Discussion
cognitive deterioration, AD, dementia
DISEASE
Masitinib was administered as an adjunct therapy to standard of care in patients with mild to moderate dementia due to probable AD. After 24 weeks of treatment, masitinib (4.5 mg/kg/day) significantly slowed cognitive deterioration (as measured by the primary endpoint of ADAS-cog), with acceptable safety. This positive outcome was supported by convergence in ADAS-cog sensitivity analyses (jump-to-reference and ITT), a statistically significant clinical response rate, and a nonsignificant trend towards improved overall function relative to placebo (as measured by the second primary endpoint of ADCS-ADL). Conversely, results from the titrated masitinib 6.0 mg/kg/day parallel group did not demonstrate any treatment effect. One explanation of this divergent result is that the titrated 6.0 mg/kg/day parallel group placebo arm showed an atypical improvement over 24 weeks, as exemplified by the positive change from baseline in ADCS-ADL score (eFigure 1 in the Administering masitinib as an adjunct to cholinesterase inhibitor and/or memantine only slightly increased the overall incidence rate ratio of AEs with respect to placebo (regardless of severity). Regarding the higher rate of patient discontinuation due to treatment-related AE in the masitinib arm as compared with placebo, a large proportion of this (about 60%) was attributable to AEs of mild or moderate severity that can be efficiently managed by dose reduction or temporary interruption.A limitation of our trial was the lack of fluid- and imaging-based biomarkers as evidence to support modification of underlying disease processes (e.g., cerebrospinal fluid tests measuring tau or measuring the brain volume using MRI scanning), or proof of target engagement (e.g., neuroinflammatory markers). Biomarker tests, as recommended by the IWG or by the NIA-AA diagnostic criteria [