Merck & Co has started phase II/III trials of Alzheimer’s disease therapy candidate MK-8931, the first compound in its class to reach this stage of development.
MK-8931 is leading the field among beta-amyloid precursor protein site-cleaving enzyme (BACE) inhibitors, a new class of orally-available drugs that have been plagued by developmental difficulties, with many early candidates failing to enter or be retained in the central nervous system.
BACE cuts amyloid precursor protein (APP), interrupting the formation of beta amyloid and preventing the formation of the amyloid plaques that are found in patients with the disease.
The hope is that interrupting the plaque formation process early on in the course of the disease could have a greater therapeutic effect than agents such as Pfizer & Johnson & Johnson’s bapineuzumab, which was designed to dissolve already-formed plaques and failed in phase III testing.
Merck has started a 78-week trial of MK-8931 in 200 patients with mild-to-moderate Alzheimer’s disease called EPOCH which will initially evaluate the safety of MK-8931 in a cohort of 200 patients prior to a larger phase III study.
Earlier this year, Merck presented findings of a multidose phase I study which showed that MK-8931 reduced cerebral spinal fluid (CSF) beta-amyloid by more than 90 per cent in healthy volunteers. Adverse events were generally mild to moderate and included headache, nasal congestion, dizziness, and back pain.
Along with Merck, other companies developing BACE inhibitors include Lilly, Roche and Eisai, although these are all in early-stage testing.
Other emerging classes include gamma secretase inhibitors, despite the failure of lead candidate, Lilly’s semagacestat, after late-stage trials revealed serious side effects.
Bristol-Myers Squibb has also encountered problems with gamma secretase inhibitors, terminating the development of avagacestat.