Therapeutics

Verubecestat

Overview

Name: Verubecestat
Synonyms: MK-8931, MK-8931-009 , BACE inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Merck

Background

MK-8931 is a small-molecule inhibitor of BACE1 and BACE2. BACE1 is the β-secretase enzyme that cleaves the APP protein to release the C99 fragment of APP, which gives rise to various species of Aβ peptide during its subsequent cleavage by γ-secretase. The rationale of BACE inhibition is that it represents an upstream interference with the amyloid cascade, regardless of which species or aggregation states of Aβ then exert toxicity in the brain. BACE inhibition is sometimes envisioned as long-term maintenance therapy to limit Aβ production after an initial round of immunotherapy to remove existing amyloid deposits. 

MK-8931 was developed preclinically with extensive use of a translational rhesus monkey model, in which a catheter implanted into the cisterna magna at the base of the neck enabled repeated CSF sampling for long-term monitoring studies without ill effects on the animal (see Dec 2007 conference news; Aug 2006 conference news).

To support the clinical development of MK-8931, Merck is using the FDA-approved amyloid PET tracer flutemetamol and, in 2013, forged an agreement with Luminex Corporation to develop a companion diagnostic device to measure Aβ and tau concentration in the CSF.

Findings

Phase 1 included four public studies of a total of 68 healthy controls, patients with mild to moderate Alzheimer's disease, and people with renal insufficiency, held in Japan and the United States, to gather initial data on safety, tolerability, and pharmacology. One trial particularly studied how renal insufficiency—a common condition in the aged—would alter clearance of the drug and inform dosing in future trials. Phase 1 trials tested single doses up to 450 mg and multiple doses from 12 to 150 mg/day. At the 2012 AAIC conference in Vancouver, Canada, MK-8931 was reported to have been generally safe, without any discontinuations due to side effects, and to have reduced the CSF Aβ concentration in AD patients.

Two Phase 1/2 dose-ranging trials further evaluated the tolerability and pharmacology of single and multiple doses, respectively, in 88 healthy adults. These results, too, were presented at the same conference to show good tolerability without withdrawals due to side effects, dose-proportional increases in plasma and CSF exposure, and dose-dependent reduction in Aβ40 across the 2.5 to 550 mg/day administered to the study volunteers. These studies involved repeated CSF sampling, which found that CSF Aβ was reduced by up to 90 percent (see Jul 2012 conference news).

In November 2012, Merck started EPOCH, an 18-month Phase 2/3 trial comparing 12, 40, or 60 mg/day of MK-8931 given as once-daily tablets to placebo in people with mild to moderate AD. EPOCH started out treating 200 people in Phase 2 and, after an interim safety analysis, expanded to Phase 3 with a total of 2,221 participants. This trial included conventional cognitive and functional primary outcomes, as well as substudies for biomarker outcomes indicating changes in brain amyloid, CSF tau levels, and brain volume. In response to questions about why this drug was being tested in mild to moderate AD rather than earlier-stage disease, Merck’s Johan Luthman said that the overall Phase 3 program includes plans to test the drug across all disease stages, starting with mild to moderate, and that a trial in prodromal AD is planned (see Dec 2012 news). In December 2013, Merck announced that EPOCH had passed an interim safety evaluation and was proceeding to full enrollment and Phase 3. As of October 2016, this trial was fully enrolled, and data collection for the primary outcome is expected to wrap up in summer 2017.

In November 2013, Merck began the APECS trial in 1,500 participants with prodromal AD, aka mild cognitive impairment due to AD (aMCI). These patients have measureable cognitive deficits and a positive PET scan with the newly FDA-approved amyloid tracer flutemetamol, but are not functionally impaired. APECS compares the 12 and 40 mg once-daily dose to placebo; treatment lasts for two years. APECS uses change from baseline on the Clinical Dementia Rating Sum of Boxes (CDR-SB), a continuous measure, as its primary outcome. Secondary outcomes will evaluate a range of newer measures, including a cognitive composite, CSF tau, brain imaging of hippocampal volume and amyloid load, and others. This trial is being conducted in more than 90 locations worldwide; it is expected to complete data collection for its primary outcome in 2019.

In October 2016, Merck started an additional Phase 1 study in the United States to compare the liver metabolism of verubecestat in 32 people with hepatic insufficiency to people with normal liver function.

In November 2016, Merck formally published data on verubecestat's discovery, in vitro characteristics, activity, and safety profile in rats and monkeys, as well as on pharmacokinetic modeling used for dose finding, and initial Phase 1 data for exposure to drug of up to one week (see Nov 2016 news on Kennedy et al., 2016).

For all trials on this drug, see clinicaltrials.gov.

Clinical Trial Timeline

  • Phase 1
  • Phase 2/3
  • Phase 3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026
Merck NCT01496170
N=32
Merck NCT01537757
N=12
Merck NCT01739348
N=2221
Merck NCT01953601
N=1500

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References

News Citations

  1. Wave of New BACE Inhibitors Heading to Phase 2
  2. Q&A With Merck’s Johan Luthman
  3. Paper Alert: Verubecestat Preclinical and Phase 1 Data Published
  4. San Diego: Merck Reports BACE Inhibition in Primates
  5. Madrid: γ-secretase Dimers, A New Model, A Drug in Clinic

Paper Citations

  1. . The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med. 2016 Nov 2;8(363):363ra150. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer's disease patients. Sci Transl Med. 2016 Nov 2;8(363):363ra150. PubMed.