Efficacy results from a 12-month double-blind randomized trial of arimoclomol for treatment of Niemann-Pick disease type C (NPC): Presenting a rescored 4-domain NPC Clinical Severity Scale
Year: 2025
Type: article
Abstract: Background In the 12-month, randomized, double-blind, placebo-controlled Phase 2/3 NPC-002 study ( NCT02612129 ), arimoclomol significantly reduced annual disease progression versus placebo, measured by the 5-domain NPC Clinical Severity Scale (5DNPCCSS). Arimoclomol has been approved in the US for treatment of Niemann-Pick disease type C (NPC) in combination with miglustat. This paper introduces the rescored 4-domain NPCCSS (R4DNPCCSS) as a post-hoc primary endpoint in NPC-002, discusses its validation, and presents the results of the post-hoc primary analysis. Methods To more accurately assess changes in disease course over a 12-month time period in a heterogeneous group of patients, the Cognition domain was removed from the 5DNPCCSS and the Swallow domain was rescored to reflect linearity in disease progression. Rescoring of the Swallow domain was based on input from clinical NPC and swallow experts from a qualitative interview-based study ( N = 12), resulting in the R4DNPCCSS. To supplement prior validation analyses, data supporting the overall validity and reliability of the R4DNPCCSS was gathered through additional analyses of construct and convergent validity. The NPC-002 prespecified primary efficacy endpoint analysis based on the 5DNPCCSS score change from baseline to 12 months was repeated with R4DNPCCSS. Results Construct validity analysis demonstrated high agreement between the R4DNPCCSS domain scores and the Clinical Global Impression Scale of Severity (CGI-S) and NPC Clinical Database (NPC-cdb) scores. Convergent validity was confirmed by strong correlations between the R4DNPCCSS domains and corresponding items on the Scale for Assessment and Rating of Ataxia (SARA), 9-hole peg test (9-HPT), and Video Fluoroscopic Swallowing Study (VFSS) performance tests. The NPC-002 post-hoc primary analysis showed a mean standard error (SE) change in R4DNPCCSS score of 0.35 (0.40) with arimoclomol ( N = 34) versus 2.05 (0.54) with placebo ( N = 16), and a treatment effect in favor of arimoclomol over placebo of −1.70 ( p = 0.0155). In the miglustat subgroup analysis, mean (SE) change in R4DNPCCSS score was −0.23 (1.02) with arimoclomol ( N = 22) versus 1.92 (3.37) with placebo (N = 12), representing a treatment effect of −2.21 ( p = 0.0077). Conclusion The R4DNPCCSS is a valid and reliable measure of disease progression demonstrating consistent outcomes with the prespecified 5DNPCCSS endpoint. Arimoclomol significantly slowed disease progression through 12 months as measured by the R4DNPCCSS versus placebo.
Authors: Eugen Mengel, Marc C. Patterson, Rosalia M. Da Riol, Mireia Del Toro, Federica Deodato, Matthias Gautschi, Stephanie Grunewald, Sabine Weller Grønborg, Paul Harmatz, Julia B. Hennermann, Bénédicte Héron, Esther M. Maier, Agathe Roubertie, Saikat Santra, Anna Tylki-Szymanska, Lisa LaGorio, Elizabeth Berry-Kravis, Forbes D. Porter, Beth Solomon, Louise Himmelstrup, Travis Mickle, Sven Guenther, Christine í Dali
Institutions: Mayo Clinic, Ospedale Santa Maria della Misericordia di Udine, Vall d'Hebron Hospital Universitari, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, University of Bern, University Hospital of Bern, Great Ormond Street Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, NIHR Great Ormond Street Hospital Biomedical Research Centre, Copenhagen University Hospital, Rigshospitalet, University of California, San Francisco, UCSF Benioff Children's Hospital, University Medical Center of the Johannes Gutenberg University Mainz, Sorbonne Université, Hôpital Armand-Trousseau, Assistance Publique – Hôpitaux de Paris, Ludwig-Maximilians-Universität München, Inserm, Centre Hospitalier Universitaire de Montpellier, Institute for Neurosciences of Montpellier, Birmingham Children's Hospital, Children's Memorial Health Institute, Rush University, Rush University Medical Center, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health Clinical Center
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,400
OpenAlex ID: W4410809709