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

Abstract

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.

Keywords: NPC clinical severity scale; Niemann-Pick disease type C; arimoclomol; biomarker; double-blindplacebo-controlled; heat shock protein.

Conflict of interest statement

Eugen Mengel has received investigator fees and consultant honoraria from Actelion, Alexion, Orphazyme A/S, Sanofi Genzyme, and Takeda. Marc C. Patterson has received, or will receive, research support from Actelion, Amicus, Glycomine, NIH, Orphazyme A/S, and Shire/Takeda; has served as Chair of the Scientific Advisory Committee of a Registry of Niemann‐Pick disease type C, sponsored by Actelion Pharmaceuticals, Inc.; has received consultancy fees from Amicus, Genzyme, IntraBio, Novartis, Orphazyme A/S, Takeda, and Vtesse‐Sucampo‐Mallinckrodt; holds stock in IntraBio; and receives a stipend as Editor‐in Chief of the Journal of Child Neurology and Child Neurology Open (Sage), as an editor of the Journal of Inherited Metabolic Disease (JIMD) and JIMD Reports (Society for the Study of Inborn Errors of Metabolism), and royalties from UpToDate (Section Editor for Pediatric Neurology). Rosalia M. Da Riol has received travel expenses and congress fees reimbursements from Sanofi Genzyme and Takeda. Mireia Del Toro has received consulting fees and speaker honoraria, travel expenses, and congress fees from Biomarin, Sanofi Genzyme, and Takeda, and is an investigator for industrial trials (Orphazyme, Takeda, Vtesse‐Sucampo‐Mallinckrodt). Federica Deodato has received speaker honoraria from Sanofi Genzyme and Takeda, and travel reimbursement and congress fees from Actelion, Sanofi Genzyme, and Takeda. Matthias Gautschi has received consulting fees from Sanofi Genzyme, and travel expenses and congress fees from Takeda, and is an investigator for industrial trials from Horizon, Idorsia, Kaleido, Mallinckrodt, and Orphazyme A/S. Stephanie Grunewald has received consultancy funding from Hyperion, Moderna, Nutricia, Sobi, and Ultragenyx, and has participated in commercially funded research and received travel grants from Orphazyme A/S. Sabine Grønborg has received speaker honoraria from Actelion and Novo Nordisk, and travel grants from Sanofi Genzyme. Paul Harmatz has provided consulting support to and/or has received grant support from Aeglea, Alexion, Armagen, Audentis, BioMarin, Chiesi, Denali, Enzyvant, Genzyme, Homology, Inventiva, JCR, Orphazyme, Paradigm, Pfizer, PTC Therapeutics, RegenXbio, Sangamo, Shire, Sobi, and Ultragenyx. Bénédicte Héron has received consulting fees and speaker honoraria from Actelion and Takeda, travel expenses and congress fees reimbursements from Sanofi Genzyme and Takeda, and is an investigator for industrial studies and trials (Abeona Therapeutics, Chiesi Idorsia, Lysogene, Orphazyme A/S, and Vtesse‐Sucampo‐Mallinckrodt). Esther M. Maier has received fees from Sanofi. Saikat Santra has participated in commercially funded research, has received education and travel grants from Actelion and Orphazyme A/S, and has participated in commercially funded research from Vtesse‐Sucampo‐Mallinckrodt. Anna Tylki‐Szymanska has received speaker honoraria and/or travel grants from BioMarin, Chiesi, Sanofi Genzyme, and Takeda. Simon Day is a paid consultant to Orphazyme A/S. Anne Katrine Andreasen, Marie Aavang Geist, Nikolaj Havnsøe Torp Petersen, Linda Ingemann, Thomas Blaettler, Thomas Kirkegaard, and Christine í Dali are employees and shareholders of Orphazyme A/S. Thomas Hansen is an employee of Orphazyme A/S. Agathe Roubertie has nothing to disclose.

© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Figures

FIGURE 1

A, CT‐ORZY‐NPC‐002 trial design. B, Patient flow. Completers analysis set excluded two patients in the arimoclomol group who did not have assessments at 12 months. PK, pharmacokinetic

FIGURE 2

5‐domain NPCCSS score observed change from baseline at month 12: A, Overall (N = 50; full analysis set); B, in patients aged ≥4 years (n = 44); C, in patients receiving miglustat (n = 39). The solid line represents least‐squares mean estimates ± SE based on data obtained while patients were exposed to study treatment. The mixed model for repeated measures included the main effect of baseline and stratum, respectively, and interaction between treatment and visit. Change from baseline and absolute estimates correspond to the at‐baseline overall average patient. Numbers of patient are presented for each time point. CI, confidence interval; NPC, Niemann‐Pick disease type C; NPCCSS, Niemann‐Pick disease type C Clinical Severity Scale

FIGURE 3

Biomarker analyses. A, Change in HSP70 in PBMCs from months 0 to 12 in arimoclomol‐treated patients (n = 11; P = .001); B, Change in unesterified cholesterol level at month 12 (between‐group difference: P = .096); C, Change in serum cholestane‐triol level at month 12 (between‐group difference: P = .225); D, ratio of plasma Lyso‐SM‐509 to baseline (between‐group difference: P = .043). Error bars show SE. Wilcoxon signed‐rank test was used to assess significance within treatment group (HSP70). For unesterified cholesterol and serum cholestane‐triols, between‐group analysis of covariance was conducted with baseline, stratum and treatment as covariates. Estimates were adjusted to reflect baseline distribution. HSP70, heat shock protein 70; NPC, Niemann‐Pick disease type C; PBMC, peripheral blood mononuclear cell