The Alzheimer’s Clinical Trials Consortium (ACTC) will assess Eisai’s elenbecestat in a pair of upcoming clinical trials studying prevention of early stages of the memory-robbing disease—including a study that will evaluate a combination with a second treatment, the Eisai/BioArctic-partnered BAN2401.
Elenbecestat, a beta amyloid cleaving enzyme (BACE) inhibitor, will be studied in the Consortium’s A3 study aimed at primary prevention of Alzheimer’s disease (AD) by preventing amyloid build-up in the brain.
The Consortium’s A45 study, designed to target the preclinical (pre-symptomatic) stage of Alzheimer’s, will evaluate a regimen of elenbecestat followed by BAN2401, an anti-amyloid beta (Abeta) protofibril antibody.
The A3 and A45 studies will start in early 2020.
“We are excited to partner with the ACTC group with trials focusing on therapies for earlier stages of AD, and will thus allow us to understand the benefit of BAN2401 and elenbecestat across a broader spectrum of the disease,” Lynn Kramer, MD, chief clinical officer and chief medical officer, neurology business group, Eisai, said in a statement.
Elenbecestat is an inhibitor of BACE, a key enzyme in the production of Aβ. Reducing Aβ production lowers amyloid aggregates in the brain—which Eisai reasons may have potential to slow the progression of Alzheimer’s. Elenbecestat is under study in the global Phase III MISSION AD clinical study program in early Alzheimer’s, which is underway.
BAN2401—BioArctic’s lead candidate—is a humanized monoclonal antibody for Alzheimer’s that is designed to work by selectively binding to neutralize and eliminate soluble, toxic Aβ aggregates (protofibril) that are thought to be a causative factor for the disease. As a result, BioArctic reasons, BAN2401 may also have potential to slow the progression of Alzheimer’s. A global Phase III clinical study (Clarity AD) of BAN2401 in early AD is underway.
Last year, BioArctic released 18-month results from a Phase IIb study (NCT01767311) in 856 early Alzheimer’s patients showing BAN2401 significantly slowed the rate of disease progression at the highest dose arm (10 mg/kg twice a month) compared to placebo. The effects of BAN2401 on clinical endpoints were supported by strong effects on amyloid PET as well as effects on several CSF biomarkers, BioArctic added.
The A3 Study will focus on primary prevention of Alzheimer’s, through preventing amyloid build-up in the brain. The study targets cognitively normal individuals who are currently below the threshold for amyloid elevation on amyloid PET but are at high risk for further accumulation of the oligomer A.
All about that BACE
A3 will be a global, multicenter, double-blind, randomized trial to compare the effects of two doses of elenbecestat vs. placebo, with the aim of assessing whether a BACE inhibitor can slow brain amyloid accumulation at this very early stage of disease. The study will also measure accumulation of tangle pathology using tau PET and exploratory cognitive outcomes.
The A45 study plans to enroll clinically normal participants with 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 Alzheimer’s disease dementia. Researchers will assess the combination’s ability to prevent cognitive decline and delay biomarkers of pathological progression versus placebo.
In A45’s active arm, individuals will be provided first with BAN2401 with the goal to clear amyloid deposits and Abeta protofibrils from the brain, after which they will be maintained on elenbecestat, with the aim of decreasing the production of Abeta and preventing the re-accumulation of amyloid plaques and protofibrils.
A3 and A45 are led by three academic principal investigators: Paul Aisen, MD, of Keck School of Medicine of University of Southern California (USC); Reisa A. Sperling, MD, MMSc, and Keith A. Johnson, MD, both at Brigham and Women’s Hospital and Massachusetts General Hospital, Harvard Medical School.
Aisen is director of USC Alzheimer’s Therapeutic Research Institute (ATRI), which serves as the coordinating center for the ACTC. Sperling is director of the Center for Alzheimer Research and Treatment at Brigham and Women’s.
“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,” Sperling stated.
The studies will be conducted with funding from sources that include the NIH’s National Institute on Aging (NIA) and Eisai.
ACTC is a clinical trial network with 35 primary clinical study sites nationwide. It was established in December 2017 through NIA funding, with the goal of accelerating and expanding studies for therapies in Alzheimer’s and related dementias across the spectrum from pre-symptomatic to more severe stages of disease.
ACTC is expected to receive $70 million over five years, subject to availability of funds.