Pfizer Gambles on Three-Times-per-Day Antihistamine for Alzheimer's Disease

But that's what Pfizer agreed to give Medivation last week for the worldwide marketing rights to Dimebon (dimebolin), a defunct, nonselective histamine blocker that is now in phase 3 clinical development for Alzheimer's disease: $225 million upfront and another $500 million when (or if) the drug is approved by the FDA.

The agreement—which splits development costs and profits on a 60-40 basis (Pfizer assumes the larger share)—also confers licensing rights to Pfizer for use of the drug in Huntingdon's Huntington's disease. (Dimebon is currently in phase 1/2 development for this condition.)

Pfizer is evidently betting on the chance that the 3-times-per-day Dimebon will sail through clinical development, given recent phase 2 results published in The Lancet. In a randomized, double-blind, placebo-controlled, multicenter study (N = 183) that was conducted entirely within Russia and funded by Medivation, patients with mild-moderate AD who received Dimebon* demonstrated significantly less cognitive decline at 6 months, as measured by the ADAS-cog (mean score difference, 4.0; P < .0001).

Specifically the mean ADAS-cog score of those who received Dimebon improved by approximately 2 points and the mean score of placebo-treated patients declined by more than 2 points. Secondary outcome measures (eg, MMSE) supported these findings. In a blinded, 26-week extension phase, the difference in the mean ADAS-cog score between patients who originally received Dimebon and those who originally received placebo increased further (6.9; P < .0001). The most common adverse effects observed with Dimebon treatment in this phase 2 study were dry mouth and depression.

By comparison, the mean ADAS-cog score difference between the once-daily blockbuster Aricept (donepezil; Eisai/Pfizer) and placebo was approximately 3 points at 30 weeks in patients with mild-moderate AD. The basic patent on Aricept, the most widely used AD drug, will expire in 2 years.

According to Medivation, Dimebon has been shown to inhibit brain-cell death in preclinical models of AD. A PubMed search reveals at least 4 rodent studies and 1 pilot study of the agent at the Moscow Center of Gerontology. The company further proposes that Dimebon confers benefits in AD by "improving mitochondria function."

Also according to Medivation, the Russian study can be used as 1 of 2 pivotal trials to support the FDA approval of Dimebon, as long as a "significant portion" of the current phase 3 trial occurs within the United States. A 6-month, placebo-controlled phase 3 trial of Dimebon (5 or 20 mg tid) in 525 patients with mild-moderate AD was initiated in the second quarter of this year; results are expected in 2010, reports The Street. Dimebon is also being assessed in combination with donepezil in a phase 1 study.

ADAS-cog: Alzheimer's Disease Assessment Scale-cognitive subscale; MMSE = Mini-Mental State Examination.

* 10 mg tid for 7 days, followed by 20 mg tid. 

Images of defunct Russian and defunct Russian antihistamine from Wikipedia.