Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomized, placebo-controlled, multinational phase 2/3 trial of a novel treatment.

Abstract

BACKGROUND\nNiemann-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.\n\n\nMETHODS\nIn a 12-month, prospective, randomized, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18\u2009years) were randomized 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.\n\n\nRESULTS\nFifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol versus 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; p =\u20090.046) 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 stabilization of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (p =\u20090.006). 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%) versus placebo (5/16, 31.3%). Treatment-related serious adverse events (n\xa0=\xa02) included urticaria and angioedema.\n\n\nCONCLUSIONS\nArimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated. This article is protected by copyright. All rights reserved.