尼曼-匹克病C型(NPC)是一种罕见的,遗传,进行性神经退行性疾病,具有高度未满足的医疗需求。我们调查了安莫罗的安全性和有效性,这放大了对目标NPC蛋白错误折叠的热休克反应,并改善了溶酶体功能,在NPC患者中。在12个月内,prospective,随机化,双盲,安慰剂对照,2/3期试验(ClinicalTrials.gov标识符:NCT02612129),患者(2-18岁)随机分为2:1,接受arimoclomol:安慰剂,由Miglustat使用分层。维持常规临床护理。Arimoclomol每天口服三次。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。50名患者登记;42名完成。在第12个月,5域NPCCSS中从基线的平均进展是arimoclomol的0.76,安慰剂的2.15。观察到有利于阿利莫罗的统计学差异为-1.40(95%置信区间:-2.76,-0.03;P=.046),相当于每年疾病进展减少65%。在预先设定的接受miglustat作为常规护理的患者亚组中,Arimoclomol导致12个月内疾病严重程度的稳定,治疗差异为-2.06,有利于arimoclomol(P=.006)。不良事件发生在接受arimoclomol的30/34患者(88.2%)和接受安慰剂的12/16(75.0%)中。与安慰剂(5/16,31.3%)相比,更少的患者出现严重不良事件(5/34,14.7%)。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。
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.