β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) is required for the production of β‐amyloid peptides, which are implicated in the etiology of Alzheimer's disease. The safety and pharmacokinetics of the BACE1 inhibitor verubecestat have previously been studied in young adults aged 19–45 years. In this randomized, placebo‐controlled, phase I study (protocol MK‐8931‐006), we investigated the safety, tolerability, and pharmacokinetics of a single dose (100 mg) or multiple doses (30, 80, and 120 mg) once daily for 28 days of verubecestat in healthy elderly subjects. Safety end points were assessed at baseline and during the duration of the study period and indicated that verubecestat was generally well tolerated. Verubecestat pharmacokinetics were similar between healthy elderly male and female subjects and similar to those reported in healthy young males in previous studies. These data supported subsequent studies to assess the potential efficacy of verubecestat in subjects with Alzheimer's disease.

β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β‐amyloid (Aβ) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics (PKs), and pharmacodynamics of the BACE1 inhibitor verubecestat (MK‐8931) in 24 healthy Japanese adults in a two‐part, single‐center, randomized, placebo‐controlled phase I trial (protocol MK‐8931‐007) and compared the results with historical data from non‐Japanese subjects. Both single (20, 100, and 450 mg) and multiple (80 and 150 mg once daily for 14 days) doses of verubecestat were well tolerated. Verubecestat's PK profile was similar in Japanese and non‐Japanese subjects. Verubecestat also reduced mean cerebrospinal fluid concentrations of the Aβ proteins Aβ40, Aβ42, and soluble β fragment of amyloid precursor protein; the level of reduction was comparable between Japanese and non‐Japanese subjects. These results support the continued global development of verubecestat as a potential disease‐modifying agent for Japanese and non‐Japanese subjects who are at risk for developing AD.

β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer’s disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures >40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.

The CXCR2 antagonist MK-7123 causes dose-dependent reductions in absolute neutrophil counts (ANC) and decreases neutrophil tissue responses, but its effects on bone marrow functions are not yet known. We conducted a double-blind, randomized study in 18 healthy subjects comparing the effects of either MK-7123 (30mg, po, daily for 28days) or placebo on peripheral blood counts and bone marrow myeloid cell populations. MK-7123 caused a reversible decrease (approximately 50%) in the ANC as demonstrated on days 1 and 28, the first and last days of the treatment period. Bone marrow aspirate smears and biopsy imprints did not differ in the proportion of mature neutrophils in pretreatment, day 28, day 56 or placebo samples. There were no treatment effects on biopsy or aspirate clot cellularity, myeloid to erythroid or myeloid post-mitotic to mitotic ratios; flow-cytometric analyses of aspirate cells; or bone marrow fat to cell balance as assessed by MRI. MK-7123 was generally well tolerated with neutropenia being the most common adverse event; however, there were no clinical symptoms associated with decreased ANCs. These findings indicate that the CXCR2 antagonist MK-7123 causes rapidly reversible decrease in the ANC without measurable myelosuppressive effects. The results support the development of CXCR2 antagonists as potentially useful anti-inflammatory agents, primarily interrupting neutrophil trafficking.

Compelling evidence implicates the abnormal accumulation of Aβ in the pathogenesis of Alzheimer's disease (AD). Inhibition of BACE1 to reduce Aβ production is a promising approach to test the amyloid hypothesis. In prior studies in healthy volunteers, the BACE1 inhibitor MK-8931 was generally well-tolerated and resulted in a dose-dependent reduction of CSF Ab. Here we report the initial characterization of the pharmacodynamics of MK-8931 in AD patients. Randomized, double-blind, placebo-controlled, multiple-dose study in mild-to-moderate AD patients. Subjects were administered 12, 40 or 60-mg MK-8931 or placebo (n=8 per dose; n=6 for placebo) daily for 7days. CSF Aβ40, Aβ42 and sAPPβ concentrations were determined over 36 hours postdose on Day7 using samples collected via lumbar catheterization. A semi-mechanistic mathematical model was developed to describe Ab 40, Ab 42 and sAPP b modulation in CSF and used to generate dose-response profiles for AD patients. Following placebo administration, mean CSF concentrations of Aβ40, Aβ42 and sAPP b increased relative to baseline. By contrast, administration of MK-8931 resulted in a dose-dependent and sustained reduction in CSF Ab levels with mean percent reduction from baseline of up to: Aβ40=84%, Aβ42=81%, and sAPPβ=88%. CSF modulation of Ab 40, Ab 42 and sAPP b was best described by a sigmoid Emax model and transit compartments accounted for the delay between brain and lumbar CSF Ab. Based on dose-response profiles generated using this model, t argeted CSF A b reductions between 50–75% and between 75–100% from baseline are predicted to be achieved in AD patients at dose levels of 12 and 40mg MK-8931, respectively. This study is the first demonstration of a pharmacodynamic effect of BACE1 inhibition in AD patients. Multiple doses of 12 to 60-mg MK-8931 resulted in a dose-dependent reduction in CSF A β, similar to that observed in healthy volunteers and have enabled robust dose-response modeling. Dose-response profiles predict that 12 and 40mg MK-8931 will inhibit Aβ production by >50% and >75%, respectively, in the majority of AD patients. Thus, MK-8931 presents a unique opportunity to test the amyloid hypothesis of AD pathogenesis. Ref 1: Forman et al. 2012 AAIC abstract.

This randomized, open‐label, parallel group study examined the effects of food, antacid, and age on the pharmacokinetics of vorapaxar. In total, 101 subjects were enrolled including 83 young adults (18–45 years) and 18 elderly subjects (>65 years). Subjects received single‐dose vorapaxar 40 mg after a 10‐hour fast (young and elderly) or with extra‐strength antacid, food, or 1 or 2 hours after food (young only). Vorapaxar 40 mg was rapidly absorbed after a fast (median Tmax: 1 hour). Administration with food or 1 or 2 hours post‐meal modestly increased vorapaxar mean area under the curve (AUC) and Cmax and prolonged median Tmax by 1 hour. Concomitant food modestly increased vorapaxar AUC from time zero to infinity [AUC(I)] and Cmax 43% and 31%, respectively. Antacid modestly decreased vorapaxar AUC(I) by 15% and Cmax by 38%, and increased median Tmax by 1 hour. Vorapaxar AUC(I) and Cmax were 41% and 29% higher, respectively, in elderly versus young subjects. Concomitant food and older age were associated with modest increases, and antacid was associated with a small decrease in vorapaxar exposure, which are not expected to affect the drug's safety or efficacy.

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.

Compelling evidence implicates abnormal accumulation of Aβ 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 initial safety and pharmacokinetics of the novel BACE inhibitor, MK-8931, in humans. Randomized, double-blind, placebo-controlled rising single (RSD) and rising multiple dose (RMD) studies were conducted in healthy adults, 18-45 years of age. In the RSD study, single doses of 2.5 to 550-mg MK-8931 were administered to either two alternating (Part 1, five single doses/cohort) or three sequential (Part 2) cohorts (n = 8/cohort, active: placebo = 3:1). In the RMD, five sequential cohorts (n = 8-12/cohort, active: placebo = 3:1) were administered 10 to 250-mg MK-8931 daily for 14 days. Plasma and CSF were collected for pharmacokinetic analysis. All randomized subjects completed the single (n = 40) or multiple (n = 48) dose studies. MK-8931 was generally well-tolerated. No clinically significant changes in safety labs, vital signs or ECGs were noted. Small mean increases in QTc interval (6-15 msec) were observed following single doses ≥ 300 mg (Cmax ≥ 1.7 m M); QTc prolongation was not observed following multiple dose administration up to 250 mg (Cmax = 1.9 m M). There were no serious adverse events (AEs) and no discontinuations due to AEs related to study drug. AEs were generally mild-to-moderate in intensity and there were no dose-related increases in AEs. There were two severe AEs: one postdural puncture headache and one rash. The most frequent AEs were headaches, musculoskeletal pain, asymptomatic orthostatic tachycardia, nasopharyngitis, dizziness, and nausea. Following MK-8931 administration, there was an approximately dose proportional increase in plasma and CSF exposure over the dose range tested. Maximum MK-8931 plasma concentrations were achieved at 1.0-4.5 hrs. Mean effective half-life was 14-22 hrs and mean exposure accumulation ratio following multiple dose administration was 1.5-1.8. CSF concentrations peaked at 4-6 hrs and declined in parallel with plasma, indicating a dynamic equilibrium between plasma and CSF. CSF to plasma exposure was 0.09-0.12. O verall pharmacokinetic variability in plasma and CSF was low (CV 12-36%). Single (2.5-550-mg) and multiple (10-250-mg) doses of MK-8931 were well-tolerated and demonstrated an overall pharmacokinetic profile suitable for QD dosing.

Large hour-to-hour variability has previously been demonstrated in the cerebrospinal fluid (CSF) concentrations of Alzheimer's disease (AD) biomarkers amyloid β42 (Aβ42) and Aβ40 in healthy younger subjects. We investigated the within-subject variability over 36 hours in CSF Aβ and tau proteins, in older subjects and AD patients. Six patients with mild stage AD (59–85 years, Mini Mental State Examination (MMSE) 16–26) and 6 healthy older volunteers (64–77 years) received an intrathecal catheter from which, during 36 hours, each hour 6 mL of CSF was drawn. Concentrations of Aβ42, Aβ40, total tau, and phosphorylated tau were determined and the variability was analyzed. Within-subject variability within 3-hour periods was assessed as the coefficient of variation, which was comparable for these 4 biomarkers in controls (4.2%–4.6%) and AD (3.1%–5.8%). Variability over 12 hour periods was 5.3% to 9.5%. These findings suggest that CSF biomarker variability is relatively low in healthy older controls and AD patients. Furthermore, continuous sampling of CSF proved to be a useful and robust method, which may also be used to investigate AD pathogenesis and to evaluate pharmacotherapeutic interventions.

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.

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.

Recently it was demonstrated that diurnal fluctuation of brain specific proteins amyloid β 1-42 (Aβ42) and Aβ40 in cerebrospinal fluid (CSF) of healthy subjects is considerable and may be related to diurnal rhythms1. A better understanding of intra-individual variability in CSF Aβ and tau proteins, especially in AD patients, is essential for implementation of CSF analysis in clinical practice. To investigate diurnal fluctuations in CSF Aβ and tau proteins in AD patients and age-matched controls. Six healthy elderly volunteers (64-77 yrs) and six patients with mild stage AD (59-85 yrs, MMSE 16-26) received an intrathecal catheter from which hourly for 36 hours 6 ml CSF was drawn. CSF Aβ42, t-tau and p-tau concentrations were determined using an xMAP-based assay and Aβ40 concentrations using ELISA. Variation coefficients in the AD group were 12.1-18.5% for the four CSF biomarkers. For the healthy control group these were 11.4- 16.7%, not significantly different from the AD group. In comparison, within sample intra-laboratory variation coefficients were 8.3-11.8%. We did not observe a diurnal pattern of CSF Aβ, t-tau and p-tau levels. Furthermore, we did not observe differences in mean biomarker concentrations in either group when daytime and nighttime samples were compared or when periods of sleep were compared to periods being awake. In the AD-group, t-tau and p-tau levels continued to increase over 36 hours. We realized a safe and innovative methodology to longitudinally monitor and analyze CSF biomarkers in both healthy volunteers and AD patients. Intra-individual variability did not differ between groups and was not larger than analytic measurement error. CSF biomarker levels in both AD patients and healthy controls seem unrelated to diurnal or sleep patterns. The increase in t-tau and p-tau levels in AD patients might be explained by reduced CSF production at stable tau production due to Alzheimer related pathology. This study implies that lumbar puncture to collect CSF for AD biomarker analysis can be performed any time of day, without reference ranges related to time of puncture. Reference: 1Bateman RJ, et al. Neurology 2007;68:666-669.