Synonyms: MK-8931-009 , β-secretase inhibitor
Therapy Type: Small Molecule
Target Type: APP and Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
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 that gives rise to various species of Aβ peptide during subsequent γ-secretase cleavage. 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. This drug was developed 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 story; Aug 2006 conference story).
Phase 1 included four studies in a total of 68 healthy controls, patients with mild to moderate Alzheimer's disease, and people with renal insufficiency 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. MK-8931 was reported at the 2012 AAIC conference in Vancouver, Canada, to be generally safe, and it was not discontinued due to side effects in Phase 1. The drug 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 2012 AAIC 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 also involved repeated CSF sampling, which found reduced CSF Aβ by up to 90 percent (see Jul 2012 conference story).
In November 2012, Merck started EPOCH. This is 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 Alzheimer's disease. The trial will start out treating 200 people in Phase 2 and, after an interim safety analysis, expand to Phase 3 with a total of 1,960 participants. This trial includes conventional cognitive and functional primary outcomes, as well as substudies for biomarker outcomes indicating change in brain amyloid and CSF tau levels, and change in 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 story). In December 2013, Merck announded that EPOCH had passed an interim safety evaluation and was proceeding to full enrollment and Phase 3.
In November 2013, Merck began the APECS trial in 1,500 participants with prodromal Alzheimer's disease, aka mild cognitive impairment due to Alzheimer's disease (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 will compare the 12- and 40-mg once-daily dose to placebo, and treatment will last for two years. This trial 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. The trial is set to run until 2018.
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
- Wave of New BACE Inhibitors Heading to Phase 2
- Q&A With Merck’s Johan Luthman
- San Diego: Merck Reports BACE Inhibition in Primates
- Madrid: γ-secretase Dimers, A New Model, A Drug in Clinic