Scientists target prime suspect in Alzheimer's disease

07/07/04

Scientists report preliminary success in a variety of strategies to rein in beta-amyloid, one of the substances thought to kill brain cells in alzheimer's disease.

PHILADELPHIA, July 21, 2004 Researchers report favorable results in two safety trials of drugs that may be able to prevent the formation of beta-amyloid, the sticky substance that many believe kills brain cells in people with Alzheimer's disease. The data were reported today at The 9th International Conference on Alzheimer's Disease and Related Disorders (ICAD), presented by the Alzheimer's Association.

"The current generation of Alzheimer drugs primarily treat symptoms but they do not stop the progression of the disease," said William Thies, Ph.D., vice president of Medical & Scientific Affairs for the Alzheimer's Association. "Therefore, it is imperative that we push forward vigorously with research to develop therapies that attack the underlying disease process."

Amyloid-Interfering Product Candidate Found Safe In Trial Of Alzheimer Patients The toxic protein fragment beta-amyloid is a major suspect in Alzheimer's disease. Beta-amyloid accumulates into the characteristic amyloid plaques that distinguish the brains of people who died with Alzheimer's. A drug that interferes with the accumulation of amyloid in the brain appears to be safe, and has now moved into Phase III human trials.

At ICAD, Paul Aisen, M.D., Professor, Departments of Neurology and Medicine, and Director, Memory Disorders Program, Georgetown University Medical Center, reported safety and preliminary results on a drug intended to interfere with the ability of beta-amyloid proteins to "stick" to each other to form plaques. The drug, NC758 (Alzhemed), is produced by Neurochem Inc., a Canadian biopharmaceutical company that funded and conducted the study.

In the Phase II clinical trial, people with mild-to-moderate Alzheimer's were randomized to a double-blind trial of either NC758 or a placebo for three months. All participants were then offered the drug for an additional 21 months. Overall, NC758 was found to be safe and well-tolerated. Of the 58 patients who began the study, only six (four from the NC758 group; two from the placebo group) dropped out early during the double-blind part of the study. Three of them withdrew due to side effects (nausea/vomiting in two patients; weakness/weight loss in one patient). The author reported that there were no serious side effects related to study medication.

Researchers pointed out that the drug was detected in the cerebrospinal fluid (CSF) suggesting that it successfully crossed over from the blood into the brain, a major hurdle for any neurological therapy. They also report that levels of beta-amyloid protein circulating in the CSF were reduced after three months of treatment in the highest dose groups, suggesting the brain may have experienced less amyloid accumulation.

"Although these are preliminary results, we consider them promising. The efficacy of NC758 in the treatment of Alzheimer's is now being assessed in a large Phase III trial," said Aisen.

Experimental Therapies Aim To Halt Beta-Amyloid Formation A more radical approach to reducing beta-amyloid levels in the brain is to prevent the protein from forming in the first place. The strategy is to interfere with a series of enzymes called secretases, which generate beta-amyloid by clipping it from a much longer protein known as the amyloid precursor protein (or APP).

Researchers from Eli Lilly and Company in Indianapolis, Indiana, reported on their attempts to inhibit gamma-secretase. Safety has been a special concern with gamma-secretase because of fears that inhibiting this enzyme could interfere with other essential physiological processes and cause unacceptable side-effects.

Lilly's researchers tested various doses of a gamma-secretase inhibiting compound (LY450139) or placebo in a Phase I study in volunteer subjects without Alzheimer's 37 healthy adults over the age of 45. During the 14-day trial, no significant side-effects related to the drug were noted. Blood levels of beta-amyloid were reduced following drug administration each day, with greater reduction seen after higher doses. Drug was detected in CSF, but there was no change in the concentration of beta-amyloid in CSF in this study.

Even before gamma-secretase, another enzyme termed beta-secretase is involved with the first step of beta-amyloid production. Ming-Tain Lai of Merck and Co., West Point, Pennsylvania, reported on the company's efforts to halt formation of beta-amyloid early in the process by interfering with beta-secretase.

As are several other pharmaceutical companies, Merck is designing beta-secretase inhibitors nearly from the ground up. Lai and his colleagues first identified a small compound that displayed moderate potential to inhibit beta-secretase. Using the X-ray structure of beta-secretase as a guide, the researchers improved the potential ability of their test compounds to inhibit beta-secretase.

"Previous animal studies that used genetic engineering methods to eliminate the beta-secretase indicate that this enzyme can be blocked without significant health effects," said Lai. "We hope the same will be true of beta-secretase-inhibiting drugs in humans."

The 9th International Conference on Alzheimer's Disease and Related Disorders (ICAD), presented by the Alzheimer's Association, is the largest gathering of Alzheimer researchers in history. More than 4,500 scientists from around the world will present and discuss the findings of 2,000 studies showcasing the newest treatment advances in Alzheimer's disease and steps toward prevention. ICAD will be held July 17-22, 2004, at the Pennsylvania Convention Center in Philadelphia, Pennsylvania.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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