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Alzheimer's Doctors Rethink Disease After Mice Study
  By Michelle Fay Cortez
July 15 (Bloomberg) -- Researchers and drugmakers studying Alzheimer's disease may need to rethink how the condition cripples the brains of patients based on research in mice released today.
Pfizer Inc. and Medivation Inc.'s experimental therapy Dimebon, shown to reduce signs of memory loss in early studies, unexpectedly boosted levels of brain-clogging amyloid associated with disease development in a study presented at the International Conference on Alzheimer's Disease in Vienna.
Beta amyloid has long been considered a culprit in the development of the disease and is the target of experimental drugs from companies including Elan Corp., Wyeth and Eli Lilly & Co. Johnson & Johnson this month gained access to Elan's Alzheimer's drugs, most of which focus on the brain protein, with a $1 billion investment.
"This certainly causes one to question whether we should be aiming for amyloid-lowering agents," said lead researcher Samuel Gandy, associate director of the Alzheimer's Disease Research Center at Mount Sinai School of Medicine in New York.
Gandy, who has worked on understanding the action of the protein in the brain for two decades, said he has recently revised his personal version of the "amyloid hypothesis." While amyloid itself may have damaging effects on the brain, there is likely another process under way, not yet identified, that is toxic to brain cells, he said a press conference.
Another Target?
"These results raise more questions than they answer," he said in Vienna. "It's still very early days." The findings come from experiments in cells and in mouse models. Human studies don't always produce the same results as animal ones.
Investigators still aren't sure how Dimebon works. The drug was once sold as an allergy medication in Russia and is now in the third and final stage of testing for Alzheimer's disease. A study published in the journal Lancet last year found it improved memory in a study of 183 patients in Russia, posting some of the best results yet seen in a therapy for the disease.
"We need more research to further clarify" how Dimebon affects beta amyloid, said Gandy, who examined the effects in mice after just a few hours of giving them the drug.
The drug may have positive effects on the brain that outweigh the effect of increasing beta amyloid, according to Gandy. It may also get the toxic amyloid out of brain nerve cells, making it seem more prevalent. The drug's benefit may also have nothing to do with beta amyloid, indicating that there is another important target for treatment, Gandy said.
Not All Bad
The results aren't completely confusing, said Maria Carrillo, director of medical and scientific relations at the Chicago-based Alzheimer's Association.
Researchers studying beta amyloid in recent years found it's an active molecule, almost a byproduct of the synaptic transmission that's essential in learning and memory, she said. It's produced for a reason and it's not all bad, Carrillo said.
"The thought that we should be getting rid of amyloid is maybe too simplistic," she said in an interview. "The mechanisms are so much more complex than we originally thought. We are moving beyond the idea that beta amyloid is a molecule we want to get rid of, though we may want to block some of its effects."
Pfizer paid San Francisco-based Medivation $225 million, plus fees of as much as $500 million as the drug moves through the development process, for rights to Dimebon last September. New York-based Pfizer will pay for 60 percent of U.S. development and marketing costs and will be responsible for sales outside the U.S.
'Learn More'
The fact that Dimebon works in an entirely new way to treat Alzheimer's disease is giving investigators a variety of avenues for their research, said Lynn Seely, Medivation's chief medical officer. The company believes Dimebon works mainly in the mitochondria, the part of the cell that produces energy, protecting it and enhancing brain cell survival, she said.
"Once you have an effective drug, it allows you to learn more about the underlying disease," Seely said in a telephone interview. "What we may learn is that some of the things we thought about Alzheimer's disease may not be correct."
The company's final study, needed to confirm the results published last year, should be completed in the first half of 2010. The study involving 598 patients is already fully enrolled, and researchers will track their patients' performance for six months to see if the drug is effective, she said.
To contact the reporter on this story: Michelle Fay Cortez in London at
Last Updated: July 15, 2009 07:13 EDT
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