Masitinib as an add-on therapy to riluzole is beneficial in the treatment of amyotrophic lateral sclerosis (ALS) with acceptable tolerability: Results from a randomized controlled phase 3 trial
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Objective: Evaluate masitinib plus riluzole (100 mg/kg) in amyotrophic lateral sclerosis (ALS). Background: Masitinib, an oral tyrosine kinase inhibitor targeting CSF1R, generates neuroprotective effects by targeting aberrant microglial cells and regulating neuroinflammation.
Design: ALS patients received riluzole plus masitinib 3.0 mg/kg/day (M3.0), 4.5 mg/ kg/day (M4.5), or placebo (1:1:1) up to 48 weeks. Two groups were defined according to pre-randomization ALSFRS-R progression: ‘Normal Progressor’ (NP) of <1.1 points/ month, and ‘Fast Progressor’ of ≥1.1 points/month; thereby, reflecting the inherent heterogeneity of phenotype and disease progression within the overall population. Primary endpoint was absolute change in ALSFRS-R[W0–W48] (∆ALSFRS-R). The analysis was executed via a stepwise, sequential method with significance at P<0.05 (rerandomization). Step 1 was M4.5 in NP; step 2 was M3.0 in NP; step 3 was M4.5 in ‘Normal+Fast Progressors’ (NFP); step 4 was M3.0 in NFP. Missing data handled via LOCF with sensitivity analyses based on reason of discontinuation and single imputation methodology. Secondary endpoint analyses included progression free survival (PFS), progression being defined as ALSFRS-R deterioration of >9 points from baseline or death, quality-of-life by ALSAQ40, and FVC. Safety analysis included patients administered at least one dose of study drug.
Results: 394 patients (NFP cohort) were randomized to the M4.5 (130), M3.0 (131) and placebo (133) arms. The NP cohort comprised 330 patients: 106, 110 and 114, respectively. For the primary endpoint analysis (M4.5 in NP), masitinib showed a significant benefit in ∆ALSFRS-R over placebo with a least-square means difference (∆LSM) of 3.4 (9.2 vs.12.6); 95%CI 0.6–6.1; P=0.0158. In terms of ALSFRS-R[W0–W48] slope, masitinib showed a clinically meaningful retardation of 27% (0.77 vs.1.21 points/month). All sensitivity analyses were positive, with P<0.02 according to single imputation methodology. Masitinib also demonstrated benefit over placebo in the secondary variables, significantly improving median PFS by 25% (20 vs.16 months, P=0.0159); ALSAQ40 by 28.5% (∆LSM of 19.4 vs.27.2, P=0.0078); and FVC by 22% (∆LSM of 26.0 vs.33.4, P=0.0332). For M3.0 in NP, masitinib showed benefit over placebo for ∆ALSFRS-R=2.73 (-8.6 vs.-11.3, a 24% improvement, P=0.0661); and FVC (∆LSM of -23.1 vs.-27.9, a 17% improvement, P=0.1662) that did not reach statistical significance. The benefit reached significance for ALSAQ40 (∆LSM of 15.6 vs.23.7, a 34% improvement, P=0.0057). No significant difference was seen between treatment-arms for analysis according to the NPF cohort. Common (>10%) adverse events (AEs) with masitinib in the NP cohort were rash, nausea, diarrhea, and weight loss. Frequency of AEs, serious AEs, and severe AEs (placebo versus M4.5 and M3) was respectively: 79% vs. 90% and 84%; 20% vs. 28% and 18%; 18% vs. 24% and 17%.
Conclusions: Masitinib orally administered at 4.5 mg/kg/day as an add-on to riluzole demonstrated a significant therapeutic benefit with acceptable safety in ALS patients with a baseline ALSFRS-R progression rate of <1.1 points/month. Significant disease retardation was evident in terms of ∆ALSFRS-R and ALSFRS-R slope (slowed loss of function), PFS (delayed progression), ALSAQ-40 (reduced decline in quality-of-life), and FVC (surrogate measure of survival). Masitinib may therefore be an important new therapeutic option for these patients.
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