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).

Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib

“…The current investigation was conducted to determine the major P450 enzymes involved in the metabolism and bioactivation of masitinib, a tyrosine kinase inhibitor under clinical investigation for diverse therapeutic areas, including neurodegenerative diseases, , mast cell disorders, and COVID-19 . Masitinib is a structural analogue of the widely used anticancer tyrosine kinase inhibitor imatinib, but studies suggest that masitinib may have unique therapeutic potential.…”

“…Masitinib is a small molecule tyrosine kinase inhibitor of stem cell growth factor receptor KIT and platelet-derived growth factor receptors along with Lyn and Fyn kinases. , Masitinib has been studied as an investigational drug for the treatment of amyotrophic lateral sclerosis (ALS), , gastrointestinal stromal tumors, Alzheimer’s disease, multiple sclerosis, , and mastocytosis . Masitinib is currently used in veterinary medicine for the treatment of mast cell tumors in dogs .…”

Towards a general framework for innovation shaped with AI to create and transform market offerings

“…Dose‐escalation also applies to the main forerunner competing drug so‐called Imatinib – a Tyrosine Kinases (TKs) inhibitor involved in cancer and other proliferative disorders – used against amyotrophic lateral sclerosis (Soria et al, 2009; Mora et al, 2021). That is to say, regardless of the uncertain future of the MD1003, especially in Phase III (to evaluate how the new medication works in comparison to existing medications for the same condition), dose‐escalation remains at the very heart of the extension framework.…”

“…This pictures how the extension framework leads to a novel representation generalizing both the (meta-)structure and the identity of things and phenomena while including any prior representation as a sub-one. We can draw a close parallel here with the geometrization of space (see subsection 1.2) Dose-escalation also applies to the main forerunner competing drug so-called Imatiniba Tyrosine Kinases (TKs) inhibitor involved in cancer and other proliferative disordersused against amyotrophic lateral sclerosis (Soria et al, 2009;Mora et al, 2021). That is to say, regardless of the uncertain future of the MD1003, especially in Phase III (to evaluate how the new medication works in comparison to existing medications for the same condition), dose-escalation remains at the very heart of the extension framework.…”

New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022

“…The results from an international, phase 2/3, placebo-controlled trial in 394 adult patients with ALS showed that masitinib combined with riluzole could significantly slow the deterioration of ALSFRS-R scores by 27% ( Mora et al, 2020 ). The long-term overall survival analysis indicated that oral masitinib, if delivered early, could prolong survival by 2 years and decrease the mortality rate by 44% ( Mora et al, 2021 ). Moreover, a phase-3, multicenter, placebo-controlled, double-blind, randomized trial (NCT03127267) will compare the efficacy and safety of masitinib in combination with riluzole in 495 patients with ALS from 13 countries (United States, Denmark, France, Germany, Israel, Russian, Ukraine, etc., mainly American and European cohorts), sponsored by AB Science.…”