Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis : a randomized clinical trial
Mora, J. S. (ALS Unit. Hospital San Rafael)
Genge, A. (Department of Neurology and Neurosurgery. Montreal Neurological Institute and Hospital. McGill University)
Chiò, Adriano (Department of Neuroscience. University of Turin)
Estol, C. J. (Neurological Center for Treatment and Rehabilitation)
Chaverri, D. (Hospital Carlos III (Madrid))
Hernández, M. (Hospital Carlos III (Madrid))
Marín, S. (Hospital Carlos III (Madrid))
Mascias, J. (Hospital Carlos III (Madrid))
Rodriguez, G. E. (Neurology Department. Neuron Motor Disease Clinic. Hospital JM Ramos)
Povedano, M. (Institut d'Investigació Biomèdica de Bellvitge)
Paipa, A. (Institut d'Investigació Biomèdica de Bellvitge)
Dominguez, Raúl (Institut d'Investigació Biomèdica de Bellvitge)
Gamez, Josep (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Salvado, M. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Lunetta, C. (NEMO Clinical Centre. Serena Onlus Foundation)
Ballario, C. (Neurorosario)
Riva, N. (Department of Neurology-INSPE. San Raffaele Scientific Institute)
Mandrioli, J. (Department of Neurosciences. St. Agostino-Estense Hospital. Azienda Ospedaliero Universitaria di Modena)
Moussy, A. (AB Science)
Kinet, J. P. (Department of Pathology. Harvard Medical School and Beth Israel Deaconess Medical Center)
Auclair, C. (Department of Biology. Université Paris Sud Université Paris-Saclay CNRS UMR 8113. Ecole Normale Supérieure de Cachan)
Dubreuil, P. (Institut Paoli-Calmettes Cancer Centre (Marsella, França))
Arnold, V. (AB Science)
Mansfield, C. D. (AB Science)
Hermine, O. (Imagine Institute. INSERM UMR 1163 and CNRS ERL 8254. Laboratory of Cellular and Molecular Mechanisms of Hemathological Disorders and Therapeutic Implication. Hôpital Necker)
Universitat Autònoma de Barcelona

Data:	2020
Resum:	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.
Nota:	Financial support for medical editorial assistance was provided by AB Science. We thank the study participants, their families, and caregivers. We also thank the AB10015 Study Group collaborators (Supplementary eTable 1). The Spanish ALS Research Foundation, FUNDELA, contributed to Dr. Mora's group support.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Clinical trials ; Therapy ; Tyrosine kinase inhibitor ; Masitinib
Publicat a:	Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, Vol. 21 Núm. 1-2 (february 2020) , p. 5-14, ISSN 2167-9223

DOI: 10.1080/21678421.2019.1632346
PMID: 31280619

12 p, 1.1 MB

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