19 Dec 2013

On December 10, Merck announced that its BACE inhibitor, MK-8931, had met initial safety requirements in the Phase 2/3 EPOCH study of patients with mild to moderate Alzheimer’s disease. Not only will the company proceed with this large trial, but it also announced the start of a separate Phase 3 trial called APECS, which will test the same compound for two years in people with prodromal Alzheimer's. 

The initial safety portion of the EPOCH study involved 200 patients who took a 12-, 40-, or 60-milligram pill once a day for at least three months. After reviewing the results, the data-monitoring committee judged that the trial could continue enrolling the remainder of the anticipated 1,960 patients. Periodically throughout the 78-week trial, scientists will administer the AD Assessment Scale Cognitive Subscale (ADAS-Cog) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL) tests to look for differences between treatment and placebo groups. They will also compare scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), Neuropsychiatric Inventory (NPI), and Mini-Mental State Examination (MMSE) tests. Variation in hippocampal volume will be determined by MRI, as well. Two substudies will examine whether MK-8931 modulates brain amyloid load, as measured by PET scans with the Aβ ligand flutemetamol, and level of cerebrospinal fluid (CSF) tau. A Merck media spokeswoman told Alzforum that company researchers hypothesize the treatment will lower both.

In 2012, the EPOCH trial raised some eyebrows when Merck announced that it would enroll people with mild to moderate AD (see Dec 2012 news story), a disease stage that many scientists suspect is too late to apply Aβ-related therapies. Now that the safety requirements have been met, Merck is starting the APECS study (see press release) ) to test the BACE inhibitor in earlier stages. APECS will enroll 1,500 people diagnosed with amnestic mild cognitive impairment who also show amyloid plaques in the brain on a PET scan with flutemetamol. Mild symptoms combined with a positive biomarker of amyloidosis are also called prodromal AD. Participants will receive either 12 or 40 milligrams of the drug per day, and researchers will primarily look for changes in the CDR-SB relative to people treated with placebo. They will also monitor hippocampal volume, how long it takes to progress to AD, and functional changes using the ADCS-ADL. As in the EPOCH study, two substudies will track CSF total tau and amyloid load. Between the time it takes to enroll for a prodromal AD trial and the two-year treatment phase, this trial is expected to take five years to complete.

Merck's positive safety results emerge amidst news of setbacks for other BACE inhibitors. Earlier this year, Eli Lilly and Company halted development of its LY2886721 because of liver abnormalities that cropped up in almost 10 percent of patients (see Jun 2013 news story). Roche recently terminated development of its RG7129 in Phase 1, though a company representative declined to explain why the program was halted or when Roche will release details. Several other companies, including Eisai and AstraZeneca, have BACE inhibitors currently in the pipeline (see Jul 2012 news story and Aug 2010 news story).—Gwyneth Dickey Zakaib