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.

N-acetyl-L-leucine improves symptoms and functioning in GM2 Gangliosidosis (Tay-Sachs & Sandhoff)

“…The results of the trial are consistent with a parallel trial completed for NPC, where treatment also had a statistically significant and clinically meaningful effect on the primary CI-CS and secondary (SARA, CGI-C, etc) endpoints. 7 As briefly described, these clinical findings correlate directly with studies in the GM2 gangliosidosis mouse model (Hexb -/-) and NPC mouse model (NPC -/-) where N-acetyl-leucine reduced ataxia when treatment was commenced pre-symptomatically (from 3-weeks of age onward) or symptomatically (for 1-week treatment, starting at 8-weeks of age). NALL restored aerobic (pyruvate dihydrogenase-dependent) and enhanced anaerobic (lactate dehydrogenasedependent) glycolysis, and returned the glutamate-metabolizing enzyme, glutamate dehydrogenase, to levels observed in Hexb +/+ and NPC +/+ null mice.…”

“…We used the same methodology study design as the one employed in a previous study and described in detail before. 7,12 The IB1001-201 clinical trial was separated into two study phases to enable the investigation of both the symptomatic ("Parent Study"), and long-term ("Extension Phase") safety and efficacy of NALL. The results of the Parent Study are reported below.…”

“…This result was comparable with the inter-rater correlation of 70% in the NALL clinical trial for NPC (IB1001-201). 7 In the IB1001-201 (NPC) and IB1001-202 (GM2 gangliosidoses) trials, different primary and adjudication raters were used. That this degree of consistency is produced is supportive of the robustness and consistency of the CI-CS methodology.…”

“…[3][4][5][6] Recently, a parallel, multinational, Phase IIb clinical trial with NALL for NPC demonstrated a statistically significant (primary and secondary endpoints) and clinically meaningful improvement in symptoms, functioning, and quality of life for children and adults with NPC. 7 In all observational and clinical studies, NALL has been well tolerated with no serious side effects.…”

Acetyl-dl-leucine in cerebellar ataxia ([18F]-FDG-PET study): how does a cerebellar disorder influence cortical sensorimotor networks?

“…In patients with Niemann-Pick type C (NPC), the SARA and SCAFI scores also improved; only one patient reported transient dizziness [8]. These findings in NPC were supported by a more recent phase 2 trial [9] and preclinical studies in animal models as well as in gangliosidosis GM2 [10,11]. The third case series applying AL (500 mg, 4-3-3 tablets per day) in different types of cerebellar ataxia showed improved walking stability in 14 out of 18 patients measured on a GAITRite system [12].…”