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Lu 25-109, a muscarinic agonist, fails to improve cognition in Alzheimer’s disease

From the Department of Neurosciences (Dr. Thal), University of California San Diego School of Medicine, La Jolla; and H. Lundbeck A/S (Drs. Forrest, Loft, and Mengel), Copenhagen-Valby, Denmark.

Address correspondence and reprint requests to Dr. Leon J. Thal, Professor and Chairman of Neurosciences, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0624; e-mail: 1thal{at}uscd.edu

OBJECTIVE: To evaluate the therapeutic effect of the selective muscarinic receptor m1 partial agonist, m2 antagonist, Lu25-109—a compound that directly stimulates muscarinic cholinergic receptors—in patients with probable AD.

METHODS: A 6-month, randomized, double-blind, placebo-controlled, parallel group trial comparing three doses of Lu25-109 with placebo was carried out. A total of 496 patients with probable AD with a Mini-Mental State Examination score between 10 and 26 were enrolled at 29 centers and randomized to 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 Study Clinical Global Impression of Change. Secondary efficacy variables included 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 the highest drug dose to worsen in the completer’s analysis. Adverse events included dizziness, nausea, diarrhea, fatigue, increased sweating, and anorexia, all of which increased with increasing drug dose.

CONCLUSION: Lu25-109, a selective partial m1 agonist and an m2/m3 antagonist, failed to improve cognition in patients with mild to moderate AD.

Key words: AD—Cognition—Cholinergic—Muscarinic agonist

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