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- W2898059676 abstract "The BACE inhibitor verubecestat (MK-8931) failed to slow cognitive and functional decline in a Phase 3 trial of individuals with mild-to-moderate AD (NCT01739348). Pharmacokinetic (PK) and biomarker data from the trial were examined to characterize target engagement and exposure-response in the trial and to investigate whether these factors impacted the study results. Plasma and/or Dried-Blood-Spot samples were collected during 4-7 visits over 18 months on treatment for determination of verubecestat concentrations (6200 samples from 1465 participants). Drug exposure (AUC, Cmax, Ctrough) was estimated using a population PK modeling approach. Exposure-response relationships for the clinical efficacy outcomes (ADAS-cog11, CDR-SB, ADCS-ADL) versus AUC were evaluated graphically and utilizing an established ADAS-cog disease progression model (Ref 1). Mean (SD) AUC was 1.513 (0.315) and 5.009 (1.031) μM·h, respectively in the 12 mg (n=686) and 40 mg (n=680) verubecestat arms, consistent with Phase 1 PK. CSF Aβ40, Aβ42, and sAPPβ data from a subset of patients (n=152) were generally consistent with the expected dose-response from Phase 1 studies, such that the 40 mg dose falls near the plateau of maximal BACE inhibition with 12 mg providing substantial inhibition but less than maximal. There was no apparent PK exposure-dependency in the clinical outcomes. The decline in cognition and other clinical endpoints over 18 months in participants receiving verubecestat was similar across all exposure quartiles. The estimated slope of AUC effect on ADAS-cog disease progression was small (-4.4e-5) and the 90% CI contained zero. Overall, these results indicate that EPOCH tested drug exposures and target engagement consistent with 72% and 90% inhibition of Aβ production at the 12 and 40 mg doses, respectively. Together with the lack of exposure-dependency in the cognition data, these results suggest that insufficient dose or target engagement was not the driver for the failure to meet the clinical endpoints as expected exposures were achieved. Ref 1. Clin Pharmacol Ther. 2015 Mar;97(3):210-4." @default.
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- W2898059676 date "2018-07-01" @default.
- W2898059676 modified "2023-10-16" @default.
- W2898059676 title "P1‐038: VERUBECESTAT PHARMACOKINETIC AND EXPOSURE‐RESPONSE RESULTS FROM EPOCH: A PHASE 3 TRIAL IN MILD‐TO‐MODERATE ALZHEIMER'S DISEASE" @default.
- W2898059676 doi "https://doi.org/10.1016/j.jalz.2018.06.039" @default.
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