Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis
Patrick Vermersch, Luís Brieva, Robert J. Fox, Friedemann Paul, Lluís Ramió‐Torrentà, Matthias Schwab, Alain Moussy, Colin D. Mansfield, Olivier Hermine, Maciej Maciejowski, on behalf of the AB07002 Study Group, Nassima Hecham, Norma Deri, Jasminka Djelilović-Vranić, Ivan Milanov, Penko Shotekov, Gregg Blevins, J Girard, Yves Lapierre, William Camu, Giovanni Castelnovo, Pierre Clavelou, P. Hautecoeur, Martin Marziniak, Christoph Mayer, Patrick Oschmann, Gerd Reifschneider, I. Schoell, Björn Tackenberg, Florian Then Bergh, Ν. Fakas, Nikolaos Grigoriadis, D. Kalochristianakis, Dimos D. Mitsikostas, Anastasios Orologas, Antonios Tavernarakis, Thomas Thomaidis, Krisztina Kovács, K Mátyás, Pálma Piros, Mária Sátori, K.J.S. Anand, Alexander L. Shifrin, Krzysztof Banaszkiewicz, Robert Bonek, M. Chahwan, M. Czernichowska - Kotiuszko, Lidia Darda-Ledzion, J. D. Wojcik, M Dziki, Ewa Krzystanek, Marianna Kulka, Paweł Lisewski, Marcin Ratajczak, Andrzej Szczudlik, Jarosław Szczygieł, Małgorzata Pańczyk-Tomaszewska, Jacek Wójcik, Daniel Zielonka, M. Chiru, Swaroopa Deme, S Mănescu, S.A. Nica, Christian Popescu, Szabolcs Szatmári, A. L. Fedyanin, N A Malkova, D.V. Popov, Л. И. Волкова, Vorob'eva Ov, M Brozman, Andrea Cimprichová, P. Cuchran, Ladislav Gurcik, Georgi Krastev, I. Lisá, M. Nyeky, J. Poljaková, Peter Turčáni, Adaani Frost, Josef G. Heckmann, Eduardo Agüera, Francisco Coret, Antonio Escartín, Victoria Fernández, JR. Ara Callizo, Greg S. Martin, José Rodríguez, M. Martinez Gines, Daniel Muñoz, Javier Olascoaga, José M. Prieto, Cristina Ramo‐Tello, Samir Belal, S. Ben Ammou, Mahbouba Frih-Ayed, Riadh Gouider, Chokri Mhiri, Ridha Mrissa, Alla Cherkez
Abstract
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: = 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).