1. 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
- Author
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Esther M. Maier, Rosalia M Da Riol, Nikolaj H.T. Petersen, Saikat Santra, Federica Deodato, Paul Harmatz, Anne Katrine Andreasen, Thomas Hansen, Matthias Gautschi, Thomas Blaettler, Thomas Kirkegaard, Simon Day, Mireia del Toro, Christine í Dali, Sabine Grønborg, Marie Aavang Geist, Linda Ingemann, Stephanie Grunewald, Agathe Roubertie, Marc C. Patterson, Bénédicte Héron, Eugen Mengel, Anna Tylki-Szymańska, Mayo Clinic [Rochester], Ospedale 'Santa Maria della Misericordia' = University Hospital 'Santa Maria della Misericordia', Vall d'Hebron University Hospital [Barcelona], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Bern University Hospital [Berne] (Inselspital), Institute of Child Health [London], University College of London [London] (UCL), Rigshospitalet [Copenhagen], Copenhagen University Hospital, UCSF Benioff Children's Hospital Oakland, University of California [San Francisco] (UCSF), University of California-University of California, Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Children's Hospital [Munich, Allemagne], Helmholtz-Zentrum München (HZM)-Technische Universität München [München] (TUM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Birmingham Children’s Hospital, Children’s Memorial Health Institute [Warsaw, Poland] (CMHI), and Helmholtz-Zentrum München (HZM)-Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)
- Subjects
Male ,Internationality ,[SDV]Life Sciences [q-bio] ,heat shock protein ,Arimoclomol ,Type C ,Severity of Illness Index ,NPC clinical severity scale ,double-blindplacebo-controlled ,chemistry.chemical_compound ,0302 clinical medicine ,Miglustat ,Clinical endpoint ,arimoclomol ,Prospective Studies ,Child ,Genetics (clinical) ,Genetics & Heredity ,0303 health sciences ,Niemann-Pick disease type C ,Niemann-Pick Disease, Type C ,3. Good health ,Treatment Outcome ,6.1 Pharmaceuticals ,Child, Preschool ,Disease Progression ,Biomarker (medicine) ,biomarker ,Female ,medicine.symptom ,medicine.drug ,medicine.medical_specialty ,Adolescent ,Clinical Trials and Supportive Activities ,Clinical Sciences ,610 Medicine & health ,Placebo ,Hydroxylamines ,03 medical and health sciences ,Young Adult ,Double-Blind Method ,Clinical Research ,Internal medicine ,Niemann-Pick Disease ,Genetics ,medicine ,Humans ,Adverse effect ,Preschool ,030304 developmental biology ,Angioedema ,business.industry ,Evaluation of treatments and therapeutic interventions ,Confidence interval ,chemistry ,business ,030217 neurology & neurosurgery - 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.
- Published
- 2021
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