Old Antihistamine Pops Up as Potential Alzheimer's Therapy

By Crystal Phend
HOUSTON, 19 july 2008 -- A nonselective antihistamine that was once sold in Russia, but is no longer marketed anywhere, can reverse cognitive effects of mild-to-moderate Alzheimer's disease, researchers here suggested. In a phase III trial, treatment with the drug known as dimebon improved scores on the cognitive subscale of the Alzheimer's disease assessment scale compared with both baseline (mean difference -1.9, P=0.0005) and placebo (-4.0, P<0.0001), reported Rachelle S. Doody, M.D., of Baylor College of Medicine, and colleagues in the July 19 issue of The Lancet. By contrast, commonly used cholinesterase inhibitors for mild-to-moderate Alzheimer's disease only temporarily stabilize or slow progressive deterioration without improvements over baseline, they wrote.
Dimebon appeared promising with significant improvements in five functional, cognitive, and behavioral outcomes, Dr. Doody said, "whereas with previously approved drugs we never saw benefit on all of the outcome measures in any of the trials."
Dimebon was approved in Russia decades ago, said Dr. Doody, and sold for many years there as a non-selective antihistamine but was withdrawn for commercial reasons when more selective agents came on the market. It was never FDA-approved.
In an accompanying Lancet commentary, Alistair Burns, M.D., of the University of Manchester in England, and Robin Jacoby, D.M., of the University of Oxford in England, said that now the drug has been discovered to attack multiple mechanisms involved in Alzheimer's disease, with weak cholinesterase, weak glutamatergic, and neuroprotective activity.
Following a pilot study in Alzheimer's disease patients, the researchers conducted the current randomized trial in 183 patients with mild-to-moderate Alzheimer's disease seen at 11 sites in Russia. The study was done in Russia because that was the country where there had been at least some experience with dimebon and it was considered ethical to compare it to placebo there because cholinesterase inhibitors weren't commonly used there.
Patients were randomized to oral dimebon at a dose of 20 mg three times a day or matched placebo without any other antidementia drugs allowed. Treatment continued for 26 weeks with the option of a six-month extension phase.
For the primary outcome measure of the main 26-week phase of the study, patients given dimebon had roughly the same degree of clinical improvement as placebo group patients had clinical deterioration.
Scores on the cognitive subscale of the Alzheimer's disease assessment scale improved by 1.9 points from baseline with dimebon (P=0.0005) but declined about two points among placebo group for a four-point difference favoring dimebon (P<0.0001).
By 52 weeks for the 134 patients who continued blinded treatment in the extension phase, the difference in scores had further widened as dimebon-treated patients continued to have an average 1.23 higher score than at baseline whereas placebo group patients had clinical deterioration (mean difference -6.9, P<0.0001).
These findings suggested both that the improvements with the drug were not solely driven by deterioration in the placebo group and that benefits might continue to increase over time, Dr. Doody's group said.
A secondary measure of cognition, the Mini-Mental State Examination (MMSE), likewise showed improvement with dimebon but worsening with placebo at 26 weeks (P<0.0001).
Activity of daily living and behavioral scores also improved significantly with the drug compared with placebo at 26 weeks (P=0.002 and P=0.006, respectively).
These treatment effects were likely clinically relevant, the researchers said, because improvements extended to independent physician-assessed global function as measured with the Clinician's Interview-based Impression of Change plus Caregiver Input (CIBIC-plus, mean change 0.28 with dimebon versus -0.33 with placebo).
At 52 weeks, the advantage of dimebon over placebo continued to grow for both physician-assessed improvement on the CIBIC-plus and activity of daily living scores.
Dimebon was well tolerated, with no increase in adverse events, although dry mouth did appear to be more common.
Both the researchers and commentators noted that Alzheimer's care in Russia is still based on custodial care and drug treatment without wide or routine use of cholinesterase inhibitors and memantine (Namenda).
"A larger multinational study is needed to confirm the finding," the investigators concluded. But "if such a study confirms our results, dimebon will represent an important advance in the treatment of Alzheimer's disease."
The FDA has said the trial could potentially be considered a phase III trial for the purposes of registration and a multinational phase III trial with the drug was initiated just last month, Dr. Doody said.
Medivation, a San Francisco firm, acquired the license to develop dimebon in 2003 from a research institute in Russia.
Any compassionate use of the drug would have to be through the confirmatory phase III trial, which is still enrolling up to a planned 525 patients, according to Medivation.
The study was funded by Medivation of San Francisco, which also provided the study drug.
Dr. Doody reported serving on the Scientific and Clinical Advisory Board of Medivation and holding stock options in the company. Co-authors reported paid consulting for, serving on the Scientific and Clinical Advisory Board of, and holding stock options or royalty rights in Medivation. Two authors were employees of the company.
Dr. Burns reported receiving research grants and consultancy fees from Pfizer, Eisai, Shire Janssen, and Novartis. Dr. Jacoby reported being chairman of the Global Initiative on Psychiatry, which works to reform psychiatric services and practice in former Soviet countries.
Primary source: The Lancet Source reference:Doody RS, et al "Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: A randomised, double-blind, placebo-controlled study" Lancet 2008; 372: 207-15. Additional source: The Lancet Source reference: Burns A, Jacoby R "Dimebon in Alzheimer's disease: Old drug for new indication" Lancet 2008; 372: 179-180.