Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients

Masitinib is a selective, oral tyrosine kinase inhibitor with neuroprotective capability demonstrated via numerous preclinical studies. Two of masitinib's main cellular targets are the mast cell and microglia cell. It is well-established that mast cells play a prominent role in neuroinflammatory processes. Microglia, resident immune cells of the central nervous system (CNS), also constitute an important source of neuroinflammatory mediators and may have fundamental roles in numerous neurodegenerative disorders. The development of masitinib in ALS is therefore based on the pharmacological action of masitinib in microglia cells and mast cells, thereby slowing microglial-related disease progression, reducing neuro-inflammation, and modulating the neuronal microenvironment in both central and peripheral nervous systems. This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group (two ascending dose titrations of masitinib and matching placebo), comparative study of oral masitinib in the treatment of patients with amyotrophic lateral sclerosis (ALS).

• Masitinib (6.0) (Drug), also known as AB1010: Masitinib (titration to 6.0 mg/kg/day)
• Riluzole (Drug), also known as Rilutek: Riluzole 50 mg tablet, treatment per os
• Placebo (Drug), also known as Placebo Oral Tablet: treatment per os
• Masitinib (4.5) (Drug), also known as AB1010: Masitinib (titration to 4.5 mg/kg/day)

Primary outcomes

• ALSFRS-R [48 weeks]: Change in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised.

Secondary outcomes

• ALSAQ-40 [48 weeks]: Change in ALS quality of life patient questionnaire (ALSAQ-40)
• PFS [From day of randomization to disease progression or death, assessed for a maximum of 36 months]: Progression free survival (PFS) is defined as the time from randomization to progression (decline of more than 9 points in ALSFRS-R score from baseline) or death
• FVC [48 weeks]: Change in Forced Vital Capacity (FVC)
• HHD [48 weeks]: Change in evaluation of upper- and lower-limb muscle strength using hand-held dynamometry (HHD)
• Change in the Combined Assessment of Function and Survival (CAFS) score from baseline to week 48 [48 weeks]: CAFS ranks patients' clinical outcomes based on survival time and change in the ALS Functional Rating Scale-Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score indicates a better group outcome.

Sex: All, ages: 18 Years to 81 Years

Main inclusion criteria include:

* Patients diagnosed with laboratory supported probable, clinically probable or definite ALS according to the World Federation of Neurology Revised El Escorial criteria
* Patient with a familial or sporadic ALS
* ALS disease duration from diagnosis no longer than 24 months at the screening visit
* Patient treated with a stable dose of riluzole (100 mg/day) for at least 12 weeks days prior to the baseline visit
* Patient with an ALSFRS-R score progression between onset of the disease and screening of > 0.3 per month, confirmed with an ALSFRS-R score progression of ≥ 1 point during a 12-week run-in period between screening and randomization.
* Patient with a score, at screening, of at least 26 overall, including a score of at least 3 on item #3 and at least 2 on each of the 12 ALSFRS-R individual component items and with a score, at randomization, of at least 2 on each of the 12 ALSFRS-R individual component items

Main exclusion criteria include:

* Patient with dementia or significant neurological, psychiatric, systemic or organic disease, uncontrolled or that may interfere with the conduct of the trial or its results
* Patient with a FVC < 60% predicted normal value for gender, height, and age at screening and baseline
* Pregnant, or nursing female patient

• Results publication: Latham BD, Oskin DS, Crouch RD, Vergne MJ, Jackson KD. Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib. Chem Res Toxicol. 2022 Sep 19;35(9):1467-1481. doi: 10.1021/acs.chemrestox.2c00057. Epub 2022 Sep 1. PMID 36048877

• Albert Ludolph, MD, PhD, Principal investigator, Department of Neurology, University of Ulm, Germany