Efficacy and Safety of N-Acetyl-l-Leucine in Children and Adults With GM2 Gangliosidoses

Abstract

Background and objectives: 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, multinational, 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/d in patients ≥13 years, weight-tiered doses for patients 6-12 years), followed by a 6-week posttreatment washout period. For the primary Clinical Impression of Change in Severity analysis, patient performance on a predetermined 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: Thirty patients between the age of 6 and 55 years were enrolled. Twenty-nine had an on-treatment assessment and were included in the primary modified intention-to-treat analysis. The study met its CI-CS primary end point (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.

Discussion: 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 favorable risk:benefit profile. NALL is a promising, easily administered (oral) therapeutic option for these rare, debilitating diseases with immense unmet medical needs.

Trial registration information: The trial is registered with ClinicalTrials.gov (NCT03759665; registered on November 30, 2018), EudraCT (2018-004406-25), and DRKS (DRKS00017539). The first patient was enrolled on June 7, 2019.

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

Figure 1. IB1001-202 Study Flow Diagram

Figure 2. Primary End Point: Clinical Impression of Change in Severity (CI-CS) (mITT)

The CI-CS was calculated from a 7-point scale, ranging from −3, “significantly worse”, to 0, “no change”, to +3 “significantly improved.” The panel compares the CI-CS score calculated for the end of the treatment period vs end of baseline (left-hand column, in blue) with the CI-CS score calculated for the end of the washout period vs end of treatment (right-hand column, in orange). The vertical length of the column represents the 90% Hodges-Lehmann (HL) CI of the CI-CS. Solid lines are used to denote the Hodges-Lehmann Median Estimator, and cross symbols are used to denote the mean response.

Figure 3. Forest Plot Subgroup Analyses for the Primary End Point: CI-CS Scores (mITT)

The change in the CI-CS scores during the treatment period (end of treatment vs baseline; depicted in blue) and during the washout period (end of washout vs end of treatment; depicted in orange) is displayed for individual, predefined subgroups. The dots represent the pseudo-medians or Hodges-Lehmann estimators. Some subgroups were large enough to calculate 90% CIs (represented by the horizontal lines). Only values from patients with reported data were included in the subgroup analyses—no last observation carried forward (LOCF) approach was applied.

Figure 4. Secondary End Point: Clinical Global Impression of Change (mITT)

(A) Physician's CGI-C. (B) Caregiver CGI-C. (C) Patient's CGI-C. For each scale, the results comparing baseline to end of treatment (left-hand column, blue) are compared with the results comparing the end of the treatment period to the end of the washout period (right-hand column, orange). The vertical length of the column represents the 90% Hodges-Lehmann (HL) CI of the CGI-C. Solid lines are used to indicate the Hodges-Lehmann Median Estimator, and cross symbols are used to denote the mean response.

Figure 5. Secondary Functional End Points (mITT)

(A) Scale for the Assessment and Rating of Ataxia (SARA). (B) Modified Disability Rating Scale (mDRS). (C) Spinocerebellar Ataxia Functional Index (SCAFI). (D) PATA Speech Test. For each test, the results comparing baseline to end of treatment (left-hand column, blue) are compared with the results comparing the end of the treatment period to the end of the washout period (right-hand column, orange). The vertical length of the column represents the 90% Hodges-Lehmann (HL) CI. Solid lines are used to denote the Hodges-Lehmann Median Estimator, and cross symbols are used to denote the mean response.