Merck Scientists Publish New Research Detailing the Early Development of Verubecestat, an Investigational BACE1 Inhibitor in Science Translational Medicine


November 2, 2016 4:30 pm ET

Results of First Phase 3 Trial Anticipated in Late 2017

Merck (NYSE: MRK), known as MSD outside the United States and Canada,
today announced the publication of research conducted by Merck
scientists on the discovery and development of verubecestat, 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 (AD). The research was published online in the
latest edition of the peer-reviewed journal Science
Translational Medicine
and includes results from the Phase 1
clinical trials in healthy volunteers and people with AD. 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 AD and prodromal AD, respectively.

“The development of a potential disease modifying therapy for treatment
of Alzheimer’s disease has long been a focus of biomedical research,”
said Dr. Michael Egan, vice president, clinical development
neurosciences, Merck Research Laboratories. “We believe this research
has the potential to contribute important evidence regarding the amyloid
hypothesis, a leading scientific theory for what causes Alzheimer’s
disease, and we look forward to seeing the data from our ongoing Phase 3
clinical trials.”

BACE1 is an important enzyme in the initiation of the toxic Aβ peptide
production in the brain. Researchers believe that sustained, selective
inhibition of BACE1 leading to a significant decrease in the toxic Aβ
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 Merck scientists 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 Aβ 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 AD for a duration of
one week demonstrated significant decreases in the levels of Aβ peptide
production, a key marker of BACE1 activity, in the cerebral spinal fluid
(CSF) of up to 80 percent. Data from patients with AD were initially
presented at the 2013 Alzheimer’s
Association International Conference (AAIC)

Results of the Phase 1 trial of patients with Alzheimer’s

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 β
40 (Aβ40), amyloid β 42 (Aβ42) and soluble amyloid precursor protein β
(sAPPβ) 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 Aβ40 from
baseline in the CSF, a measure of BACE1 activity, of 57, 79 and 84
percent, 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 AD. No
dose-dependent increase in the incidence of adverse events was observed.
Adverse events included headache, nasal congestion and dizziness.

About the EPOCH Study

is a Phase 2/3 randomized, placebo-controlled, parallel-group,
double-blind study evaluating efficacy and safety of two oral doses of
verubecestat (12 mg and 40 mg) administered once-daily versus placebo in
patients with mild-to-moderate AD currently using standard of care
treatment. The primary efficacy outcomes of the study 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, following 78 weeks of treatment. For more information
about the EPOCH study, visit

About the APECS Study

is a randomized, placebo-controlled, parallel-group, double-blind Phase
3 clinical trial to evaluate the efficacy and safety of verubecestat in
subjects with prodromal AD. The study is designed to enroll 1,500
participants. Patients will be randomized to receive placebo, or 12 mg
or 40 mg verubecestat, once-daily. The primary efficacy outcome of the
study is change from baseline in the Clinical Dementia Rating Scale-Sum
of Boxes (CDR-SB) score following 104 weeks of treatment.

About Merck

For 125 years, Merck has been a global health care leader working to
help the world be well. Merck is known as MSD outside the United States
and Canada. Through our prescription medicines, vaccines, biologic
therapies, and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access to
health care through far-reaching policies, programs and partnerships.
For more information, visit
and connect with us on Twitter,
and LinkedIn.

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Pam Eisele, 267-305-3558
Ian McConnell, 908-740-1921
Teri Loxam, 908-740-1986
Amy Klug, 908-740-1898

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