While Eisai and Biogen’s oral BACE inhibitor elenbecestat was able to demonstrate a reduction in amyloid beta levels in 35 patients with Alzheimer’s disease, it failed to slow the decline of clinical symptoms more than placebo in exploratory endpoints.
The 18-month phase 2 study enrolled 71 patients with mild cognitive impairment or mild to moderate dementia, administering varying doses of elebecestat and measuring amyloid beta levels through PET scans. The study was not powered to show statistical significance in clinical symptom changes compared to placebo, the companies said in a statement.
A clinical dementia rating scale—Clinical Dementia Rating Sum of Boxes, or CDR-SB—was used to evaluate 41 patients and showed “numerically less decline” in the elebecestat arm compared to placebo. Similar results were also seen in a post-hoc analysis using a new, Eisai-developed assessment scale, ADCOMS, or Alzheimer’s disease composite score.
A better gauge of efficacy, such as a statistically significant 20-25% difference in symptom decline compared to placebo over 18-24 months, would require accruing 450 to 650 patients in each arm, according to an Eisai spokesperson. The companies' two phase 3 trials are currently recruiting, and aim to enroll 1,330 patients each.
The phase 2 study was primarily designed to measure safety, the spokesperson said, and elenbecestat was found to be generally safe and well tolerated, with no observations of serious adverse reactions suggesting liver toxicity. That news—plus what Eisai described as the first time a BACE inhibitor study was able to show a significant effect on amyloid beta levels in patients with mild cognitive impairment—is leading the two companies to remain hopeful.
“Eisai and Biogen will continue to work together to advance the ongoing phase 3 program (MISSION AD) in order to contribute a new potential treatment option to Alzheimer’s disease patients as soon as possible,” said Lynn Kramer, chief clinical officer and chief medical officer of Eisai’s Neurology Business Group.
Jointly developed by Eisai and Biogen since 2014, the two companies are currently conducting two global phase 3 clinical studies of the BACE inhibitor in early Alzheimer’s under the MISSION AD program. Eisai said it plans to present more detailed phase 2 results at an upcoming medical meeting.
The once-promising class of BACE inhibitors has seen a string of disappointing clinical results in the past several years.
Last month, Janssen terminated its remaining trials of atabacestat after failing to demonstrate efficacy, as well as liver safety difficulties in late-onset Alzheimer’s. And in February, Merck halted a phase 3 trial of verubecestat following an interim review of prodromal patients.
Meanwhile, Novartis, Amgen and Banner Alzheimer’s Institute launched a global prevention program using the BACE inhibitor CNP520, in new trials that will include cognitively healthy participants who are at genetic risk of developing Alzheimer’s.