Publication | Open Access
O1–06–05: The novel BACE inhibitor MK‐8931 dramatically lowers CSF beta‐amyloid in patients with mild‐to‐moderate Alzheimer's disease
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2013
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Placebo AdministrationDose-response ProfilesNeurochemical BiomarkersPharmacotherapyMild‐to‐moderate AlzheimerExperimental PharmacologySocial SciencesPharmacodynamic ModelingNeurobiology Of DiseaseAlzheimer's DiseaseDegenerative PathologyNeurologyAging-associated DiseaseBrain PathologyNeuroimmunologyAmyloid HypothesisNeuropharmacologyNeuroprotectionNeurodegenerationPharmacologyCsf Beta‐amyloidNeurodegenerative DiseasesNeuroscienceMedicine
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.