痛（14 [16%] vs 5 [13%]）和关节痛（13 [15%]）vs 5 [13%] ）。cipaglucosidase alfa加miglustat组的8名患者发生了12次严重不良事件；只有一种事件（过敏反应）被认为与研究药物有关。阿葡萄糖苷酶α加安慰剂组发生了一项严重不良事件（中风），该事件被认为与研究药物无关。没有死亡。

解释

在改善晚发庞贝病患者的 6 分钟步行距离方面，西帕葡萄糖苷酶 alfa 联合米格司他并未达到统计学上的优越性。进一步的研究应该调查 cipaglucosidase alfa 加 miglustat 的长期安全性和有效性，以及这种研究性双成分疗法是否可能带来益处，特别是在呼吸功能方面以及对于已经接受酶替代疗法超过 2 年的患者，如所建议的通过我们的二级和亚组分析。

资金

阿米克斯治疗公司。