Inhibiting gamma secretase may prevent amyloid plaque build-up thought to trigger Alzheimer's disease

Mar 21 2006

Oregon Health & Science University is participating in a national study of a drug that may prevent Alzheimer's disease by blocking an enzyme that produces plaques believed to trigger the disorder.

OHSU is one of six sites around the country taking part in a double-blind, placebo-controlled study of the agent known as LY450139, a gamma secretase inhibitor manufactured by Indianapolis-based Eli Lilly and Co. Other study sites are in Indianapolis, St. Louis, Philadelphia, Seattle, and La Jolla, Calif. Lilly is funding the study.

Gamma secretase is an enzyme that produces beta-amyloid by snipping a fragment of the protein from a larger protein that extends across the plasma membrane of the cell. The beta-amyloid fragments clump together to form dense, insoluble plaques inside the hippocampus, a curved, elongated ridge deep in the brain that controls learning and memory, and the cerebral cortex, the surface layer of gray matter of the cerebrum where sensory and motor information is coordinated.

The gamma secretase enzyme is made up of a complex of four proteins, and LY450139 is thought to de-activate it by binding within the complex, although the exact location is still being studied.

"There is a theory that beta-amyloid produces Alzheimer's disease, so if you stop the amyloid, you stop the disease," said Joseph Quinn, M.D., associate professor of neurology, and cell and developmental biology, OHSU School of Medicine and the Portland Veterans Affairs Medical Center. He also is an investigator at OHSU's Layton Aging & Alzheimer's Disease Center.

The study is "focused on the presumed underlying cause of the disease instead of symptoms. This is the beginning of the 'anti-amyloid' era of Alzheimer's disease treatment, attacking what are thought to be the roots of the disease," Quinn said.

The 29-week-long study, set for completion in September, is a Phase II trial involving 45 participants that will determine LY450139's safety, whether it causes any side effects, how much of the drug should be given and how long it can be detected in the blood. Researchers hope to measure levels of biomarkers in blood and spinal fluid that might relate to Alzheimer's disease, changes in the study subjects' thinking and memory, and changes in their daily living activities.

Study participants will be asked to make an initial office visit, followed by visits for treatments every other week for 14 weeks. They then will make two follow-up visits.

In a study co-authored by Quinn and published in the Feb. 28 issue of the journal Neurology, LY450139 was shown to reduce blood plasma levels of beta-amyloid by 38 percent in 70 Alzheimer's patients given 30 milligrams of LY450139 for one week, followed by 40 milligrams for five weeks. They reported that the lowest concentration of the protein occurred three hours after a 40 milligram dose was taken. The drug also was well tolerated.

"This study involved active treatment for only six weeks," Quinn said. "Clinical outcomes were not expected to change. This was the first step toward a trial intended to achieve clinical effects." OHSU was the largest recruiter for the study, enrolling 14 of the 70 participants.

A study published last summer in the journal Clinical Neuropharmacology found results similar to those in the Neurology study. In that Phase I trial, researchers saw a "dose-dependent" reduction blood plasma levels of beta-amyloid in 37 volunteers taking between 5 and 50 milligrams of LY450139 during a 14-day period. Side effects, which can include headache and abdominal pain, were manageable.

Eric Siemers, M.D., a neurologist at Eli Lilly and lead investigator for the Neurology and Clinical Neuropharmacology studies, said his company has been interested in finding therapies for Alzheimer's disease "for a number of years," and that LY450139 is "the first putative disease-modifying drug" to reach the clinical trial stage.

But that doesn't mean a therapy that will stop the cognitive decline caused by Alzheimer's disease is right around the corner, Siemers emphasized.

"The current study is primarily to look at tolerability, and also to confirm the biomarkers effects," he said. "Studies that look at clinical measures of cognitive decline in Alzheimer's disease patients typically require 12 to 18 months of treatment, and hundreds of subjects."

According to OHSU's Layton Aging and Alzheimer's Disease Center, 76,000 Oregonians are among an estimated 4.5 million Americans who have Alzheimer's disease, the most common form of dementia, or a related disorder. These dementias are especially common with increasing age and are expected to afflict half of those 85 and older in the coming years.