2 Planned Clinical Trials to Test Ways of Preventing Alzheimer’s at Early Stages

Elenbecestat and BAN2401, two potential anti-amyloid therapies, were selected by the Alzheimer’s Clinical Trials Consortium (ACTC) to be evaluated in clinical studies aiming to prevent progression to early stages of Alzheimer’s disease.

ACTC is a network of 35 primary clinical trial sites across the U.S., established by the National Institute on Aging (NIA) in 2017 is to accelerate and expand testing of possible Alzheimer’s treatments.

Expected to start early next year, the so-called A3 and A45 studies will focus on the potential of elenbecestat and BAN2401 — being jointly developed by Eisai and Biogen — to slow disease progression in people at high risk of developing Alzheimer’s or  showing very early signs of the disease.

“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,” Reisa Sperling, director of Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and a study leader, said in a press release.

A3 will be a global, placebo-controlled and randomized trial focused on preventing Alzheimer’s. It will compare two doses of elenbecestat against placebo to assess whether compound can prevent the formation of beta-amyloid aggregates (a disease hallmark) in people cognitively healthy but at risk of developing these protein clumps at levels toxic to the brain.

This trial will also measure the buildup of tau tangles in the brain — another disease hallmark — and collect preliminary data on cognitive manifestations of Alzheimer’s.

Elenbecestat is an oral inhibitor of BACE, a key enzyme in the production of beta amyloid. By reducing amyloid production, elenbecestat might work to lessen their aggregation in the brain, and potentially delay Alzheimer’s progression.

Results of Phase 2 study (NCT02322021), reported in 2018, showed that elenbecestat effectively reduced amyloid buildup in the brain while being safe and well-tolerated in patients with early Alzheimer’s. Two Phase 3 trials — MISSION AD1 (NCT02956486) and MISSION AD2 (NCT03036280) — are now enrolling patients to access the effectiveness of oral elenbecestat, at 50 mg once each morning, against a placebo in people with early Alzheimer’s.

A45 will be a global, randomized and placebo-controlled trial in people with pre-symptomatic Alzheimer’s, meaning they show signs of disease-associated brain alterations but do not have noticeable symptoms. In other words, participants in this trial will have minor or no cognitive problems, but evidence of amyloid buildup in the brain.

Researchers for the A45 study will evaluate whether a combination of BAN2401 and elenbecestat can prevent clear cognitive decline and delay biomarkers of disease progression compared to placebo.

Treated participants will first be given BAN2401 to possibly clear the brain of amyloid deposits and beta-amyloid protofibrils, a form of amyloid accumulation distinct that’s from amyloid plaques but also thought to contribute to Alzheimer’s. They will then move to maintenance therapy with elenbecestat, which is thought to work to lessen amyloid production and prevent further buildup. 

BAN2401 is a humanized monoclonal antibody that selectively targets beta-amyloid protofibrils. Like elenbecestat, BAN240 is seen as a potential disease-modifying treatment to slow Alzheimer’s progression. Early data from an ongoing Phase 2 trial (NCT01767311) supported its potential to slow cognitive decline. A Phase 3 study called Clarity AD (NCT03887455) is now enrolling people with early Alzheimer’s to further test the antibody’s safety and effectiveness.

Funding for A3 and A45 is through a public-private partnership between the NIA and Eisai, supported by several other philanthropic groups.

“We are excited to partner with the ACTC group with trials focusing on therapies for earlier stages of Alzheimer’s disease” that might “allow us to understand the benefit of BAN2401 and elenbecestat across a broader spectrum of the disease,” said Lynn Kramer, chief clinical officer and chief medical officer at Eisai.