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Dimebon Improves Alzheimer's Symptoms, Vaccination Doesn't

Science Editor

The July 19, 2008, issue of The Lancet brings some good and some bad news for Alzheimer's sufferers. A report on a yearlong clinical trial using Medivation Inc.'s Dimebon for the treatment of Alzheimer's disease showed the drug was effective at improving the clinical course of the disease. But immunization against amyloid plaques fared less well. A long-term analysis of patients immunized in 2000, as part of a Phase I study, reported that despite reducing amyloid plaque load, immunization with synthetic A-beta peptide had no effect on either overall survival or cognitive symptoms.

Dimebon is shaping up to be the pharmaceutical equivalent of an immigrant success story. The drug is approved in Russia as an antihistamine, but currently is not on the market there or anywhere else, due to the availability of second-generation, more-specific antihistamines.

But a Russian scientist screening libraries for compounds that could fight Alzheimer's found that Dimebon showed some promise in that area. Based on his preclinical data, in 2003 Medivation Inc. decided to in-license the drug and give it a whirl for neurodegenerative diseases. And for now, indications are that Dimebon might find a happy home in that market.

The company recently reported that Dimebon was shown to be safe and well tolerated and also significantly improved cognitive function in a Phase II study in Huntington's disease patients. (See BioWorld Today, July 9, 2008.)

And in the current issue of The Lancet, researchers from Baylor College of Medicine reported that in a trial conducted in Russia, Dimebon improved the cognitive symptoms and functioning of Alzheimer's patients, demonstrating increasing benefits over a period of 12 months.

In the study, which began with 183 patients and ended 12 months later with 120 patients, those receiving Dimebon did better than controls on each of five tests designed to assess memory, thinking, activities of daily living, behavior and overall clinical function.

Medivation CEO David Hung told BioWorld Today that the data showed Medivation's effects on Alzheimer's were "robust, broad and durable over time." He said that 18-month follow-up data of the study will be presented at the International Conference on Alzheimer's Disease in late July. The company is conducting another Phase III trial of Dimebon in the U.S. and Europe, and plans to file for regulatory approval in both jurisdictions in 2010.

In the same issue of The Lancet, the news was less cheerful for another approach to Alzheimer's disease: vaccination with Elan Pharmaceutical's synthetic A-beta peptide AN-1792. AN-1792 has a checkered history. In 2002, development of the vaccine was halted when it became clear in a Phase IIa trial that patients receiving the vaccine were at increased risk of meningoencephalitis.

The current Lancet study reported long-term follow-up of an earlier Phase I study in which 80 patients were immunized with either synthetic A-beta peptide or a vaccine adjuvant only. The paper reported postmortem data collected from eight of those patients in 2006. The data were first reported at a meeting of the New York Academy of Sciences in March.

Like the Dimebon study, the researchers tested their drug in patients with mild-to-moderate Alzheimer's disease.

Previous studies had tested serum antibody response to the vaccine, but it was unclear how well such an antibody response corresponds to reduction in plaque load in the brain, as well as whether such a reduction - if there was any - would improve survival or cognitive symptoms. The researchers addressed that question by analyzing brain tissue from eight Alzheimer's patients who had received the vaccine and died either during the study or during follow-up, comparing plaque load to serum antibody response on the one hand and cognitive functioning on the other.

The researchers found that notwithstanding the highly variable immune response to A-beta vaccination, reduction in brain plaque levels correlated well with the serum antibody response. What the reduction in plaque load did not correlate with, however, was cognitive symptoms before death. Seven of the eight patients whose brain tissue the scientists analyzed postmortem had severe dementia before death, including, the researchers noted, "those with virtually complete plaque clearance."

They concluded that "Although [immunization] with Abeta42 resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration."

In an accompanying commentary, scientists said they are not ready to completely give up on the vaccination approach, suggesting further clinical trials that can detect even small changes in disease progression might be useful.

Those trials are not going to be on AN-1792, though. An Elan spokesperson told BioWorld Today that, though the company does have data from the Phase IIa trial showing that AN-1792 can slow cognitive decline, the program is shelved. Instead, Elan is pursuing a passive immunization approach, going after amyloid-beta with its monoclonal antibody bapineuzumab.

Published: July 18, 2008