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Clinical Trial
. 2025 Aug;145(4):109189.
doi: 10.1016/j.ymgme.2025.109189. Epub 2025 Jul 7.

Long-term efficacy and safety of arimoclomol in Niemann-Pick disease type C: Final results of the phase 2/3 NPC-002 48-month open-label extension trial

Eugen Mengel  1 , Rosalia M Da Riol  2 , Mireia Del Toro  3 , Federica Deodato  4 , Matthias Gautschi  5 , Stephanie Grunewald  6 , Sabine Weller Grønborg  7 , Paul Harmatz  8 , Julia B Hennermann  9 , Bénédicte Héron  10 , Esther M Maier  11 , Saikat Santra  12 , Reena Sharma  13 , Anna Tylki-Szymanska  14 , Malene Cording  15 , Louise Himmelstrup  15 , Sven Guenther  16 , Christine Í Dali  15
Affiliations
Free article
Clinical Trial

Long-term efficacy and safety of arimoclomol in Niemann-Pick disease type C: Final results of the phase 2/3 NPC-002 48-month open-label extension trial

Eugen Mengel et al. Mol Genet Metab. 2025 Aug.
Free article

Abstract

Background: This paper presents efficacy and safety outcomes from the 48-month open-label extension (OLE) of the phase 2/3 NPC-002 trial (NCT02612129) which evaluated arimoclomol treatment in patients with Niemann-Pick disease type C (NPC). Arimoclomol was recently approved by the US Food and Drug Administration for treatment of NPC in combination with miglustat.

Methods: Patients with NPC who completed the double-blind (DB) phase of the randomized controlled NPC-002 trial were eligible to continue in the OLE, during which all patients received arimoclomol in addition to routine clinical care. Primary efficacy outcomes were the 5-domain NPC Clinical Severity Scale (5DNPCCSS), and the rescored 4-domain NPCCSS (R4DNPCCSS), which was introduced post-hoc. Additional outcomes included NPC-specific measures (full scale NPCCSS, and NPC clinical database [NPC-cdb] score), and safety evaluations.

Results: Of the 50 patients who started the DB phase, 41 entered the OLE phase, with 29 completing 48 months. During the OLE, mean (SD) 5DNPCCS and R4DNPCCSS scores increased by 3.2 (4.8) and 2.7 (4.2) over 48 months, respectively. Among patients switching from placebo to arimoclomol after the DB phase, mean annual change in 5DNPCCSS decreased from 2.0 (on placebo) to 0.1 in the first year of receiving arimoclomol and mean annual change in R4DNPCCSS decreased from 1.9 to 0.2, indicating slowing of disease progression. Annual scores for both endpoints remained numerically smaller throughout the OLE than during the DB phase. The score pattern in the subset of patients who received miglustat as part of their standard care regime in addition to arimoclomol (N = 33) was similar to that seen in the total population. 17-domain NPCCSS (excluding hearing domains) and NPC-cdb results further supported sustained efficacy of arimoclomol. Arimoclomol was well-tolerated over 48 months, with no new safety concerns identified.

Conclusion: The OLE of the NPC-002 trial provides evidence for a sustained reduction in disease progression for at least 5 years in a heterogeneous population of NPC patients receiving arimoclomol in addition to routine clinical care, with no new safety concerns. These results align with the statistically significant and clinically meaningful reduction in disease progression observed over 12-months in the DB phase, further highlighting the potential of arimoclomol as an effective and well tolerated disease modifying treatment for NPC.

Keywords: NPC Clinical Severity Scale; Niemann-Pick disease type C; arimoclomol; open-label, progression, safety.

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Conflict of interest statement

Declaration of competing interest Eugen Mengel has received investigator fees and/or consultant honoraria from Cyclo Therapeutics, Amicus, Idorsia, Intrabio, Denali, JCR, Prevail, Freeline Therapeutics, Alexion, Zevra, Sanofi Genzyme, and Takeda. 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 (Zevra, 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 PTC Therapeutics, and travel expenses and congress fees from Sanofi Genzyme, and is an investigator for industrial trials from Horizon, Idorsia, Kaleido, Mallinckrodt, Zevra, and Intrabio. Stephanie Grunewald has received consultancy funding from Hyperion, Origin, Moderna, Nutricia, Sobi, Glycomine, and Ultragenyx, and has participated in commercially funded research and received travel grants from Zevra. Sabine Weller Grønborg has received travel expenses and congress fee reimbursements from Sanofi Genzyme, participated in Orchard Therapeutics advisory board and sponsored meetings, and has received speaker honoraria from Actelion and Novo Nordisk. Paul Harmatz has provided consulting support to and/or has received grant support from Adrenas, Aeglea, Alexion, Allievix, Amicus, Armagen, Ascendis, ASPA, Audentis, Azafros, BioMarin, Bridgebio, Calcilytics, Capsida, Chiesi, Denali, Edigene, Enzyvant, GC Pharma, Genzyme, Grace Science, Homology, Idorsia, Immusoft, Inventiva, JCR, Mirum Pharma, Neurogene, Novel Pharma, Orchard Therapeutics, Orphazyme, Paradigm, Pfizer, Prevail, PTC Therapeutics, QED, Rallybio, RegenXbio, Renoviron, SalioGen, Sanofi, Sangamo, Shire, Sobi, Takeda, and Ultragenyx, and Zevra. Julia B. Hennermann received honoraria and/or travel expenses from Amicus, Chiesi, Immedica, Takeda, and Sanofi. Bénédicte Héron has received honoraria for advisory boards from Orchard Therapeutics, Actelion, and Takeda, Zevra; received honoraria/travel support from Actelion, BioMarin, Shire/Takeda, Sanofi Genzyme; is principal investigator for Abeona, Zevra, Lysogene, Mallincrodt, Idorsia, JCR Pharmaceuticals, and Chiesi studies; is an expert consultant for Lysogene, Takeda and Zevra. Esther M. Maier has received fees from Sanofi. Saikat Santra has participated in commercially funded research, advisory boards and has received unrestricted education/travel grants from Actelion, Zevra, BioMarin, Sanofi-Genzyme, PTC Therapeutics, Takeda-Shire, SOBI, Immedica, Moderna, Amgen, Glycomine, Novartis and Ultragenyx and has participated in commercially funded research from Vtesse-Sucampo-Mallinckrodt, Alexion, Denali, Shire, Sobi, Takeda. Reena Sharma received consultation fees and financial support to attend medical conferences from Amicus, Immedica, Sanofi, Spur Therapeutics, Traver, and Ultragenyx. Anna Tylki-Szymanska has received speaker honoraria and/or travel grants from BioMarin, Chiesi, Sanofi Genzyme, and Takeda. Christine í Dali is an employee and shareholder of Zevra Therapeutics Inc. Malene Cording Christensen and Louise Himmelstrup are employees of Zevra Therapeutics Inc. Sven Guenther was an employee of Zevra Therapeutics at the time of the study.

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