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Alzheimer’s still eludes treatment

By Shari Roan
Los Angeles Times
This year was supposed to herald the arrival of the first Alzheimer’s disease-modifying drug ó which pharmaceutical experts predict will be a multimillion-dollar product. Instead, it’s been marked by two failed clinical trials. The arrival of such a disease-modifying medication is now unlikely before 2010, perhaps later.
As such, Alzheimer’s disease research is at a crossroads, according to several scientists attending last week’s meeting of the Alzheimer’s Association 2008 International Conference in Chicago. Though technology to detect the condition early is advancing rapidly, there is still no way to halt or reverse the devastating disease.
Five Alzheimer’s disease medications are available. But all of these drugs treat the symptoms of the disease, such as memory problems and mental confusion. They do not cure, halt or even slow the disease process, and a review published earlier this year in the Annals of Internal Medicine concluded that the drugs produce few, if any, meaningful benefits.
Although the clinical trials on these drugs did find statistically significant improvements in people taking medications, the actual effect on their lives was so small that it’s reasonable for patients and families to decide not to take the drugs because of the cost or side effects, the authors of the report explained.
As dissatisfaction with these options grows, leading researchers in the field insist they are in heavy pursuit of something that will improve the lives of the great gray wave of Americans entering their retirement years.
“The first drug to treat symptoms was introduced in 1993. That was a pretty important step forward because, until then, there was a general view that we would never be able to treat the disease,” says Dr. Paul Aisen, a leading Alzheimer’s researcher at the University of California, San Diego. “We have a long way to go. However, I have no doubt we are making progress and that major advances can be expected in the next few years. It’s a devastating disease. We need to move very quickly.”
The setbacks have not convinced scientists that the disease is incurable. Dozens of other experimental medications are in the pipeline, Aisen says, and every day researchers are learning more about the disease and why it has been so resistant to treatment.
The current leading theory about what causes Alzheimer’s disease is that a sticky protein called amyloid beta clumps together in the brain, forming plaques that kill cells ó and the current drugs have been based on this theory.
A drug trial halted in June was for the first member of a class of drugs called selective amyloid-lowering agents ó aimed at inhibiting an enzyme, called gamma secretase, that helps form amyloid beta. However, the drug, Flurizan, did not benefit patients in a phase-three trial ó joining the list of recent late-stage flops. A phase-three study on the drug Alzhemed, also pegged as a disease-modifying medication, was canceled in November because the drug was ineffective. And an early-phase study on a vaccine designed to prevent amyloid from developing was suspended in April amid safety concerns.
“If we don’t learn from these negative trials we fail,” says Dr. Ronald C. Petersen, a neurologist at the Mayo Clinic in Rochester, Minn., and vice chairman of the Medical and Scientific Advisory Council for the Alzheimer’s Association. “There is always a lesson out there when a clinical trial does not succeed. But I think the chances for a disease-modifying therapy on the market in the next few years is fairly low.”
Though some experts doubt that removing the plaque will improve cognitive function, many leading researchers still support the beta amyloid theory.
“It was definitely a disappointment but not entirely surprising,” says Dr. Jeffrey Cummings, a professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles and director of the UCLA Alzheimer Disease Center. “All of us who work in the field know that, in general, Alzheimer’s disease has proved to be very difficult to treat.”
Aisen is more optimistic that a medication will be found to halt the formation of plaque in the brain or even reduce it.
“It doesn’t mean that other drugs that share a mechanism with Flurizan will be ineffective,” he says. “Several more trials are underway and several are in pivotal trials right now. The field will move forward, and I think major advantages in the next few years are quite likely.”
With the failures of Flurizan and Alzhemed, researchers’ hopes turn to other candidates.
– Another medication targeting gamma secretase, this time by blocking its production, has just entered a 21-month trial by Eli Lilly and Co. It is unnamed but referred to as LY450139.
– A drug called bapineuzumab, which uses antibodies designed to clear beta amyloid, is about to enter a phase-three trial. Results for that drug, made by Elan Pharmaceuticals Inc. and Wyeth Pharmaceuticals Inc., are due in 2010.
– An antihistamine, Dimebon, discovered more than two decades ago, has completed a phase-two trial in Russia that the Food and Drug Administration has accepted as one of two necessary “pivotal trials” that must be performed to prove a medication’s effectiveness. A study published this month in the Lancet by researchers at Baylor College of Medicine in Houston found that patients taking the drug experienced improved thinking processes and ability to function and that the benefits improved over time. The drug is being developed by a San Francisco company, Medivation Inc.
It’s characterized as a medication to treat Alzheimer’s disease symptoms. But Cummings says, “it may also have disease-modifying properties but the clinical trials have been designed to capitalize on the symptomatic benefits.”
– In addition, some researchers are looking at a different target to halt the disease process, such as a protein, called tau, that becomes modified in people with Alzheimer’s disease, contributing to neurofibrillary tangles in the brain. Data on a therapy to prevent abnormal tau formations will be presented this week.
“I’m not totally discouraged,” Petersen says. “Sooner or later, one of these drugs is going to hit. But we need to pursue additional research.”

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