Efficacy and safety of N-acetyl-L-leucine in children and adults with GM2 gangliosidoses

Martakis K, Claassen J, Gascon-Bayari J, Goldschagg N, Hahn A, Hassan A, Hennig A, Jones S, Kay R, Lau H, Perlman S, Sharma R, Schneider S, Bremova-Ertl T. Efficacy and Safety of N-Acetyl-L-Leucine in Children and Adults With GM2 Gangliosidoses. Neurology. 2022 Dec 1:10.1212/WNL.0000000000201660. doi: 10.1212/WNL.0000000000201660. Epub ahead of print. PMID: 36456200.

Abstract

Background and objective: GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases) are rare, autosomal-recessive, neurodegenerative diseases with no available symptomatic or disease modifying treatments. This clinical trial investigated N-acetyl-L-leucine (NALL), an orally administered, modified amino acid in pediatric (≥ 6 years) and adult patients with GM2 gangliosidoses.

Methods: In this Phase IIb, multi-national, open-label, rater-blinded study (IB1001-202), male and female patients aged ≥6 years with a genetically confirmed diagnosis of GM2 gangliosidoses received orally-administered NALL for a 6-week treatment period (4 g/day in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week post-treatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a pre-determined primary anchor test (the 8-Meter Walk Test or the 9-Hole Peg Test) at baseline, after 6 weeks on NALL, and again after a 6-week washout period, was videoed and evaluated centrally by blinded raters. Secondary outcomes included assessments of ataxia, clinical global impression, and quality of life.

Results: 30 patients between the age of 6 and 55 were enrolled. 29 had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary endpoint (mean difference 0.71, SD=2.09, 90% CI 0.00, 1.50, p=0.039), as well as secondary measures of ataxia and global impression. NALL was safe and well-tolerated, with no serious adverse reactions.

Conclusions: Treatment with NALL was associated with statistically significant and clinically-relevant changes in functioning and quality of life in patients with GM2 gangliosidosis. NALL was safe and well-tolerated, contributing to an overall favourable risk: benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs.

Classification of evidence: This study provides Class IV evidence that NALL improves outcomes for patients with GM2 gangliosidoses.