Drugs in Clinical Pipeline: Verubecestat

Verubecestat [N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide] is an oral, potent and selective small molecule inhibitor of BACE that has progressed into Phase III studies demonstrating significant and dose-dependently reduction in the levels of amyloid beta (Aβ) in the cerebrospinal fluid (CSF) of Alzheimer’s patients and healthy volunteers.

The β secretase, widely known as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), initiates the production of the toxic amyloid β (Aβ) that plays a crucial early part in Alzheimer's disease pathogenesis. BACE1 is a prime therapeutic target for lowering cerebral Aβ concentrations in Alzheimer's disease, and clinical development of BACE1 inhibitors is being intensely pursued. It is expected that developing a new treatment for Alzheimer's disease which reduces amyloid beta will not only improve symptoms, but also help slow down the progression of the disease. Verubecestat reduces the overall amount of amyloid beta by inhibiting Beta-site amyloid precursor protein cleaving enzyme (BACE). Single and multiple (daily for 14 days) oral doses of Verubecestat were analyzed for safety, tolerability, pharmacokinetics, and pharmacodynamics. In healthy volunteers, Verubecestat was well tolerated and no serious adverse events were reported.

This novel compound was discovered and also being developed at Merck.

The activity of Verubecestat is as follows [1]:

K_i (BACE1 binding assay) = 1.753 nM

K_i (BACE2 binding assay) = 0.37 nM

Common Name: Verubecestat

Synonyms:  MK-8931; MK8931; MK 8931; SCH-900931; SCH 900931; SCH900931

IUPAC Name: N-[3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-6H-1,2,4-thiadiazin-5-yl]-4-fluorophenyl]-5-fluoropyridine-2-carboxamide

CAS Number: 1613380-81-6

Mechanism of Action: BACE1 Inhibitor; Beta-site amyloid precursor protein (APP) cleaving enzyme 1 Inhibitor

Indication: Alzheimer's disease; Treatment of Dementia

Development Stage: Phase III

Company: Merck

Phase I Study

MK-8931 was tested in 88 healthy volunteers (18–45 years old) as a two-part randomized, double-blind, placebo-controlled rising single dose (RSD) and rising multiple dose (RMD) studies were conducted in healthy adults, 18-45 years of age. In the RSD, the pharmacodynamic effects of MK-8931 (20, 100, 550-mg) were assessed in 3 sequential cohorts. In the RMD, 5 sequential cohorts were administered 10 to 250-mg MK-8931 daily for 14 days. CSF Aβ40, Aβ42 and sAPPβ concentrations were determined over 36 hrs postdose (Day 1 in RSD; Day 14 in RMD) using samples collected via lumbar catheterization. Determining whether MK-8931 was able to enter the brain and engage its target, the β-secretase enzyme, were primary goals of the study. To do so, biomarkers of BACE1 activity were measured in the CSF, including Aβ40, Aβ42, and sAPPβ, the latter being the BACE1-cleaved ectodomain of APP. MK-8931 markedly reduced levels of Aβ in the CSF in a sustained and dose-dependent manner. A single oral dose of 100 or 550 mg of MK-8931 decreased CSF Aβ40 levels by 75% or 92%, respectively, at 36 hours after dosing. Levels of Aβ42 and sAPPβ in the CSF were also reduced to similar extents. Multiple oral dosing of MK-8931 lowered Aβ levels in the CSF by over 90%. MK-8931 has a plasma half-life of ~20 hours, suggesting that a single daily oral dose may maintain stable drug levels in vivo. MK-8931 was well-tolerated and demonstrated a profound reduction in CSF Aβ. Thus, MK-8931 presents a unique opportunity to test the amyloid hypothesis of AD pathogenesis [2].

Phase Ib Study

MK-8931 was tested in a randomized, double-blind, placebo-controlled, multiple-dose study in mild-to-moderate AD patients. Subjects were administered 12, 40 or 60-mg MK-8931 or daily for 7 days. CSF Aβ40, Aβ42 and sAPPβ concentrations were determined over 36 hours postdose on Day7 using samples collected via lumbar catheterization. A semi-mechanistic mathematical model was developed to describe Aβ40, Aβ42 and sAPPβ modulation in CSF and used to generate dose-response profiles for AD patients. Following placebo administration, mean CSF concentrations of Aβ40, Aβ42 and sAPPβ increased relative to baseline. By contrast, administration of MK-8931 resulted in a dose-dependent and sustained reduction in CSF Aβ levels with mean percent reduction from baseline of up to: Aβ40=84%, Aβ42=81%, and sAPPβ=88%. CSF modulation of Aβ40, Aβ42 and sAPPβ was best described by a sigmoid Emax model and transit compartments accounted for the delay between brain and lumbar CSF Aβ. Based on dose-response profiles generated using this model, targeted CSF Aβ reductions between 50-75% and between 75-100% from baseline are predicted to be achieved in AD patients at dose levels of 12 and 40mg MK-8931, respectively. This study is the first demonstration of a pharmacodynamic effect of BACE1 inhibition in AD patients. Multiple doses of 12 to 60-mg MK-8931 resulted in a dose-dependent reduction in CSF Aβ, similar to that observed in healthy volunteers and have enabled robust dose-response modeling. Dose-response profiles predict that 12 and 40mg MK-8931 will inhibit Aβ production by greater than 50% and greater than 75%, respectively, in the majority of AD patients [3].

Phase I Study Involving Japanese Adults

Two-part randomized, double-blind, placebo-controlled rising single dose (SD; Part-1) and multiple dose (MD; Part-2) study conducted in healthy Japanese adults, ages 18-55. In Part-1, three single doses of MK-8931 (20, 100, 450-mg) were assessed in a single cohort. In Part-2, 2 cohorts were administered 80 or 150-mg MK-8931 daily for 14 days. The pharmacodynamic effect of MK-8931 was determined following the 450 mg dose in Part -1 and in the 80 mg Cohort in Part-2 by assessment of CSF concentrations of Aβ40, Aβ42 and sAPPβ 24 hours after the last dose compared to baseline values. Single and multiple MK-8931 doses were generally well-tolerated; adverse events (AEs) were mild-to-moderate in intensity and no subjects discontinued due to AEs. Following SD and MD administration, maximum MK-8931 concentrations were achieved at ~2 hr and there was a dose-related increase in plasma exposure. The terminal phase half-life was 16-21 hr. Over the dose range tested, exposure (AUC) in Japanese was similar to that observed previously in non-Japanese.  Following single and multiple dose administration, MK-8931 was well-tolerated and the pharmacokinetics in Japanese was similar to non-Japanese. MK-8931 also demonstrated a profound reduction in mean CSF Aβ in Japanese, similar to that observed in non-Japanese [4].

References:

1. Scott, J. D.; et. al. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use. US8729071B2 (example 25)
2. Forman, M.; et. al. The novel BACE inhibitor MK-8931 dramatically lowers cerebrospinal fluid Aβ peptides in health subjects following single- and multiple-dose administration. Alzheimers Dement 2012, 8, P704.
3. Forman, M.; et. al. The novel BACE inhibitor MK-8931 dramatically lowers CSF beta-amyloid in patients with mild-to-moderate Alzheimer's disease. Alzheimers Dement 2013, 9(4), P139.
4. Forman, M.; et. al. A study to evaluate the pharmacokinetics and pharmacodynamics of single and multiple oral doses of the novel BACE inhibitor MK-8931 in Japanese subjects. Alzheimers Dement 2012, 8(4), P186.