13 Sep 2019

Marking the fall of the only remaining BACE inhibitor currently being tested for AD, Biogen and Eisai announced today the discontinuation of two Phase 3 studies of elenbecestat in people with mild cognitive impairment and mild AD. The companies have yet to release details about the decision, but noted it was based on a safety review. The announcement struck an all-too-familiar chord after a spate of other BACE Phase 3 failures caused by side effects (Dec 2017 news; Feb 2018 news; Nov 2018 news; and Jul 2019 news). An open-label, long-term extension program of a Phase 2 study on elenbecestat will also halt.

Two Phase 3 trials testing elenbecestat in early AD are stopping.

The trials were halted due to safety concerns.

Elenbecestat was the last active BACE inhibitor trial for AD.

The Phase 3 elenbecestat clinical program, called MISSION AD, comprised two global, multicenter trials with identical protocols. MISSION AD1 and AD2 aimed to enroll a total of 2,100 participants diagnosed with mild cognitive impairment or mild AD and confirmed Aβ pathology. Participants were randomized to receive placebo or 50 mg elenbecestat daily for two years. The Clinical Dementia Rating Sum of Boxes served as the primary endpoint.

Paul Aisen, University of Southern California, San Diego, called the trial discontinuation another terribly disappointing result for the field. Unlike some others in the field, he does not view elenbecestat’s demise as a nail in the coffin for the amyloid hypothesis, nor for β- or γ-secretase inhibition, both of which he said still warranted further study. “We must vigorously pursue non-amyloid targets such as tau pathology and microglial modulation,” Aisen added. “But the numerous setbacks should not deter our efforts to control the amyloid dysregulation that is the key driver of this illness.”

What about the Alzheimer’s Clinical Trials Consortium’s planned A3 and A45 trials? “They will move forward. ACTC and Eisai are evaluating the emerging data, and will adapt the trial designs accordingly,” Aisen wrote to Alzforum.—Jessica Shugart.