Efficacy and safety of masitinib in amyotrophic lateral sclerosis patients prior to loss of functionality: A subgroup analysis optimizing the benefit-risk profile of masitinib

Abstract Background Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that urgently requires new treatments. Masitinib, a tyrosine kinase inhibitor targeting microglia and mast cells, aims to slow disease progression by reducing neuroinflammation. A previously reported phase 2b/3 study showed that masitinib (4.5 mg/kg/day) with riluzole significantly slowed decline of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) over 48 weeks in a specific patient population. However, a baseline imbalance was noted, with a higher proportion of patients with very severe loss of functionality (those with a score of 0 on at least one item of the ALSFRS-R) in the masitinib group. This post-hoc analysis evaluated the efficacy and safety of masitinib in the subgroup ‘ALS prior to any complete loss of functionality’ to eliminate potential bias and evaluate the effect of treatment in the early phase of the disease. Methods Data from study AB10015 were analyzed for patients with a score of at least 1 on all ALSFRS-R items at baseline. The primary endpoint was the change in ALSFRS-R score (ΔALSFRS-R) at week 48. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results In the subgroup (N=84 for masitinib, N=104 for placebo), masitinib demonstrated an increase of the treatment effect compared with that in the primary analysis population. The ΔALSFRS-R difference between masitinib and placebo was 4.04 points (p=0.0065), an improvement from 3.39 points in the primary analysis. The median PFS gain increased from +4 months to a statistically significant +9 months (p=0.0057), and the median OS gain increased from +6 months to a statistically significant +12 months (p=0.0192). Safety was consistent with that of the overall study safety population or even improved, with the incidence of serious adverse events in the masitinib group decreasing from 27.6% to 22.6%. Conclusion Excluding patients with very severe loss of functionality eliminated baseline imbalances and revealed a favorable benefit-risk profile for masitinib treatment. The subgroup ‘ALS prior to any complete loss of functionality’ experienced consistently greater benefits in terms of function, survival, and quality of life. This subgroup is easily identifiable using the ALSFRS-R assessment and is an option as the target population for future development, informing the design of confirmatory study AB23005.