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July 17, 2009
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July 15, 2009 (Vienna, Austria) Despite promising clinical effects in the treatment of mild to moderate Alzheimer's disease (AD), new animal research shows that dimebolin (Dimebon, Medivation) increases beta-amyloid (Aβ) levels, raising new questions about whether pursuing the development of antiamyloid therapies is the best way go.
Presented here at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD 2009) investigators, led by Sam Gandy, MD, PhD, professor of neurology and psychiatry and associate director of the Alzheimer's Disease Research Center at the Mount Sinai School of Medicine, in New York City, found dimebolin caused up to a 2-fold increase in Aβ levels in mouse brain tissue.
No Amyloid-Lowering Effect
"The chronic effects [of Dimebon] are still unknown, and I think it is fair to say that these data raise more questions than they answer. But I think it's clear that Dimebon's mechanism of action does not include an acute Aβ-lowering effect," Dr. Gandy told reporters attending a press conference here.
Intrigued by the promising results of previous research, including a phase 2 trial clinical trial published in the Lancet in 2008 by Rachelle Doody, MD, PhD, from Baylor College of Medicine, in Houston, Texas (Doody R et al. Lancet 2008;372:207-215), Dr. Gandy and colleagues wanted to explore the effect of the drug on Aβ, which is widely considered to be a key player in the development and progression of AD.
The Lancet study showed patients with mild to moderate AD who were taking the drug experienced significant improvements in cognitive function, memory, ability to perform tasks of daily living, global function, and behavior, which increased and were sustained over time.
"We were immediately drawn to wonder what was going on with beta amyloid in this clinical setting, in which subjects receiving this drug demonstrated a cognitive benefit," said Dr. Gandy.
"It is also evident that there are major efforts in the field aimed at amyloid-beta lowering and so we wanted to determine whether we could see that relationship with Dimebon and whether it regulated Aβ levels," he added.
Using transgenic mice, investigators at 2 laboratories conducted a series of experiments looking at Dimebon's effect on Aβ levels in 3 systems, including the conditioned media of cells, the interstitium, and the releasate of CRND8 synaptoneurosomes.
Dose-Dependent Effect
They found there was a dose-dependent effect, with increased doses of the drug associated with an increased release of Aβ. The mice received Dimebon at a dose of 3.5 mg/kg, which is comparable to clinical doses. The investigators found average Aβ levels across all 3 systems increased between 50% and 2-fold.
The fact that Dimebon appears to improve cognition while raising Aβ levels remains something of a mystery that requires further research. However, said Dr. Gandy it would be premature to abandon the so-called "amyloid hypothesis," which purports that Aβ plays a major role in AD pathogenesis.
"I don't think the question is whether amyloid can cause AD; there are clearly examples of genetic forms of the disease in which it can. I think the real question is whether in the common and sporadic forms of AD there is an etiological agent that is both directly neurotoxic and promotes Aβ formation."
First used in Russia more than 30 years ago, Dimebon was originally marketed as an antihistamine but was shelved when more targeted therapies came to market.
First Look at Underlying Mechanisms
According to Dr. Gandy, this research is the first attempt to elucidate Dimebon's mechanism of action in AD. "Clinically, Dimebon is better than anything we've ever seen, so understanding the underlying mechanisms is critical, because there may be hidden targets that we aren't exploiting, and researching this drug may help reveal them," Dr. Gandy told Medscape Neurology in a follow-up interview.
Dr. Gandy also stated he was surprised by the study findings. "Considering most of the field is oriented toward amyloid and is looking for amyloid-lowering agents, we were very surprised by our findings. This orientation toward amyloid, he added, was "the reason we took such care with the study and looked at 3 different systems in 2 labs before we made the report public. We wanted to be sure this elevation was real."
Commenting on the findings, Ralph Nixon, MD, professor of psychiatry at the Center of Excellence in Brain Aging and the Silverstein Institute for Aging and Dementia at New York University School of Medicine, said if the clinical effects of Dimebon can be reproduced in a phase 3 trial it will be "an incredibly powerful tool" that will help the research community explore potential mechanisms of action and "give us additional clues about the disease and further insights into the role of Aβ," he said.
Dr. Gandy has no financial relationships with Medivation.
Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD 2009): Abstract 09-HT-2700-ALZ. Presented July 15, 2009.
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Authors and Disclosures
Journalist
Caroline Cassels
Caroline Cassels is the news editor for Medscape Psychiatry. A medical and health journalist for 20 years, Caroline has written extensively for both physician and consumer audiences. She helped launch and was the editor of Health Digest, an award-winning Canadian consumer health publication. She was also national editor of the Heart & Stroke Foundation of Canada's Web site before joining Medscape Neurology & Neurosurgery in 2005. She is the recipient of the 2008 American Academy of Neurology Journalism Fellowship Award. She can be contacted at CCassels@webmd.net.
