Efficacy and safety of N-acetyl-L-leucine in Niemann-Pick disease type C

Abstract

Objective: To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick disease type C (NPC) patients.

Methods: In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments.

Results: 33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred.

Conclusions: NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS.

Gov identifier: NCT03759639.

Keywords: Acetyl-leucine; Ataxia; Lysosomal storage disorder; Niemann–Pick disease type C; Symptomatic therapy.

Fig. 1

Trial profile

Fig. 2

Forest plot for CI-CS scores for pre-defined subgroup analysis, based on the mITT population. The lines and dots in blue represent the change per subgroup on the CI-CS scores during the treatment period: Visit 4 (end of treatment) vs. Visit 2 (baseline). The lines and dots in orange represent the change per subgroup on the CI-CS scores during the washout period: CI-CS scores visit 6 (end of washout) vs. Visit 4 (end of treatment). The dots represent the pseudo-medians or Hodges–Lehmann estimators, the horizontal lines represent the 90% confidence intervals. LCL lower confidence limit, UCL upper confidence limit. For some subgroups the number of patients was too small to calculate the LCL and/or UCL, in that case, the result is presented as missing and no line presenting the confidence interval is drawn. No last observation carried forward (LOCF) approach was used for this figure. Only values from patients with reported data are included.

Fig. 3

Results of the primary and key secondary endpoints. All analysis based on the mITT population. For each figure, the left-hand column (blue) illustrates CI-CS results comparing baseline to the end of the treatment period; the right-hand column (orange) illustrates the CI-CS results comparing the end of the treatment period to the end of the washout period. The vertical extent of the column represents the 90% Hodges–Lehman (HL) confidence interval of the CI-CS; a solid line is used to indicate the Hodges–Lehman median estimator, and a cross symbol indicates the Mean response. A Results of the primary endpoint: Clinical Impression of Change in Severity (CI-CS), based on a 7-point scale, ranging from − 3, “significantly worse”, 0, “no change”, to + 3 to “significantly improved”. B Results on the secondary endpoint: Scale for the Assessment and Rating of Ataxia (SARA); C results on the secondary endpoint: Clinical Global Impression of Change—Physician, Caregiver, Patient; based on a 7-point scale, ranging from − 3, “significantly worse”, 0, “no change”, to + 3 to “significantly improved”; D results on the secondary endpoint: Modified Disability Rating Scale (mDRS); E results on the secondary endpoint: Spinocerebellar Ataxia Functional Index (SCAFI)