Results of a Phase III, Randomized, Placebo-controlled Crossover Trial with N-acetyl-L-leucine for Niemann-Pick Disease Type C
Tatiana Bremova-Ertl1, Taylor Fields2, Mallory Factor2, Kyriakos Martakis3, Michael Strupp4
1Department of Neurology, University Hospital Inselspital Bern, 2IntraBio, 3Justus Liebig University, Giessen, Department of Child Neurology, 4Department of Neurology, Ludwig Maximilians University, Munich, Germany
Objective:

We conducted a Phase 3 trial to confirm the safety and efficacy of the active L-enantiomer, N-acetyl-L-leucine (NALL) for pediatric (≥ 4 years) and adult patients with NPC.

Background:
Niemann-Pick disease type C (NPC) is a rare inherited neurodegenerative disorder. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in cellular and animal models of NPC, observational case studies, and a multinational, rater-blinded Phase IIb clinical trial. 
Design/Methods:

In this phase III, double-blind, randomized, placebo-controlled, crossover trial, subjects (aged 5 – 67 years) were enrolled across 13 multinational sites. Subjects were randomly assigned (1:1) to receive three-time daily orally administered NALL or matching placebo over two consecutive 12-week treatment periods.  The primary outcome was based on the Scale for the Assessment and Rating of Ataxia (SARA). The Clinical Global Impression of Improvement (CGI-I), Spinocerebellar Ataxia Functional Index (SCAFI), and Modified Disability Rating Scale (mDRS) were secondary endpoints included to further assess neurological function and symptoms (including cognition) and quality of life. The trial was registered with ClinicalTrials.gov (NCT05163288) and EudraCT (2021-005356-10).

Results:

60 patients were randomized and included in the primary intention-to-treat analysis set. The average improvement in the SARA score with NALL was superior to Placebo [95% CI -1.94, -0.69, p<0.001]. The secondary endpoints (CGI, SCAFI, mDRS) were also improved with IB1001 as compared to placebo (p<0.001). The frequency of adverse events (36 patients, 79 events when receiving NALL vs 30 patients, 75 events when receiving placebo) were similar between the two groups. No treatment-related serious adverse events or deaths occurred.

Conclusions:
NALL demonstrated a statistically significant improvement over placebo with a clinically meaningful benefit in symptoms (motor and cognitive), functioning, cognition, and quality of life.  NALL was safe and well-tolerated, providing a favorable benefit-risk profile for the treatment of NPC. 
10.1212/WNL.0000000000205236