Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

Abstract

Background and ObjectivesMasitinib 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.MethodsThis 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.ResultsA 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.DiscussionMasitinib (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 InformationThe 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 EvidenceThis 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).

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“…Figure 1 shows the flowchart for the study selection process. The initial research retrieved 910 articles after exclusion of duplicates; 95 studies were finally evaluated for inclusion in the analysis, of which 17 studies 1,2,4,5,9–20,21 were considered (five of these 15,16,19,20,21 tested non-approved DMTs, with diverse mechanisms of action, and were excluded). The reasons for the exclusion of the other 78 studies are reported in the Supplemental material (Table 1S).…”

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“…Indeed, there still be some limitations. Firstly, the number of researchers and total sample size included is small, and the patient number in the latest study about masitinib is more than 50% of the total population ( 27 ). However, fortunately, it is enough for analysis to get some meaningful conclusions with low heterogeneity in most analyses.…”

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“…The side effects were mild to moderate and included asthenia, leucopenia/lymphopenia, rash, and C+GI side effects [ 105 ]. A recent phase III, randomized, double-blind, 2 parallel group, placebo-controlled trial demonstrated a positive effect of masitinib 4.5 mg/kg/d on progression of disability, as measured by the EDSS, in patients with PPMS and relapse-free SPMS with no exacerbations in the last 2 years over a 96-week treatment period [ 106 ]. The side effects included diarrhea, nausea, rash, peripheral edema and neutropenia, consistent with masitinib’s known profile.…”