Introduction: We evaluated the selective M1 muscarinic positive allosteric modulator, MK-7622, as adjunctive cognitive enhancing therapy in individuals with Alzheimer's disease.
Methods: A randomized, double-blind, proof-of-concept trial was performed. Participants with mild-to-moderate Alzheimer's disease, being treated with an acetylcholinesterase inhibitor, were randomized 1:1 to 45 mg of MK-7622 or placebo for 24 weeks. Endpoints included the mean change from baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) at 12 weeks and Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory at 24 weeks.
Results: Two hundred forty participants were randomized. The trial was stopped for futility after meeting prospectively defined stopping criteria. MK-7622 did not improve cognition at 12 weeks (group difference in ADAS-Cog11: 0.18 [95% confidence interval: -1.0 to 1.3]) or function at 24 weeks (group difference in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory: 0.06 [95% confidence interval: -2.4 to 2.5]). More participants taking MK-7622 discontinued study medication because of adverse events than those taking placebo (16% vs 6%) and who experienced cholinergically related adverse events (21% vs 8%).
Discussion: MK-7622 (45 mg) does not improve cognition or function when used as adjunctive therapy in mild-to-moderate Alzheimer's disease.
Keywords: Allosteric modulator; Alzheimer's disease; Cholinergic; Clinical trial; MK-7622; Muscarinic.