Efficacy and safety of arimoclomol in patients with Niemann-Pick disease type C: Results from a double-blind, randomized placebo controlled trial with a novel treatment

Niemann Pick disease type C (NPC) is a rare, lysosomal disorder caused by mutations of the NPC1 or 2 protein. Systemic and neurological symptoms are progressive and fatal. To assess efficacy and safety, a 12-month multi-national, double-blind, randomised, placebo-controlled trial with the heat shock protein (HSP) amplifier, arimoclomol, was conducted. METHOD: Diagnosed NPC Patients, 2–18 years of age, who had at least one neurological symptom and preserved ability to walk with assistance were eligible. Patients were maintained on routine clinical care. The primary endpoint was change in NPC disease severity from baseline to 12 months based on the 5-domain NPC-severity score (NPCCSS). The 5 domains included: ambulation, fine motor skills, speech, swallowing, and cognition. The primary endpoint was further analysed in pre-specified patient-groups; and for impact of genotypes on efficacy. In addition, HSP 70 for target engagement and biomarkers of lysosomal lipid burden for down-stream effect on disease pathology were assessed. RESULTS: 50 patients were enrolled (39 patients on miglustat); 34 treated with arimoclomol and 16 with placebo. 43 patients completed the trial. Baseline demographics and characteristics were comparable between treatment groups. Arimoclomol was well-tolerated. Benefit of arimoclomol over placebo was established on the 5-domain NPCCSS score with a treatment effect of −1.34 (95% CI: −2.69, 0.00), p =.0506, corresponding to a 74% reduction in disease progression. Supplementary analyses based on genotyping and pre-specified sub-groups will be presented. Biomarker analysis showed treatment related significant increase in HSP70 levels in peripheral blood mononuclear cells (PBMC), decrease in un-esterified cholesterol in PBMC and decrease in serum cholestane-triol. CONCLUSION: Arimoclomol treatment was associated with clinically relevant treatment benefit over placebo on the 5-domain NPCCSS (primary endpoint) over the course of 12 months. Biomarker analysis indicates a biological effect supporting the mechanism of action for arimoclomol as a Heat shock protein amplifier in NPC.