"Shelved" Antihistamine Shows Promise in Alzheimer's Disease

Caroline Cassels

May 16, 2008

May 16, 2007 (Chicago, Illinois) — A largely forgotten antihistamine, first used in Russia more 30 years ago but shelved after newer, more targeted therapies came to market, is showing promise as a treatment for mild to moderate Alzheimer's disease (AD).

Recently presented at the American Academy of Neurology 60th Annual Meeting, a 1-year randomized, placebo-controlled trial of the drug Dimebon (Medivation, San Francisco, CA) in 183 AD patients showed that individuals taking the drug experienced significant improvements in cognitive function, memory, ability to perform tasks of daily living, global function, and behavior.

"One of the reassuring or hopeful findings from this study so far is that the drug/placebo differences were not driven just by a decline in the placebo group. The differences at 6 months from baseline [in patients in the active-treatment group] were statistically significant across all study measures, indicating that patients actually improved on the drug at 6 months," study investigator Rachelle Doody, MD, PhD, from Baylor College of Medicine, in Houston, Texas, told Medscape Neurology & Neurosurgery.

Improvement Over Time

The multicenter trial included 183 AD patients from 11 sites in Russia. Study subjects had an average age of 68 years and mean Mini-Mental State Examination (MMSE) scores of 18 at baseline.

Patients were randomized to receive the drug or placebo. The study's primary end points were improvement from baseline in Alzheimer's Disease Assessment Scale-cognitive (ADAS-COG), Clinician's Interview-Based Impression of Change-plus (CIBIC-plus), MMSE, Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL), and Neuropsychiatric Inventory (NPI). In addition, investigators assessed caregiver time using an item in the Resource Utilization in Dementia (RUD-lite) tool.

Initially, said Dr. Doody, the trial was designed to be a 6-month proof-of-concept study. However, the study design was amended, and subjects had the option of participating in a 6-month blinded extension trial. Of the total study group, approximately 86% opted to continue in the blinded 6-month extension study.

At 6 months, there was statistically significant improvement in all 5 study outcomes in subjects taking Dimebon vs those in the placebo group, a trend that continued at 1 year.

"The 1-year data showed us that people were at or above baseline on all of the study measures if they were on drug and at various points of decline if they were not. So the drug-placebo difference was widening over time," said Dr. Doody.

Mechanism Unclear

At 6 months, the difference in ADAS-COG scores between the placebo and drug groups was about 4 points from baseline. On the global scale, about 80% of patients in the treatment group stayed the same or improved compared with 60% on placebo.

In addition, as a result of these improvements, caregivers spent less time (about 1 hour less per day) assisting patients in their activities of daily living, which included eating, toilet use, phone use, conversation, meal preparation, traveling, keeping appointments, reading, and using household appliances. In comparison, caregiver time in the placebo group increased.

Exactly how the drug works is unclear. Investigators have looked at its potential as a cholinesterase inhibitor and as an NMDA agonist and found it is weak on both fronts. At this point, said Dr. Doody, the only other published data suggest that Dimebon may have a stabilizing or protective effect on mitochondria that might be more important than any of its other actions.

The results of the current study are encouraging, and as a result, a phase 3 clinical trial that will include 251 patients is about to get under way. If these latest findings are confirmed, Dr. Doody said, Dimebon may offer clinicians another option for the treatment of AD.

The study was funded by Medivation Inc.

American Academy of Neurology 60th Annual Meeting: Abstract P02.189. Presented April 15, 2008.


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