Lu 25-109, a muscarinic agonist, fails to improve cognition in Alzheimer'sdisease

Objective: To evaluate the therapeutic effect of the selective muscarinic r eceptor mi partial agonist, m2 antagonist, Lu25-109 - a compound that direc tly stimulates muscarinic cholinergic receptors-in patients with probable A D. Methods: A 6-month, randomized, double-blind, placebo-controlled, parall el group trial comparing three doses of Lu25-109 with placebo was carried o ut. A total of 496 patients with probable AD with a Mini-Mental State Exami nation score between 10 and 26 were enrolled at 29 centers and randomized t o placebo or Lu25-109 25, 50, or 100 mg tid. The primary efficacy measures were the AD Assessment Scale-Cognitive subscale and the AD Cooperative Stud y Clinical Global Impression of Change. Secondary efficacy variables includ ed the AD Cooperative Study Inventory of Activities of Daily Living and the Behavioral Symptoms in AD Scale. Results: In both an intent-to-treat and a completer's analysis there were no significant differences for either the two primary or the secondary variables. There was a trend for patients on t he highest drug dose to worsen in the completer's analysis. Adverse events included dizziness nausea, diarrhea, fatigue, increased sweating, and anore xia, all of which increased with increasing drug dose. Conclusion: Lu25-109 , a selective partial mi agonist and an m2/m3 antagonist, failed to improve cognition in patients with mild to moderate AD.