The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients

beta-Amyloid (Ab) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of A beta, 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 A beta 40, A beta 42, and sAPP beta (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 A beta 40, A beta 42, and sAPPb 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 Ab pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.