Long-term survival analysis of masitinib in amyotrophic lateral sclerosis

Jesus S Mora; Walter G Bradley; Delia Chaverri; María Hernández-Barral; Javier Mascias; Josep Gamez; Gisella M Gargiulo-Monachelli; Alain Moussy; Colin D Mansfield; Olivier Hermine; Albert C Ludolph

doi:10.1177/17562864211030365

Long-term survival analysis of masitinib in amyotrophic lateral sclerosis

Ther Adv Neurol Disord. 2021 Jul 19:14:17562864211030365. doi: 10.1177/17562864211030365. eCollection 2021.

Affiliations

¹ ALS Unit, Hospital San Rafael, Madrid, Spain.
² Department of Neurology, University of Miami School of Medicine, Miami, FL, USA.
³ ALS Unit, Department of Neurology, University Hospital La Paz-Carlos III, Madrid, Spain.
⁴ Neurology Department, GMA Clinic, Autonomous University of Barcelona, European Reference Network on Rare Neuromuscular Diseases (ERN EURO-NMD), Barcelona, Spain.
⁵ Hospital Universitario CEMIC-CONICET Buenos Aires, Argentina.
⁶ AB Science, Paris, France.
⁷ Department of Hematology, Necker Hospital, University of Paris, 149 Rue de Sèvres, Paris 75015, France.
⁸ Department of Neurology, University of Ulm, Oberer Eselsberg 45, Ulm 89081, Germany.

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.

Associated data

ClinicalTrials.gov/NCT02588677