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The phase 3 clinical trial program included 2 identical, multicenter, double-blind, and placebo-controlled trials of the BACE inhibitor intended for the treatment of early Alzheimer disease.
Lynn Kramer, MD
Continuing an unfortunate trend, Eisai and Biogen today announced that they will discontinue phase 3 clinical trials of elenbecestat, a BACE inhibitor intended for the treatment of early Alzheimer disease.
Results of a Data Safety Monitoring Board review suggested an unfavorable risk-benefit ratio, in turn recommending that the trials be terminated.
“We are very disappointed with the news, and intend to learn from these data and continue engaging with patients and investigators, to pursue the discovery of new medicines for Alzheimer’s disease,” Lynn Kramer, MD, chief clinical officer, Neurology Business Group, Eisai, said in a statement.
The phase 3 clinical trial program for elenbecestat included 2 identical phase 3 studies, MISSION AD1 (NCT02956486) and MISSION AD2 (NCT03036280), designed to assess the safety and efficacy of elenbecestat in 2100 patients with mild cognitive impairment or mild Alzheimer disease with confirmed amyloid pathology. A long-term extension of a phase 2 trial will also be discontinued.
Patients who participated in the core, multicenter, placebo-controlled, double-blind trials were randomly assigned to receive either 50 mg oral elenbecestat or placebo daily over 24 months. The primary end point was change from baseline in the Clinical Dementia Rating- Sum of Boxes Score at 24 months. Secondary end points included change from baseline in the Alzheimer’s Disease Composite Score and Amyloid Positron Emission Tomography Standardized Uptake Value Ratio for brain amyloid levels, both at 24 months.
Both trials included a 24-month, open-label extension study in which patients who completed the core trial were enrolled and given elenbecestat 50 mg daily by oral tablet. The open-label extension primarily monitored patients for adverse events, including treatment-emergent AEs, abnormal vital signs, significant electrocardiogram findings, abnormal neurological exams, abnormal lab values, and suicidal behavior or ideation.
During a NeurologyLive Peer Exchange on Alzheimer disease, Alireza Atri, MD, PhD, commented on BACE inhibitors and why the most recent efforts might be failing.
“There have been several BACE inhibitors tested. What we don’t know really is how much to remove and at what stage. Recently, the development of a couple of these BACE inhibitors have been stopped,” he said. “In those cases, the levels of suppression or decreased production was very high. So, it lowered amyloid levels significantly. The question is whether it was actually too much. There is some evidence that suggests that there’s actually a sweet spot, and the field may have overshot it. “
Eisai said that the discontinuation of the elenbecestat program will not affect the ongoing phase 3 clinical trial of BAN2401 (CLARITY AD; NCT03887455), an anti-amyloid-beta photofibril monoclonal antibody being examined in 1566 patients with mild cognitive impairment or mild Alzheimer disease. That study will evaluate the safety and efficacy of a 10 mg biweekly intravenous infusion of BAN2401 compared to placebo, with a primary outcome measure of change from baseline in the Clinical Dementia Rating- Sum of Boxes Score at 18 months.
Eisai And Biogen to Discontinue Phase III Clinical Studies Of BACE Inhibitor Elenbecestat In Early Alzheimer’s Disease [news release]. Tokyo and Cambridge, Massachusetts: Eisai Co. and Biogen Inc. September 13, 2019. https://www.eisai.com/news/2019/pdf/enews201965pdf.pdf. Accessed September 13, 2019.