Alzheimer's Drug Trials Offer Promising Results

Mar. 23 -- MONDAY, June 11 (HealthDay News) -- Decades of work in the laboratory may finally be paying off for Alzheimer's disease patients, as clinical trials show a variety of drugs making headway against the illness.

Two drugs, Dimebon and the diabetes medication Avandia, may help curb Alzheimer's in different ways. And close to five years of follow-up data suggest that an "Alzheimer's vaccine" might someday harness the power of the immune system to protect against dementia.

All of these agents work to alter the progression of the underlying disease, not just mask or limit its symptoms, as current Alzheimer's drugs do.

With so many varied means of attacking Alzheimer's disease on the horizon, "the clinician will have more of an arsenal to treat the patient from different approaches," said Dr. Paul Sanberg, director of the Center of Excellence for Aging and Brain Repair at the University of South Florida in Tampa.

"And what we don't even know yet is whether there are synergistic effects we could get by combining these approaches," he added.

Sanberg was not involved in the studies, the results of which were presented Monday at a special press briefing at the Alzheimer's Association's International Conference on Prevention of Dementia, in Washington, D.C.

Alzheimer's disease now affects more than 5 million Americans, according to the Alzheimer's Association. Scientists project that unless new ways are found to prevent or treat the disease, that total could climb to 16 million by mid-century. The exact causes of the illness are not known, but disease progression is highly associated with the build-up of clumped beta amyloid proteins in the brain.

One compound showing promise in a one-year trial is Dimebon, which targets Alzheimer's on a variety of fronts. According to Dr. William Thies, vice president of medical and scientific affairs at the Alzheimer's Association, the drug has symptom-limiting properties similar to anticholinesterase medications (such as Aricept) and another class of Alzheimer's drugs, called glutamate antagonists.

Dimebon may also protect vulnerable brain cells from amyloid build-up by boosting the energy output of cellular "power plants" called mitochondria.

So, besides affecting the symptoms of Alzheimer's disease, Dimebon "also has disease-modifying effects, bringing neurons long-term protection against loss of function," Thies explained.

In the trial, 120 patients in Russia with mild to moderate Alzheimer's were randomly chosen to receive either oral Dimebon or a placebo three times daily for 12 months. A team of researchers led by Dr. Rachelle Doody of Baylor College of Medicine in Houston then followed changes in the four most frequently studied aspects of the disease -- cognition, clinical function, activities of daily living and behavioral issues.

The researchers said patients on Dimebon achieved statistically significant improvements in all of these endpoints, and those improvements remained stable or even increased over the 12 months of the study. The dropout rate was similar between those on a placebo or Dimebon (about one-third of patients), and side effects were relatively low and included dry mouth (18 percent) and depression (14.6 percent).

"The natural history of untreated Alzheimer's disease includes decline in thinking abilities, social behavior and function," Doody said in a prepared statement released by the makers of Dimebon, Medivation. "By contrast, after a full year of therapy, Dimebon-treated patients did not decline in any of these areas." Medivation plans a six-month phase 3 clinical trial of the drug beginning in 2008.

A second study focused on a "Holy Grail" of neurological research: an Alzheimer's vaccine. One immune antibody-based shot called AN 1792 did show promise in small clinical trials involving 129 Alzheimer's patients, which were conducted nearly five years ago. However, hopes for the vaccine were dashed after 6 percent of the participants developed treatment-linked brain inflammation.

Although none of the affected patients died from the encephalopathy, the side effects "really did sidetrack AN 1792 as a product," Thies said, bringing a halt to further trials.

But doctors have continued to follow the mental-health histories of the trial's 25 "antibody responders" -- patients whose immune systems reacted favorably to the injection.

Antibodies are still active in blood samples taken from those patients, the researchers reported on Monday. Furthermore, these "responders showed significantly slower decline on the Disability Assessment for Dementia than placebo patients," according to the international team of researchers, led by Dr. Leon Thal of the University of California, San Diego.

"We've also seen a steady stream of autopsy data from people who were in the study demonstrating less amyloid than what one could expect," Thies noted.

So, even though AN 1792 may never make it to patients, these positive long-term outcomes mean immunotherapy research is very much alive.

"In fact, there are next-generation immunotherapies that are going forward as we speak," Thies said.

Then there's Avandia, a drug used by millions to combat diabetes, which has also appeared useful in slowing Alzheimer's in prior studies. In a new study, drugs maker GlaxoSmithKline presented safety data from a 16-month clinical trial involving 337 patients with mild to moderate Alzheimer's. The patients received either Avandia (rosiglitazone XR) or a placebo daily.

The trial, which was only designed to assess the safety and tolerability of the drug in Alzheimer's patients, found that 82 percent of participants did complete the 16 months of treatment. While about half of the patients experienced some side effects (for example, swelling), only a very few (less than 2 percent) experienced any cardiovascular abnormalities tied to the drug.

That's important, because an article last month in the New England Journal of Medicine tied long-term Avandia use by diabetics to increased heart risk. On June 6, the FDA asked that the medication carry a "black box" warning label, noting a potentially heightened risk of congestive heart failure in some patients using Avandia.

However, when it comes to treating Alzheimer's, Thies believes that "the relatively modest risk would be reasonably well-accepted by the community because of the [drug's] benefits against Alzheimer's."

Experts aren't quite sure how Avandia might ease Alzheimer's. The drug has anti-inflammatory properties, which might help, and it also helps boost the brain cell's energy supply, giving it more resilience against amyloid build-up and other Alzheimer's-related brain insults, Thies said.

A fourth study -- on an amyloid-clearing agent-- was presented at the conference on Monday with no clear message for patients yet.

Researchers at drug company Neurochem Inc. said that the results of their phase III trial of Alzhemed (tramiprosate) are in, but that the findings are too varied across the trial sites and too complex to determine the drug's efficacy at this point.

The Alzhemed study results were highly anticipated because this was the first phase III trial of any amyloid-clearing agent.

"Basically what Alzhemed does is interfere with that clumping of amyloid, so that normal clearance mechanisms can remove the amyloid before it forms plaques," Thies explained.

More information

Find out more about Alzheimer's disease at the Alzheimer's Association.

SOURCES: William Thies, M.D., vice president, medical and scientific affairs, Alzheimer's Association; Paul Sanberg, Ph.D., director, Center for Excellence for Aging and Brain Repair, University of South Florida College of Medicine, Tampa; June 11, 2007, press release, International Conference on Prevention of Dementia, Alzheimer's Association, Washington, D.C.; June 11, 2007, press release, Medivation