BOSTON—A beta-secretase (BACE1) inhibitor significantly lowered CSF beta-amyloid levels in patients with mild to moderate Alzheimer’s disease in a dose-dependent fashion, researchers reported at the 2013 Alzheimer’s Association International Conference.
“This is the first demonstration of the lowering of beta-amyloid levels by a BACE1 inhibitor [MK-8931] in people with Alzheimer’s disease,” said Mark S. Forman, MD, PhD, Director of Clinical Research at Merck Research Laboratories in Boston, and colleagues. “We believe this candidate presents a unique opportunity to test the amyloid hypothesis.”
Previous studies had found that the experimental drug was generally well tolerated and resulted in a dose-dependent reduction of CSF beta-amyloid in healthy participants.
Dr. Forman’s group conducted a randomized, double-blind, placebo-controlled Phase Ib trial of MK-8931 in persons with mild to moderate Alzheimer’s disease. The drug inhibits BACE1, one of two enzymes that produce beta-amyloid by breaking down amyloid precursor protein.
Participants received 12, 40, or 60 mg of MK-8931 or placebo (n = 8 per dose; n = 6 for placebo) daily for seven days. The investigators measured CSF beta-amyloid levels over 36 hours following the final dose using samples collected from lumbar catheterization.
In subjects who received placebo, mean CSF concentrations increased relative to baseline. In participants who received MK-8931, however, “multiple doses of 12 to 60 mg resulted in a dose-dependent reduction in CSF beta-amyloid, similar to that observed in healthy volunteers, and have enabled robust dose-response modeling,” stated Dr. Forman. “Dose-response profiles predict that 12- and 40-mg MK-8931 will inhibit beta-amyloid production by greater than 50% and greater than 75%, respectively, in the majority of Alzheimer’s disease patients.”
—Colby Stong
Editor