Amyloid-[beta]-lowering agent fails to slow Alzheimer's in phase III trial.

CHICACO -- Tarenflubil, a drug designed to reduce toxic amyloid [beta] levels in the brains of Alzheimer's disease patients, failed its large phase III trial, Dr. Robert Green reported at the International Conference on Alzheimer's Disease.

Patients who received the drug (800 mg twice daily) had virtually the same declines in cognition and function as did those who received placebo, said Dr. Green of Boston University. "The results are definitive. There was no efficacy of the compound in this trial."

Myriad Genetics Inc., of Salt Lake City, has decided to scrap its research on the drug, Dr. Green said at the meeting presented by the Alzheimer's Association.

In a somewhat encouraging phase II trial that included 207 patients, those taking tarenflurbil had significant improvements in global functioning and activities of daily living, and near-significant improvements in cognition.

No such benefits occurred in the phase III trial, which comprised 1,653 patients with mild Alzhemer's at 133 U.S. sites. Patients were randomized to the study drug or placebo for 18 months; the treatment period was followed by a 30-day washout. Patients were evaluated every 3 months.

The groups were well matched at baseline, with a mean age of 74 years and a mean Mini-Mental State Exam score of 23; 51% were female. Most of the patients were on concomitant antidementia drugs: 33% were taking only cholinesterase inhibitors, 6% were on memantine alone, 19% were taking no antidementia drugs, and the rest were on combination therapy.

After 18 months of treatment, the active and placebo groups both showed a steady and almost identical decline in cognition. Both groups lost 7 points on the Alzheimer's Disease Assessment Scale--cognition scale. In a secondary cognitive measure, the Clinical Dementia Rating sum of boxes, both groups lost 2.5 points. A similar pattern appeared on the Alzheimer's Disease Assessment Scale--activities of daily living scale. Both groups followed an almost identical pattern of decline, each losing 10 points on the scale by 18 months.

Overall adverse events were similar in the tarenflurbil and placebo arms (88% vs. 86%). More patients taking the study drug discontinued because of adverse events (18% vs. 12%). Serious adverse events occurred in 23% of the active group and 20% of the placebo group. The most common adverse event was anemia (10% tarenflurbil vs. 4% placebo--a significant difference). Infection was also significantly more common among the active group (7% vs. 3%), as was gastrointestinal ulcer (2% vs. 0.4%). There was no difference in the incidence of gastrointestinal bleeding.

Tarenflurbil was the first gamma secretase modulator tested in a phase III trial. This class of drug is thought to reduce the levels of toxic amyloid [beta] ([A[beta] sub.42]) in the brain.

Dr. Green said he did not receive compensation from Myriad Genetics for his role as a primary investigator.

BY MICHELE G. SULLIVAN

Mid-Atlantic Bureau