Long-term survival analysis of masitinib in amyotrophic lateral sclerosis

Abstract

Background: A randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001.

Methods: Survival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity.

Results: A significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31-0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001.

Conclusions: Analysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).

Keywords: clinical trials; masitinib; therapy; tyrosine kinase inhibitor.

Conflict of interest statement

Conflict of interest statement: Masitinib is under clinical development by the study funder, AB Science. AM, OH and CDM are employees and shareholders of AB Science. JSM has received research funding from AB Science. All remaining authors have no competing interests. AL, an Associate Editor of Therapeutic Advances in Neurological Disorders, is an author of this paper, therefore, the peer review process was managed by alternative members of the Board and the submitting Editor was not involved in the decision-making process.

© The Author(s), 2021.

Figures

Figure 1.

(a) Relationship between randomized treatment arms of study AB10015, cohorts used for the AB10015 long-term OS analysis, and subpopulations of interest for the NPP long-term OS analysis. (b) Time frame for study AB10015 long-term OS analysis showing a 75-month average duration of observation (time of diagnosis until cut-off of long-term OS analysis). LT, long term; NPP, Named Patient Program; OS, overall survival; PBO, placebo.

Figure 2.

Kaplan–Meier survival curves from masitinib study AB10015 long-term survival analysis. (a) Overall masitinib 4.5 mg/kg/day cohort versus placebo (regardless of baseline ΔFS or individual component scores). (b) Enriched* masitinib 4.5 mg/kg/day cohort versus placebo (⩾2 on each baseline ALSFRS-R individual component score and post-onset ΔFS < 1.1).

Figure 3.

Kaplan–Meier survival curves from masitinib NPP subgroup long-term OS analysis. (a) NPP-M4.5 versus masitinib-naïve PBO. (b) NPP-ALL versus masitinib-naïve PBO.