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\u2009mg/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\u2009points/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\u2009months (p\u2009=\u20090.037) and 47% reduced risk of death (p\u2009=\u20090.025) was observed for patients receiving 4.5\u2009mg/kg/day masitinib (n\u2009=\u200945) versus placebo (n\u2009=\u200962) 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\u2009months, 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\u2009months average follow-up from diagnosis) indicates that oral masitinib (4.5\u2009mg/kg/day) could prolong survival by over 2\u2009years 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).