Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of −1.40 (95% confidence interval: −2.76, −0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of −2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

中文翻译：

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arimoclomol 在 C 型 Niemann-Pick 病中的疗效和安全性：一项新疗法的双盲、随机、安慰剂对照、多国 2/3 期试验的结果

Niemann-Pick 病 C 型 (NPC) 是一种罕见的遗传性进行性神经退行性疾病，具有高度未满足的医疗需求。我们研究了 arimoclomol 的安全性和有效性，它可以增强 NPC 患者对靶向 NPC 蛋白错误折叠的热休克反应并改善溶酶体功能。在一项为期 12 个月、前瞻性、随机、双盲、安慰剂对照的 2/3 期试验（ClinicalTrials.gov 标识符：NCT02612129）中，患者（2-18 岁）按 2:1 随机分配至阿莫洛莫：安慰剂组，分层通过 miglustat 使用。维持常规临床护理。Arimoclomol 每天口服 3 次。主要终点是 5 域 NPC 临床严重程度量表 (NPCCSS) 评分从基线到 12 个月的变化。入组 50 名患者；42个完成。在第 12 个月，在 5 域 NPCCSS 中，从基线的平均进展为 0.76，arimoclomol 对比安慰剂为 2.15。有利于arimoclomol的统计学显着治疗差异为-1.40（95％置信区间：-2.76，-0.03；观察到P  = .046)，对应于每年疾病进展减少 65%。在预先指定的接受米格鲁他作为常规治疗的患者亚组中，arimoclomol 导致疾病严重程度在 12 个月内稳定下来，arimoclomol 的治疗差异为 -2.06（P  = .006）。30/34 名患者 (88.2%) 接受阿莫洛莫治疗，12/16 (75.0%) 接受安慰剂治疗的患者发生不良事件。与安慰剂（5/16, 31.3%）相比，使用阿莫氯醇（5/34, 14.7%）的患者发生严重不良事件的人数更少。治疗相关的严重不良事件（n = 2）包括荨麻疹和血管性水肿。Arimoclomol 在 NPC 中提供了显着且具有临床意义的治疗效果，并且耐受性良好。