Research leading to the discovery and development of verubecestat (Merck), an investigational small-molecule inhibitor of the enzyme beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1), for the potential treatment of patients with Alzheimer’s disease (AD) has been published in Science Translational Medicine. The efficacy and safety of verubecestat is being evaluated in two pivotal phase 3 trials, EPOCH and APECS, for the treatment of patients with mild-to-moderate AD and prodromal AD, respectively.
BACE1 is an important enzyme in the initiation of toxic amyloid-beta peptide production in the brain. Researchers believe that sustained, selective inhibition of BACE1 leading to a significant reduction in amyloid-beta production is a promising means for therapeutic intervention. This hypothesis, however, has not been demonstrated in clinical studies.
Historically, the development of selective BACE1 inhibitors with properties allowing oral absorption and the ability to cross the blood–brain barrier to the site of action in the brain has proved technically challenging. Over several years, detailed analysis of the structure and function of the BACE1 protein yielded the compound verubecestat. The drug’s preclinical safety and tolerability profiles supported its progression into human clinical testing for chronic use.
Subsequent phase 1 data from both healthy volunteers and AD patients demonstrated that once-daily doses of verubecestat for one week provided significant reductions of up to 80% in the levels of amyloid-beta peptide production, a key marker of BACE1 activity, in the cerebral spinal fluid (CSF).
In a phase 1, randomized, double-blind, placebo-controlled, multiple-dose study, 32 patients with mild-to-moderate AD were randomly assigned to receive one of three doses (12 mg, 40 mg, or 60 mg) of verubecestat or placebo once daily for seven days. Samples of CSF were collected during a 36-hour period via a lumbar catheter and were analyzed for levels of amyloid-beta 40, amyloid-beta 42, and soluble amyloid precursor protein-beta as biomarkers of BACE1 activity. In this study, verubecestat at doses of 12 mg, 40 mg, and 60 mg provided dose-dependent and sustained reductions in the levels of amyloid-beta 40 from baseline in the CSF, a measure of BACE1 activity, of 57%, 79%, and 84%, respectively.
The ongoing phase 2/3 EPOCH trial is a randomized, placebo-controlled, parallel-group, double-blind study evaluating the efficacy and safety of two oral doses of verubecestat (12 mg and 40 mg) administered once daily compared with placebo in patients with mild-to-moderate AD receiving standard-of-care treatment. The study’s primary efficacy endpoints are the change from baseline in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) score, as well as the change from baseline in the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score, after 78 weeks of treatment.
The ongoing phase 3 APECS trial is a randomized, placebo-controlled, parallel-group, double-blind study designed to evaluate the efficacy and safety of verubecestat in 1,500 subjects with prodromal AD. The patients will be randomly assigned to receive verubecestat (12 mg or 40 mg) or placebo once daily. The study’s primary efficacy endpoint is the change from baseline in the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score after 104 weeks of treatment.
Source: Merck; November 2, 2016.