LGND and MRK: MK-8931 Alzheimer's Disease Data from AAIC 2012Click here for related blog post on MK-8931.
P1-229 POPULATION PHARMACOKINETIC MODELING OF THE NOVEL BACE INHIBITOR MK-8931 FOLLOWING SINGLE AND MULTIPLE DOSE ADMINISTRATION IN HEALTHY SUBJECTS Lei Ma, Marissa Dockendorf, Gopal Krishna, Huub-Jan Kleijn, Jing Su, Mark Forman, Julie Stone, Merck, Whitehouse Station, New Jersey, United States. Background: Compelling evidence implicates abnormal accumulation of Ab peptides in the pathogenesis of Alzheimer’s disease (AD). Inhibition of BACE to reduce the production of Ab is a promising approach to test the amyloid hypothesis. MK-8931 is being developed as a disease modifying therapy for AD. Methods: The population PK analysis was conducted on data obtained from 4 phase 1 trials involving healthy adults (n ¼ 86, 18-45 years of age), healthy elderly subjects (n ¼ 35, 65-85 years of age) and healthy Japanese adults (n ¼ 20, 18-55 years of age). A total of 121 healthy subjects were randomized to receive either single doses (2.5, 5, 10, 20, 40, 80, 100, 150, 300, 450, 550 mg) or multiple doses (10, 30, 40, 80, 120, 150 and 250 mg, once a day) of MK-8931. MK-8931 plasma concentration data were analyzed using a nonlinear mixed effect model implemented in NONMEM VII. Results: A two-compartment model with first-order absorption and elimination adequately described the plasma concentration- time profiles of MK-8931 in healthy subjects. The estimated mean PK parameters and associated relative standard error (%RSE) for KA, CL/F, V1/F, Q and V2 were 0.67 (8) hr -1, 25.2 (2) L/hr, 482 (4) L, 4.29 (37) L/hr and 102 (16) L, respectively. Of the covariates evaluated, age, race and body weight were significant covariates on apparent total body clearance (CL/F); body weight was a significant covariate on volume of distribution (V1/F). Based on this model AUC is projected to be 26% increased in elderly relative to young adults and 13% increased in patients weighting 50 kg and 17% decreased in patients weighing 120 kg relative to 70 kg. Conclusions: The final population PK model identified age, race and body weight as significant covariates on CL/F and body weight on V1/F, respectively. The effect of these factors on exposure is projected to be modest. The population PK model was used to project PK in the AD population and to inform the therapeutic window of MK-8931 and dose selection for phase 2 trials. P4-196
THE NOVEL BACE INHIBITOR MK-8931 DRAMATICALLY LOWERS CEREBROSPINAL FLUID Ab PEPTIDES IN HEALTHY SUBJECTS FOLLOWING SINGLE- AND MULTIPLE-DOSE ADMINISTRATION Mark Forman1, John Palcza1, Jack Tseng1, Jos Leempoels2, Steven Ramael2, David Han3, Stanford Jhee3, Larry Ereshefsky3, Michael Tanen1, Omar Laterza1, Marissa Dockendorf1, Gopal Krishna1, Lei Ma1, John Wagner1, Matthew Troyer1, 1Merck, Whitehouse Station, New Jersey, United States; 2SGS Life Science Services, Antwerp, Belgium; 3Parexel International Early Phase, Glendale, California, United States. Background: Compelling evidence implicates abnormal accumulation of Ab peptides in the pathogenesis of Alzheimer’s disease (AD). Inhibition of BACE to reduce the production of Ab 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 Ab peptides in the first studies in human. Methods: 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 ¼ 8/cohort, 6-active, 2-placebo). In the RMD, 5 sequential cohorts (n ¼ 8-12/cohort, active: placebo¼3:1) were administered 10 to 250-mg MK-8931 daily for 14 days. CSF Ab40, Ab42 and sAPPb concentrations were determined over 36 hrs postdose (Day 1 in RSD; Day 14 in RMD) using samples collected via lumbar catheterization. Results: 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 Ab40 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-mg¼75% (68%, 82%), 100-mg¼52% (46%, 59%) and 550-mg¼39% (31%, 46%) and the mean CSF Ab 40 percent of baseline at 36 hrs postdose was: 20- mg¼79% (71%, 87%), 100-mg¼25% (17%, 33%) and 550-mg¼8% (0%, 17%). Following multiple dose administration, the mean CSFAb 40 percent of baseline TWA 0-36hr on Day 14 was 10-mg¼68% (59%, 77%), 40- mg¼20% (13%, 28%), 150-mg¼9% (3%, 15%) and 250-mg¼6% (1%, 12%). Similar reductions in CSFAb42 and sAPPb were observed. Conclusions: 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 CSFA b. Thus, MK-8931 presents a unique opportunity to test the amyloid hypothesis of AD pathogenesis. |
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P1-221
SAFETYAND PHARMACOKINETICS OF THE NOVEL BACE INHIBITOR MK-8931 IN HEALTHY SUBJECTS FOLLOWING SINGLE- AND MULTIPLE-DOSE ADMINISTRATION Jack Tseng1, Marissa Dockendorf1, Gopal Krishna1, Lei Ma1, John Palcza1, Jos Leempoels2, Steven Ramael2, David Han3, Stanford Jhee3, Larry Ereshefsky3, John Wagner1, Matthew Troyer1, Mark Forman1, 1Merck, Whitehouse Station, New Jersey, United States; 2SGS Life Science Services, Antwerpen, Belgium; 3Parexel International Early Phase, Glendale, California, United States Background: Compelling evidence implicates abnormal accumulation of Ab in the pathogenesis of Alzheimer’s disease (AD). Inhibition of BACE to reduce the production of Ab 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. Methods: 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 ¼ 8/cohort, active: placebo ¼ 3:1). In the RMD, five sequential cohorts (n ¼ 8-12/cohort, active: placebo ¼ 3:1) were administered 10 to 250-mg MK-8931 daily for 14 days. Plasma and CSF were collected for pharmacokinetic analysis. Results: All randomized subjects completed the single (n ¼ 40) or multiple (n ¼ 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 ¼ 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-tomoderate 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%). Conclusions: 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. P1-225
A STUDY TO EVALUATE THE PHARMACOKINETICS AND PHARMACODYNAMICS OF SINGLE AND MULTIPLE ORAL DOSES OF THE NOVEL BACE INHIBITOR MK-8931 IN JAPANESE SUBJECTS K. Min1, Mark Forman1, Marissa Dockendorf1, John Palcza1, Peter Soni1, Lei Ma1, Gopal Krishna1, Peter Hodsman2, Kazuko Masuo2, Michael Tanen1, John Wagner1, Matthew Troyer1, 1Merck, Whitehouse Station, New Jersey, United States; 2Nucleus Network LTD, Melbourne, Australia. Background: Compelling evidence implicates abnormal accumulation of Ab in the pathogenesis of Alzheimer’s disease (AD). Inhibition of BACE to reduce production of Ab 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. Methods: 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 (n¼8, 6-active, 2-placebo). In Part-2, 2 cohorts (each n ¼ 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 Ab40, Ab42 and sAPPb 24 hours after the last dose compared to baseline values. Results: 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 andMDadministration, maximum MK-8931 concentrations were achieved at w2 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 Ab40 percent of baseline at 24 hr postdose was: placebo ¼ 100% (2%) and 450 mg ¼ 20% (3%). Following MD administration of 80-mg, mean CSF A b 40 percent of baseline 24 hr postdose on Day 14 was: placebo ¼ 94% (1%) and 80 mg ¼ 12% (1%). CSF Ab42 and sAPPb demonstrated similar reductions. The pharmacodynamic effects in Japanese were similar to that observed previously in non-Japanese. Conclusions: 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 CSFAb in Japanese, similar to that observed in non-Japanese and, thus, provides a unique opportunity to test the amyloid hypothesis of AD pathogenesis. |