Merck’s failure in Alzheimer’s trial shows even earlier intervention is key

20 February 2017 (Last Updated February 20th, 2017 18:30)

In February 2017, Merck & Co. announced it was terminating the Phase II/III EPOCH trial evaluating verubecestat, a BACE1 inhibitor drug designed to treat Alzheimer's disease (AD).

Merck’s failure in Alzheimer’s trial shows even earlier intervention is key

In February 2017, Merck & Co. announced it was terminating the Phase II/III EPOCH trial evaluating verubecestat, a BACE1 inhibitor drug designed to treat Alzheimer's disease (AD).

The decision was based on an interim assessment stating that there was "virtually no chance of finding a positive clinical effect" in the trial, which was scheduled to complete this summer. This is another blow to the theory that holds beta amyloid (Ab) as the true culprit of the disease, a theory known as the 'amyloid hypothesis'. Although research progress seems bleak in AD, Merck — as well as manufacturers, such as Eisai and AstraZeneca, which are pursuing the same research approach — remains  hopeful and has already made substantial investments in this high-risk area. Merck believes the rationale of its approach is right, and the key to success in AD drug development is to target those people with high susceptibility for AD who have not yet shown symptoms.

"This is another blow to the theory that holds beta amyloid (Ab) as the true culprit of the disease."

Merck’s EPOCH study enrolled mild-to-moderate AD patients. This means that these patients had already experienced memory impairments and had developed substantial levels of protein Ab plaques and tangles in their brains. For drugs that aim to act on the disease more upstream of this Ab formation, such as BACE1 inihibtors, it is vital that the drug be tested in the population with little or no Ab deposited in the brain. Essentially, BACE1 inhibitors could have a preventative effect on Ab, a possible source of AD, and therefore, trials must enroll the early-stage population in whom this effect can be picked up.

However, 25 years of uncertainty around the amyloid hypothesis leaves the future of these Ab-targeting drugs unclear. Although the theory has driven the development of the most high-profile candidate drugs for AD, most of them have failed. These include Lunbeck and Otsuka's 5-HT6 inhibitor, idalopirdine; Eli Lilly's immunotherapy solanezumab; and Janssen's and Pfizer’s immunotherapy bapineuzumab. Learning from past failures, newer AD trials are being increasingly conducted in early-stage or at-risk populations, permitted by recent improvements in genetic and biomarker tests. Likewise, Merck’s remaining Phase III trial of verubecestat, the APECS study, is targeting pre-symptomatic people. Although the results are not due for another two years, results from this study will further clarify the potential of BACE1 inhibitors in slowing and possibly preventing AD.