TOKYO—Certainly there has been an erosion lately in the amyloid theory of Alzheimer’s disease (AD) as a primary or sole cause of the disease, but the possible role of amyloid plaques and possible necessity to treat them has not vanished. And to that end, the Alzheimer’s Clinical Trials Consortium (ACTC) has selected potential treatments from Eisai Co. Ltd., a global research and development-based pharmaceutical company, to evaluate for early AD. Eisai officials hope that the studies will clarify the benefits of BAN2401 and elenbecestat across a broader spectrum of the disease.
The investigational oral BACE (beta amyloid cleaving enzyme) inhibitor elenbecestat (development code: E2609) and the investigational anti-amyloid beta protofibril antibody BAN2401 will be evaluated in upcoming clinical studies targeting primary prevention (A3 Study) and secondary prevention (A45 Study) of AD. They will be conducted with funding from various sources, including the National Institute on Aging (NIA), part of the U.S. National Institutes of Health, and Eisai.
An NIA-funded clinical trial network with 35 primary clinical study sites across the United States, the ACTC is designed to accelerate and expand studies for therapies in AD and related dementias across the spectrum from pre-symptomatic to more severe stages of the disease. It was created with grant funding from the NIA in December 2017.
Three academic principal investigators will lead the studies. They are Dr. Paul Aisen from the University of Southern California, and Drs. Reisa Sperling and Keith Johnson of Brigham and Women’s Hospital, Massachusetts General Hospital and Harvard Medical School.
Explained Sperling, director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and co-principal investigator for ACTC: “The A3 and A45 Studies should provide critically important answers about the optimal time to intervene with anti-amyloid therapy, with the hope that starting treatment much earlier in the disease process may be advantageous in preventing future cognitive decline.”
According to Aisen, director of the University of Southern California Alzheimer’s Therapeutic Research Institute, which serves as the coordinating center for the ACTC, “The mission of the ACTC includes the development of public-private partnerships to conduct trials of promising candidate therapies. This Alzheimer’s Clinical Trials Consortium [collaboration with] Eisai will allow us to test two promising therapies in innovative studies that may advance the field.”
The A3 Study, which attempts primary prevention of AD through inhibiting amyloid build-up in the brain, targets cognitively normal individuals below the threshold for amyloid elevation on amyloid PET but at high risk for further amyloid beta (Aβ) accumulation. The study is a global, multicenter, double-blind, randomized trial to compare the effects of two doses of elenbecestat vs. placebo, and will attempt to determine whether a BACE inhibitor can slow brain amyloid accumulation at this very early stage of disease. It will also measure accumulation of tangle pathology using tau PET and exploratory cognitive outcomes.
The A45 study, which is targeting the preclinical (pre-symptomatic) stage of AD, will enroll clinically normal participants (no/minor cognitive impairment) who have elevated levels of amyloid in the brain and are at high risk for progression to mild cognitive impairment and AD dementia. It will be a global, multicenter, double-blinded, placebo-controlled, randomized trial of a treatment regimen consisting of an anti-Aβ antibody and a BACE inhibitor to prevent cognitive decline and delay biomarkers of pathological progression vs. placebo. In the active arm, individuals will be provided first with BAN2401 with the goal to clear amyloid deposits and Aβ protofibrils from the brain. Then they will be maintained on elenbecestat with the objective of decreasing the production of Aβ and preventing the reaccumulation of amyloid plaques and protofibrils.
Elenbecestat, which was discovered by Eisai, is an investigational next-generation oral candidate for the treatment of AD that inhibits BACE. By inhibiting BACE, a key enzyme in the production of Aβ, elenbecestat inhibits Aβ production, which reduces amyloid aggregates in the brain. It is thought to have disease-modifying effects, with the potential to slow the progression of AD. A global Phase 3 clinical study program of elenbecestat in early AD is underway.
BAN2401, which was discovered through a strategic research alliance between Eisai and BioArctic AB, is a humanized monoclonal antibody for AD. It selectively binds to neutralize and eliminate soluble, toxic Aβ aggregates (protofibril) that may cause AD. BAN2401 may modify AD and have potential to slow its progression. A global Phase 3 clinical study of BAN2401 in early AD is underway.
Trials will be starting early 2020. Individuals interested in participating in these trials may sign up for additional information at www.A3A45.org.