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Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis: A Randomized, Phase 3, Clinical Trial
Patrick Vermersch1, Luis Brieva-Ruiz2, Robert J Fox2
1From the Univ. Lille (P.V.), UMR Inserm U1172, CHU Lille, FHU Precise, France; Neurology Department (L.B.-R.), Hospital Arnau de Vilanova de Lleida, Spain; Mellen Center for Multiple Sclerosis (R.J.F.), Neurological Institute, Cleveland Clinic, OH; Experimental and Clinical Research Center and NeuroCure Clinical Research Center (F.P.), Max Delbrueck Center for Molecular Medicine and Charité Universitaetsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany; Neurology Department (L.R.-T.), Dr Josep Trueta University Hospital, Girona; Neurodegeneration and Neuroinflammation Research Group (L.R.-T.), IDIBGI, Salt; Medical Science Department (L.R.-T.), University of Girona, Spain; Neurology Department (M.S.), Jena University Hospital, Germany; AB Science (A.M., C.M., O.H.), Paris, France; Imagine Institute (O.H.), INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implication, Hôpital Necker, Paris, France; and MA LEK AM Maciejowscy SC Centrum Terapii SM (M.M.), Katowice, Poland. patrick.vermersch@univ-lille.fr.
Background And Objectives:
Masitinib is a selective tyrosine kinase inhibitor, targeting innate immune cells (mast cells and microglia) that are involved in the pathophysiology of progressive multiple sclerosis (MS). Study AB07002 assessed oral masitinib in patients with progressive MS who were progressing but not clinically active.
Methods:
This randomized, double-blind, 2 parallel-group, placebo-controlled trial assessing 2 dose levels of masitinib vs equivalent placebo was conducted at 116 hospital clinics and specialized MS centers in 20 countries. Randomization (2:1) with minimization was performed centrally using an automated system. Patients, physicians, and outcome assessors remained masked to treatment group allocation. Patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS) without relapse for ≥2 years, aged 18-75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0-6.0, and regardless of time from onset were treated for 96 weeks. The primary end point was overall EDSS change from baseline using repeated measures (generalized estimating equation, timeframe W12-W96, measured every 12 weeks), with positive values indicating increased clinical deterioration. Efficacy and safety were assessed in all randomly assigned and treated patients.
Results:
A total of 611 patients were randomized; 301 in the masitinib 4.5 mg/kg/d parallel group and 310 in the uptitrated masitinib 6.0 mg/kg/d parallel group. Masitinib (4.5 mg/kg/d) (n = 199) showed significant benefit over placebo (n = 101) according to the primary end point, 0.001 vs 0.098, respectively, with a between-group difference of -0.097 (97% CI -0.192 to -0.002); p = 0.0256. Safety was consistent with masitinib's known profile (diarrhea, nausea, rash, and hematologic events), with no elevated risk of infection. Efficacy results from the independent uptitrated masitinib 6.0 mg/kg/d parallel group were inconclusive, and no new safety signal was observed.
Discussion:
Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data.
Trial Registration Information:
The first participant was randomized to study AB07002 on August 25, 2011. The trial was registered with the European Clinical Trials Database (#EudraCT 2010-021219-17) on July 1, 2011 (clinicaltrialsregister.eu/ctr-search/trial/2010-021219-17/ES) and with ClinicalTrials.gov (#NCT01433497) on September 14, 2011 (clinicaltrials.gov/ct2/show/NCT01433497).
Classification Of Evidence:
This study provides Class II evidence that masitinib 4.5 mg/kg/d decreased progression of disability, measured by the EDSS, in adults with PPMS or patients with nSPMS (with no exacerbations in the last 2 years).
Insights
Masitinib at 4.5 mg/kg/d demonstrated significant benefits in slowing disability progression for patients with primary progressive multiple sclerosis (PPMS) and nonactive secondary progressive multiple sclerosis (nSPMS). Further Phase 3 trials are planned to confirm these findings.
Area of Science:
- Neuroimmunology: Investigating targeted therapies for neuroinflammatory diseases.
- Pharmacology: Evaluating tyrosine kinase inhibitors in autoimmune conditions.
Background:
- Progressive multiple sclerosis (MS) involves innate immune cells like mast cells and microglia.
- Masitinib is a selective tyrosine kinase inhibitor targeting these key cells in MS pathophysiology.
Purpose of the Study:
- To assess the efficacy and safety of oral masitinib in patients with progressive multiple sclerosis (MS).
- To evaluate masitinib's impact on disability progression in patients with primary progressive MS (PPMS) or nonactive secondary progressive MS (nSPMS).
Main Methods:
- A randomized, double-blind, placebo-controlled trial (Study AB07002) involving 611 patients across 20 countries.
- Patients received masitinib (4.5 mg/kg/d or 6.0 mg/kg/d) or placebo for 96 weeks.
- The primary endpoint was the change in Expanded Disability Status Scale (EDSS) from baseline.
Main Results:
- Masitinib 4.5 mg/kg/d significantly reduced disability progression compared to placebo (EDSS change: 0.001 vs 0.098, p=0.0256).
- The 6.0 mg/kg/d dose showed inconclusive efficacy results.
- Safety profile was consistent with known masitinib effects; no increased infection risk was observed.
Conclusions:
- Masitinib 4.5 mg/kg/d offers a potential therapeutic benefit for patients with PPMS and nSPMS.
- A confirmatory Phase 3 study is warranted to validate these efficacy and safety findings.
