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Amyotroph Lateral Scler Frontotemporal Degener. 2019 Jul 7:1-10. doi: 10.1080/21678421.2019.1632346. [Epub ahead of print]

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial.

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a ALS Unit, Hospital San Rafael , Madrid , Spain.
b Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University , Montreal , Canada.
c Department of Neuroscience, University of Turin , Turin , Italy.
d Neurological Center for Treatment and Rehabilitation , Buenos Aires , Argentina.
e Department of Neurology, ALS Unit, Hospital Carlos III , Madrid , Spain.
f Neurology Department, Neuron Motor Disease Clinic, Hospital JM Ramos , Buenos Aires , Argentina.
g Neurology Department, Bellvitge Hospital-IDIBELL , Barcelona , Spain.
h Neurology Department, Vall d'Hebron University Hospital, Vall d'Hebron Research Institute, Autonomous University of Barcelona , Barcelona , Spain.
i NEMO Clinical Centre, Serena Onlus Foundation , Milan , Italy.
j Neurorosario , Rosario , Argentina.
k Department of Neurology-INSPE, San Raffaele Scientific Institute , Milan , Italy.
l Department of Neurosciences, St. Agostino-Estense Hospital, Azienda Ospedaliero Universitaria di Modena , Modena , Italy.
m AB Science , Paris , France.
n Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center , Boston , MA , USA.
o Department of Biology, Université Paris Sud Université Paris-Saclay CNRS UMR 8113, Ecole Normale Supérieure de Cachan , Cachan , France.
p INSERM, CNRS, Institut Paoli-Calmettes, CRCM, Centre de Référence des Mastocytoses, Equipe Labelisée Ligue Nationale Contre le Cancer, Aix-Marseille University , Marseille , France ; and.
q Imagine Institute, INSERM UMR 1163 and CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hemathological Disorders and Therapeutic Implication, Hôpital Necker , Paris , France.


Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population ("Normal Progressors", ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose "Normal Progressor" cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65-6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53-6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader "Normal and Fast Progressor" masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.


Clinical trials; masitinib ; therapy; tyrosine kinase inhibitor

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