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Early development of Verubecestat, an investigational BACE1 inhibitor

Verubecestat is an investigational small molecule inhibitor of the enzyme beta-site amyloid precursor protein cleaving enzyme 1 ( BACE1 ) for the potential treatment of Alzheimer’s disease.
A research was published in the journal Science Translational Medicine and includes results from the phase 1 clinical trials in healthy volunteers and people with Alzheimer’s disease.
The efficacy and safety of Verubecestat is currently being evaluated in two pivotal phase 3 clinical trials, EPOCH and APECS, for the treatment of mild-to-moderate Alzheimer’s disease and prodromal Alzheimer’s disease, respectively.

BACE1 is an important enzyme in the initiation of the toxic amyloid-beta ( A-beta ) peptide production in the brain. Researchers believe that sustained, selective inhibition of BACE1 leading to a significant decrease in the toxic A-beta peptide production is a promising means for therapeutic intervention.
This hypothesis has not yet 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 proved technically challenging.
Detailed analysis of the BACE1 protein structure and function by researches over many years was used to design a series of drug-like compounds with an ability to inhibit the protein, both in vitro and in the central nervous system ( CNS ) of preclinical animal models. This process yielded the lead compound Verubecestat.
Verubecestat produced significant CNS A-beta lowering in rodents and non-human primates treated for 6- to 9-months. Verubecestat’s preclinical safety and tolerability profile supported its progression into human clinical testing for chronic use.

Subsequent evaluation of once-daily doses of Verubecestat in phase 1 studies of healthy volunteers and in people with Alzheimer’s disease for a duration of one week demonstrated significant decreases in the levels of A-beta peptide production, a key marker of BACE1 activity, in the cerebral spinal fluid ( CSF ) of up to 80%.
Data from patients with Alzheimer’s disease were initially presented at the 2013 Alzheimer’s Association International Conference ( AAIC ).

Results of the phase 1 trial of patients with Alzheimer’s disease

The randomized, double-blind, placebo-controlled multiple dose study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamic profile of Verubecestat in patients with mild-to-moderate Alzheimer’s disease ( n=32 ).
Patients were randomized to receive one of three doses ( 12 mg, 40 mg and 60 mg ) of Verubecestat or placebo orally once-daily for seven days.
Samples of CSF were collected over 36 hours via a lumbar catheter and analyzed for levels of amyloid-beta 40 ( A-beta40 ), amyloid-beta 42 ( A-beta42 ) and soluble amyloid precursor protein beta ( sAPP-beta ) as biomarkers of BACE1 activity.

In this study, Verubecestat at doses of 12, 40 and 60 mg caused a dose-dependent and sustained reduction in the levels of A-beta40 from baseline in the CSF, a measure of BACE1 activity, of 57, 79 and 84%, respectively.

No study discontinuations due to adverse events were recorded. Analysis of vital signs and laboratory assessments, including liver function tests, showed no statistically significant changes related to the administration of Verubecestat.
Verubecestat was generally well-tolerated in healthy volunteers and individuals with Alzheimer’s disease.
No dose-dependent increase in the incidence of adverse events was observed. Adverse events included headache, nasal congestion and dizziness. ( Xagena )

Source: Merck, 2016