Masitinib in mild to moderate Alzheimer’s disease: Results from study AB09004

Abstract

AbstractBackgroundMasitinib is a small molecule drug targeting KIT, LYN, FYN and CSF1R. Proof‐of‐concept that masitinib slowed cognitive decline in Alzheimer's disease (AD) was previously demonstrated [doi:10.1186/alzrt75; doi:10.3233/JAD‐200466]. Study AB09004 assessed oral masitinib administered as an add‐on therapy to standard care for the treatment of mild to moderate AD.MethodPhase 2B/3 study AB09004 comprised two independent, double‐blinded, placebo‐controlled, sub‐studies: masitinib at 4.5mg/kg/day versus placebo (randomized 1:1), and a titrated masitinib dose of 6.0 mg/kg/day versus matched placebo (randomized 2:1). Eligible patients that had a clinical diagnosis of AD with baseline mini‐mental state examination (MMSE) score ≥12–≤25, and had received a stable dose of cholinesterase inhibitor (donepezil, rivastigmine or galantamine) and/or memantine for ≥6 months, were treated for 24 weeks. Primary endpoint was overall change from baseline at week‐24 (analysis of covariance model) in the Alzheimer's Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog) or the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS‐ADL) score. The study was successful if a significant improvement was reached on either ADAS‐Cog or ADCS‐ADL at a 2.5% level of statistical significance, in either sub‐study.ResultMasitinib (4.5mg/kg/day) (n=182, median (age=73 years, MMSE=19, ADCS‐ADL=55.0, ADAS‐Cog=25.5)) showed significant benefit over placebo (n=176, median (age=73 years, MMSE=19, ADCS‐ADL=53.5, ADAS‐Cog=24.8)) with a least‐squares mean difference in ADAS‐Cog from baseline (δCog) of ‐1.46 versus 0.69, respectively, and corresponding least‐squares mean difference between groups (ΔCog) of ‐2.15 (97.5%CI[‐3.48,‐0.81]);p=0.0003. All ADAS‐Cog sensitivity analyses were convergent with the primary outcome, including the conservative jump‐to‐reference approach with ΔCog of ‐1.89 (95%CI[‐3.06,‐0.72];p=0.0016). Considering ADCS‐ADL, δADL was 1.01 for masitinib (4.5mg/kg/day) versus ‐0.81 for placebo, with a ΔADL of 1.82 (97.5%CI[‐0.15,3.79]);p=0.038. Safety was consistent with the known profile for masitinib. The proportion of patients presenting at least one adverse event (AE) or severe AE was respectively, 87.0% and 26.5% for masitinib (4.5mg/kg/day, n=185) versus 77.5% and 19.3% for placebo (pooled, n=280). Efficacy results from the titrated masitinib 6.0 mg/kg/day sub‐study were inconclusive and no new safety signal was observed.ConclusionMasitinib (4.5mg/kg/day), a tyrosine kinase inhibitor targeting mast cell and microglia activity, may provide a new treatment option for mild to moderate AD.