O1–06–05: The novel BACE inhibitor MK‐8931 dramatically lowers CSF beta‐amyloid in patients with mild‐to‐moderate Alzheimer's diseaseстатья из журнала
Аннотация: 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.
Год издания: 2013
Авторы: Mark S. Forman, Huub‐Jan Kleijn, Marissa F. Dockendorf, John Palcza, Jack Tseng, Christina Canales, Michael Egan, Matthew Kennedy, Omar Laterza, Lei Ma, Jack D. Scott, Michael Tanen, Jeffrey Apter, Miroslav Bačkonja, Larry Ereshefsky, Hakop Gevorkyan, Stanford S. Jhee, Rebecca Rynders, A Soukhteh Zari, Ellie Bryan, John A. Wagner, Matthew D. Troyer, Julie A. Stone
Издательство: Wiley
Источник: Alzheimer s & Dementia
Ключевые слова: Cholinesterase and Neurodegenerative Diseases, Computational Drug Discovery Methods, Alzheimer's disease research and treatments
Открытый доступ: bronze
Том: 9
Выпуск: 4S_Part_3