A test developed by physician-scientists at Washington University School of Medicine in St. Louis may help assess more quickly the ability of Alzheimer's drugs to affect one of the possible underlying causes of Alzheimer's disease in humans, accelerating the development of new treatments.
Scientists used the test to show that an Alzheimer's drug given to healthy volunteers reduced production of a substance known as amyloid beta (A-beta), a normal byproduct of human metabolism that builds to unhealthy levels forming brain plaques in Alzheimer's patients. The drug candidate, LY450139, which is also known as semagacestat, is being studied in clinical trials by Eli Lilly and Company.
Ongoing clinical trials are studying the effect that semagacestat may have on cognitive function and biochemical and brain imaging biomarkers in patients with Alzheimer's disease. Washington University researchers wanted to see whether the new measurement technique, stable isotope-linked kinetics (SILK), could detect the study drug's impact on A-beta synthesis in healthy volunteers.
"Bringing an Alzheimer's disease drug into clinical trials from tests in animal models has always been challenging," says study director Randall Bateman, M.D., a Washington University neurologist who treats patients at Barnes-Jewish Hospital. "We haven't had a way to quickly and accurately assess a drug's effects, and that meant there always had to be some degree of educated guesswork when it came to setting the optimal dosage for humans. SILK may help to eliminate much of that guesswork."
The results appear online in Annals of Neurology on April 10.
Scientists are unsure whether increased A-beta production, reduced clearance or a combination of the two lead to the A-beta buildup in the brain, a process that many believe triggers Alzheimer's disease. Bateman and his colleagues are currently using SILK to try to answer this question.
Until SILK, there has not been a way to directly measure the production or clearance of A-beta. The efficacy of potential new Alzheimer's drug candidates has been assessed by monitoring the cognitive functions of patients with the disease for extended periods of time, which require large, lengthy and expensive studies.
In their double-blind study, scientists gave 20 healthy volunteers varying doses of either a study drug or a placebo. At the start of the SILK test, volunteers were connected to an intravenous drip that gave them a slightly altered form of the amino acid leucine, which is a component of A-beta.