Arimoclomol Plus Miglustat Shows Early, Sustained Slowing of Niemann-Pick Disease Type C Progression

New post hoc findings from the phase 2/3 NPC002 trial (NCT02612129), presented at the 55th Child Neurology Society (CNS) Annual Meeting, held October 14 to 17, 2026, in Montreal, Canada, showed that arimoclomol (Miplyffa; Zevra Therapeutics) combined with miglustat significantly slowed disease progression compared with placebo plus miglustat at every timepoint assessed in patients with Niemann-Pick disease type C (NPC). Notably, separation between treatment groups emerged as early as 3 months after treatment initiation.¹

Among patients receiving concomitant miglustat, estimated treatment differences in rescored 4-domain NPC Clinical Severity Scale (R4DNPCCSS) change from baseline favored arimoclomol at 3 months (−0.85; 95% CI, −1.67 to −0.03; P = .04), 6 months (−1.48; 95% CI, −2.36 to −0.61; P <.001), 9 months (−2.07; 95% CI, −3.43 to −0.72; P = .003), and 12 months (−2.17; 95% CI, −3.80 to −0.53; P = .009). Presented by lead author Mary-Jean Fanelli, MD, MBA, vice president ofGlobal Medical Affairs & Pharmacovigilance at Zevra Therapeutics, the study noted that assessments of NPC disease progression typically require observation over at least 12 months, making the early between-group difference noteworthy.

NPC002 was a 12-month, randomized, double-blind, placebo-controlled trial that enrolled 50 patients aged 2 to 19 years with NPC, who were randomly assigned 2:1 to weight-adjusted oral arimoclomol or placebo 3 times daily.² Of the 50 participants, 26 in the arimoclomol group and 13 in the placebo group received concomitant miglustat during the trial. For this analysis, researchers evaluated efficacy in the miglustat-treated patients at months 3, 6, 9, and 12 using the R4DNPCCSS, which assesses ambulation, speech, swallowing, and fine motor skills, with higher scores indicating greater disease severity.

Authors concluded that arimoclomol combined with miglustat may slow NPC disease progression from as early as 3 months after treatment initiation. Still, the findings should be interpreted with caution given the post hoc design and the small subgroup size inherent to an ultra-rare disease. The abstract presentation also did not report absolute score changes by treatment arm or safety outcomes for this subgroup.

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NPC is an ultra-rare, progressive neurodegenerative lysosomal disease with a heterogeneous clinical presentation. In September 2024, the FDA approved arimoclomol, an orally available small molecule, in combination with miglustat for the treatment of neurological symptoms of NPC in adults and children aged 2 years and older, making it the first FDA-approved therapy for the disease. The agency noted that efficacy was demonstrated using the R4DNPCCSS in patients who received miglustat as background treatment, and that the most common adverse effects included upper respiratory tract infection, diarrhea, and decreased weight.²

The R4DNPCCSS was introduced as a post hoc primary end point for NPC002, removing the cognition domain from the original 5-domain scale and rescoring the swallowing domain to better reflect linear disease progression over 12 months. In a 2025 analysis published in Molecular Genetics and Metabolism Reports, mean (SE) change in R4DNPCCSS over 12 months was 0.35 (0.40) with arimoclomol (n = 34) vs 2.05 (0.54) with placebo (n = 16), corresponding to a treatment effect of −1.70 (P = .02).

In the miglustat subgroup, mean (SE) change was −0.23 (1.02) with arimoclomol (n = 22) vs 1.92 (3.37) with placebo (n = 12), representing a treatment effect of −2.21 (P = .008).³ The authors also reported high agreement between R4DNPCCSS domain scores and established measures, including the Clinical Global Impression Scale of Severity and the Scale for Assessment and Rating of Ataxia, supporting the validity of the rescored scale.

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REFERENCES
1. Fanelli MJ, Mengel E, í Dali C, Quartel A. Efficacy of arimoclomol combined with miglustat at months 3, 6, 9 and 12 of the double-blind, randomized, placebo-controlled NPC002 trial. Presented at: CNS 2026; October 14-17, 2026; Montreal, Canada. Poster EOP-4.
2. FDA approves first treatment for Niemann-Pick disease, type C. News release. FDA. September 20, 2024. Accessed October 13, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-niemann-pick-disease-type-c
3. Mengel E, Patterson MC, Da Riol RM, et al. 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. Mol Genet Metab Rep. 2025;43:101233. Published 2025 May 28. doi:10.1016/j.ymgmr.2025.101233