Masitinib is an oral, brain penetrant inhibitor of microglial and mast cell activity with neuroprotective potential in progressive forms of multiple sclerosis

作者：Patrick Vermersch, Alain Moussy, Colin D. Mansfield, Olivier Hermine · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.07.02.735783 · 研究领域：Mast cells and histamine、Multiple Sclerosis Research Studies、Neurological Disorders and Treatments

Abstract Introduction Progressive multiple sclerosis (MS), including primary progressive MS (PPMS) and non-active secondary progressive MS (nSPMS), remains an unmet need, as few treatments target innate immune pathways. Masitinib (AB1010) is a selective tyrosine kinase inhibitor that targets c-Kit and colony-stimulating factor 1 receptor pathways. This mechanism disrupts mast cell-microglia interactions, key innate immune effectors in progressive MS pathogenesis, reducing neuroinflammation and neuronal damage. In the phase 3 AB07002 trial, masitinib (4.5 mg/kg/d) over 96 weeks met its primary endpoint. Comparable signals in PPMS and nSPMS indicated masitinib benefited both phenotypes. Secondary analyses showed that masitinib lowered the progression to wheelchair dependence (EDSS ≥7.0, 12 weeks) and reduced the 12-week confirmed EDSS progression risk by 37% versus placebo. Methods This study aimed to confirm that oral masitinib achieves central nervous system (CNS) concentrations sufficient to modulate CSF1R and wild-type c-Kit, thereby underpinning its neuroprotective potential. Male Sprague Dawley rats (n=12, ∼200 g) were administered a single oral dose (30 mg/kg). Plasma and brain samples were collected at 2, 4, 8, and 24 hours post-dose (n=3 per time point). Masitinib (AB1010) and its metabolite (AB3280) were quantified in plasma and brain homogenates using LC-MS/MS. Results Masitinib reached a brain Cmax of 223.5 ng/mL (∼450 nM), exceeding IC 50 values for CSF1R and wild-...