In prior healthy young adults (HY) studies, administration of the BACE inhibitor MK-8931 reduced cerebrospinal fluid (CSF) Aβ40 up to ∼90%1. A multiple-dose CSF biomarker study with MK-8931 has recently been completed in Alzheimers disease (AD) patients. Model-based analysis of the pooled HY and AD data evaluated whether the drug action of MK-8931 on brain biomarker production was altered by disease and explored the influence of the oligomer and plaque pool in AD on beta-amyloid monomer kinetics. Mild-to-moderate AD patients (n=6–8 per arm) received 7 daily doses of placebo, 12, 40 or 60 mg MK-8931 with serial CSF sampling to determine drug, Aβ40, Aβ42, and sAPPβ concentrations. Data were analyzed by fitting simultaneously to the timecourses of 3 biomarkers using a mechanistic amyloid pathway model including terms for amyloid brain production and distribution to lumbar CSF. Drug effect on brain production was tested for altered maximal response (Emax) and in vivo potency (IC 50) between HY and AD. Data from all 3 biomarkers in HY and AD were well represented by a model with separate Emax values for each biomarker / population, but joint IC 50 value across all biomarkers that varied slightly by population. The ratio (AD/HY) of median IC 50 (90% CI) was 1.17 (0.91, 1.56) indicating little alteration in potency in AD vs HY. Emax was reduced in AD vs HY (A b 40 0.96 à 0.93; A b 42 0.96 à 0.90; sAPP b 0.98 à 0.96). These Emax alterations suggest that a portion of CSF amyloid is not derived from de novo production, but rather comes from other sources such as the oligomer / plaque pool. This indirect evidence of reversibility of higher order amyloid forms to monomer suggests that BACE inhibition may act to reduce these pools as well as monomer. MK-8931 has consistent drug effects on brain amyloid production in AD and HY, supporting use of HY studies for dosing guidance. MK-8931 is predicted to reduce median CSF Aβ40 by 67.4%, 83.8%, and 86.8% at steady-state 12, 40, and 60 mg daily in AD. These potent inhibition effects provide a unique opportunity to test the amyloid hypothesis. Ref 1: Forman et al. 2012 AAIC abstract.

Objective: To characterize the safety/tolerability, pharmacokinetics and pharmacodynamics of the novel BACE inhibitor MK-8931 in humans. Background Compelling evidence implicates abnormal accumulation of Aβ in the pathogenesis of Alzheimer9s disease (AD). BACE inhibition of Aβ production is a promising approach to test the amyloid hypothesis. Here we report the effects of the novel BACE inhibitor MK-8931 on reduction of CSF Aβ in humans. Design/Methods: Two-part, randomized, double-blind, placebo-controlled single rising-dose study of MK-8931 in healthy adults, 18-45 years. In Part-1, 2 cohorts (n=8/cohort, 6-active, 2-placebo) participated in an alternating-panel design to evaluate the safety/tolerability and pharmacokinetics of 2.5 to 550-mg MK-8931. Part-2 assessed the effects of MK-8931 (20-, 100-, 550-mg) on CSF Aβ40, Aβ42 and sAPPβ concentrations in 3 sequential cohorts (n=8/cohort, 6-active, 2-placebo). Results: Single doses of MK-8931 from 2.5 to 550-mg were well-tolerated; adverse events (AE) were generally mild to moderate in intensity. There were no serious AEs and no study discontinuations. Maximum MK-8931 concentrations were achieved at 1-4.5 hr in plasma and 4-6 hr in CSF and there was a dose-related increase in plasma and CSF exposure. The terminal phase half-life in plasma was 16.5-23.5 hr. Mean CSF concentrations post-peak declined in parallel with plasma, indicating a dynamic equilibrium between plasma and CSF; the CSF:plasma ratio was 0.11. Following placebo administration, CSF Aβ40 concentrations increased relative to baseline. By contrast, MK-8931 resulted in a dose-dependent and sustained reduction in Aβ40. At 36 hr postdose, the mean CSF Aβ40 percent of baseline (90% confidence interval) was: 20-mg=79% (71, 87%), 100-mg=25% (17, 33%) and 550-mg=8% (0, 17%). CSF Aβ42 and sAPPβ demonstrated similar reductions. Conclusions: Single doses of MK-8931 up to 550-mg were well-tolerated and demonstrated a profound reduction in CSF Aβ peptides. Thus, MK-8931 presents a unique opportunity to test the amyloid hypothesis of AD pathogenesis. Supported by: Merck. Disclosure: Dr. Forman has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. Forman holds stock and/or stock options in Merck & Co., Inc. Dr. Tseng has received personal compensation for activities with Merck & Co., as an employee. Dr. Palcza has received personal compensation for activities with Merck as an employee. Dr. Leempoels has nothing to disclose. Dr. Ramael has nothing to disclose. Dr. Krishna has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. Ma has received personal compensation for activities with Merck as an employee. Dr. Wagner has received personal compenstion for activities with Merck as an employee. Dr. Wagner holds stock and/or stock options in Merck, which sponsored research in which Dr. Wagner was involved as an investigator. Dr. Troyer has received personal compensation for activities with Merck & Co., Inc. as an employee. Dr. Troyer holds stock and/or stock options in Merck & Co., Inc. which sponsored research in which Dr. Troyer was involved as an investigator.

Compelling evidence implicates abnormal accumulation of Aβ in the pathogenesis of Alzheimer's disease (AD). Inhibition of BACE to reduce production of Aβ peptide is a promising approach to test the amyloid hypothesis. To support enrollment of Japanese subjects in future AD trials, the safety/tolerability, pharmacokinetics and pharmacodynamics of MK-8931 was studied in healthy Japanese subjects. Two-part randomized, double-blind, placebo-controlled rising single dose (SD; Part-1) and multiple dose (MD; Part-2) study conducted in healthy Japanese adults, ages 18-55. In Part-1, three single doses of MK-8931 (20, 100, 450-mg) were assessed in a single cohort (n = 8, 6-active, 2-placebo). In Part-2, 2 cohorts (each n = 8, 6 active: 2 placebo) were administered 80 or 150-mg MK-8931 daily for 14 days. The pharmacodynamic effect of MK-8931 was determined following the 450 mg dose in Part -1 and in the 80 mg Cohort in Part-2 by assessment of CSF concentrations of Aβ40, Aβ42 and sAPPβ 24 hours after the last dose compared to baseline values. Single and multiple MK-8931 doses were generally well-tolerated; adverse events were mild-to-moderate in intensity and no subjects discontinued due to AEs. Following SD and MD administration, maximum MK-8931 concentrations were achieved at ∼2 hr and there was a dose-related increase in plasma exposure. The terminal phase half-life was 16-21 hr. Over the dose range tested, exposure (AUC) in Japanese was similar to that observed previously in non-Japanese. Following SD administration of 450-mg, mean (standard error) CSF Aβ40 percent of baseline at 24 hr postdose was: placebo = 100% (2%) and 450 mg = 20% (3%). Following MD administration of 80-mg, mean CSF A b 40 percent of baseline 24 hr postdose on Day 14 was: placebo = 94% (1%) and 80 mg = 12% (1%). CSF Aβ42 and sAPPβ demonstrated similar reductions. The pharmacodynamic effects in Japanese were similar to that observed previously in non-Japanese. Following single and multiple dose administration, MK-8931 was well-tolerated and the pharmacokinetics in Japanese was similar to non-Japanese. MK-8931 also demonstrated a profound reduction in mean CSF Aβ in Japanese, similar to that observed in non-Japanese and, thus, provides a unique opportunity to test the amyloid hypothesis of AD pathogenesis.