P4‐196: The novel BACE inhibitor MK‐8931 dramatically lowers cerebrospinal fluid Aβ peptides in healthy subjects following single‐ and multiple‐dose administration

Compelling evidence implicates abnormal accumulation of Aβ peptides in the pathogenesis of Alzheimer's disease (AD). Inhibition of BACE to reduce the production of Aβ is a promising approach to test the amyloid hypothesis. Here we report the pharmacodynamic effects of the novel BACE inhibitor MK-8931, as reflected by reduction of CSF Aβ peptides in the first studies in human. Randomized, double-blind, placebo-controlled rising single dose (RSD) and rising multiple dose (RMD) studies were conducted in healthy adults, 18-45 years of age. In the RSD, the pharmacodynamic effects of MK-8931 (20, 100, 550-mg) were assessed in 3 sequential cohorts (n = 8/cohort, 6-active, 2-placebo). In the RMD, 5 sequential cohorts (n = 8-12/cohort, active: placebo=3:1) were administered 10 to 250-mg MK-8931 daily for 14 days. CSF Aβ40, Aβ42 and sAPPβ concentrations were determined over 36 hrs postdose (Day 1 in RSD; Day 14 in RMD) using samples collected via lumbar catheterization. Single and multiple doses of MK-8931 were generally well-tolerated; adverse events were generally mild to moderate in intensity. Following placebo administration, mean CSF Aβ40 concentrations increased relative to baseline. By contrast, MK-8931 resulted in a dose-dependent and sustained reduction in Ab 40.Following single dose administration, the mean (90% confidence interval) CSF Ab 40 percent of baseline time weighted average (TWA) from 0 to 36 hrs postdose was: 20-mg=75% (68%, 82%), 100-mg=52% (46%, 59%) and 550-mg=39% (31%, 46%) and the mean CSF Ab 40 percent of baseline at 36 hrs postdose was: 20-mg=79% (71%, 87%), 100-mg=25% (17%, 33%) and 550-mg=8% (0%, 17%). Following multiple dose administration, the mean CSF Ab 40 percent of baseline TWA 0-36hr on Day 14 was 10-mg=68% (59%, 77%), 40-mg=20% (13%, 28%), 150-mg=9% (3%, 15%) and 250-mg=6% (1%, 12%). Similar reductions in CSF Aβ42 and sAPPβ were observed. Following single (20 to 550 mg) and multiple (10 to 250 mg daily for 14 days) dose administration, MK-8931 was well-tolerated and demonstrated a profound (up to 94%) reduction in CSF A β. Thus, MK-8931 presents a unique opportunity to test the amyloid hypothesis of AD pathogenesis.