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

The BACE1 inhibitor verubecestat safely reduces β-amyloid deposition in rats, monkeys, healthy human subjects, and patients with Alzheimer’s disease. Getting to first BACE The discovery of BACE1 inhibitors that reduce β-amyloid peptides in Alzheimer’s disease (AD) patients has been an encouraging development in the quest for a disease-modifying therapy. Kennedy and colleagues now report the discovery of verubecestat, a structurally unique, orally bioavailable small molecule that potently inhibits brain BACE1 activity resulting in a reduction in Aβ peptides in the cerebrospinal fluid of animals, healthy volunteers, and AD patients. No dose-limiting toxicities were observed in chronic animal toxicology studies or in phase 1 human studies, thus reducing safety concerns raised by previous reports of BACE inhibitors and BACE1 knockout mice. β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer’s disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, 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 Aβ40, Aβ42, and sAPPβ (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 Aβ40, Aβ42, and sAPPβ 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 Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.