Long-Term Findings of N-Acetyl-L-leucine for Niemann–Pick Disease Type C

Background/Purpose: The IB1001-301 clinical trial was a Phase III, double-blind, randomized, placebo-controlled trial comparing N-acetyl-L-leucine (NALL) with placebo for the treatment of neurological signs and symptoms in children and adults with Niemann–Pick disease type C (NPC) after a treatment period of 12 weeks. The primary Scale for the Assessment and Rating of Ataxia (SARA) endpoint was reduced −1.97 points with NALL and −0.60 with placebo (p < 0.001). Extended follow-up data were obtained in an open-label Extension Phase (EP) to evaluate the long-term, neuroprotective effects of NALL for NPC.

Methods: Patients received treatment with orally administered NALL 2 to 3 times per day in tiers of weight-based dosing. The primary endpoint was the modified 5-domain NPC Clinical Severity Scale (5-Domain NPC-CSS) (range 0–25 points; lower score representing better neurological status). Comparisons were made to the expected annual trajectory of disease decline established in published natural history studies. Exploratory endpoints included the 17-domain NPC-CSS (excluding hearing) and SARA.

Results: A total of 54 patients aged 5 to 67 years were treated in the EP. After 12 months, the mean (±SD) change from baseline on the 5-domain NPC-CSS was −0.115 (±2.60) and 1.5 ± 3.1 in the historical cohort (mean difference 1.56; 95% confidence interval, 0.31–2.92; p < 0.017), a 108% reduction in annual disease progression. The result of the 17-domain NPC-CSS (excluding hearing) was supportive of the primary analysis and the improvements in neurological status demonstrated in the Parent Study’s primary SARA endpoint were sustained over the long-term follow-up. NALL was well-tolerated, and no treatment-related serious AEs occurred.

Conclusion: Children and adults with NPC who were treated with NALL after 1 year showed a statistically and clinically significant reduction in disease progression, consistent with a neuroprotective and disease-modifying effect.

 

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Publikationsverlauf

Artikel online veröffentlicht:
08. Oktober 2024