Eisai and Biogen’s experimental therapy lecanemab (BAN2401) safely leads to rapid and sustained reductions in the brain levels of beta-amyloid — the protein that forms toxic clumps in Alzheimer’s — in people in early disease stages, according to one-year, preliminary data from a Phase 2 trial’s ongoing extension phase.
Notably, greater beta-amyloid drops were observed in those patients assigned to a placebo for the first part of Study 201 (NCT01767311), who switched to lecanemab in the extension.
These findings add to previous trial results showing that the therapy slowed disease progression and cognitive decline in Alzheimer’s patients, and further support the continued development of lecanemab, which is now being evaluated in Phase 3 trials.
These data were presented by Chad Swanson, PhD, the executive director of Eisai’s clinical research of neurology business group, in an oral presentation at the 2021 virtual American Academy of Neurology Annual Meeting (AANAM), running through April 22.
His presentation was titled “Preliminary Analysis Of BAN2401 Effects On Brain Amyloid And ARIA-E Findings Over 12 Months Of Treatment In The Open-Label Extension Of The Phase2b Study BAN2401-G000-201 In Subjects With Early Alzheimer’s Disease.”
Lecanemab, administered directly into the bloodstream, is an antibody designed to specifically bind to a soluble, damaging version of the beta-amyloid protein that clumps into toxic plaques in the brain, contributing to Alzheimer’s.
By binding to this form of beta-amyloid, the antibody is expected to “tag” it as harmful in the “eyes” of the immune system, promoting its clearance before it clumps and forms toxic plaques. As such, it could slow Alzheimer’s progression.
The international Phase 2 Study 201, designed to evaluate lecanemab’s safety and effectiveness, enrolled 856 Alzheimer’s patients with mild cognitive impairment or dementia, who had amyloid protein accumulation in the brain. Patients were recruited at nearly 170 sites across 11 countries, including the U.S., Canada, and those of Europe.
In the first part of the trial (core study), participants were randomly assigned to one of five Lecanemab treatment regimens — 2.5, 5, or 10 mg/kg every other week, 5 or 10 mg/kg monthly — or to a placebo for 18 months (1.5 years).
Results showed that lecanemab was generally safe and resulted in a dose-dependent drop in amyloid levels in the brain, as assessed by positron emission tomography (PET), compared with a placebo.
Its highest dose (10 mg/kg once every two weeks) was deemed the most effective, significantly slowing disease progression and cognitive decline in these patients at 18 months.
Even at this dose, however, the trial failed to meet its main goal of showing that lecanemab had an 80% probability of being better than placebo, by 25%, at reducing patients’ Alzheimer’s Disease Composite Score — a combined measure of cognitive abilities — after one year of treatment.
This goal was also not attained at 18 months, although the highest dose reached a 76% probability of being superior to placebo, “just missing the 80% probability threshold,” Swanson said.
This prompted the initiation of an open-label extension phase, in which patients completing the core study could continue or start to receive the investigational therapy, all at the highest dose, for up to two years. Its goal is to assess lecanemab’s long-term tolerability and safety.
Of note, nine to 60 months (about five years) separated a patient’s completion of the core study and start in its extension phase.
Newly presented results cover one-year data, focused on preliminary efficacy findings and safety data, from Study 201’s extension phase, which involved 180 patients from all trial groups and recruited at 57 of its sites.
Eisai researchers evaluated amyloid level changes in the 143 patients with available PET scans, of whom 60 had been initially assigned to 10 mg/kg of Lecanemab once a month, 38 to 10 mg/kg every other week, and 45 to a placebo.
The occurrence of amyloid-related imaging abnormalities — edema (ARIA-E), a type of brain swelling often associated with amyloid-targeting therapies, was assessed in all 180 patients.
All types of ARIAs, detected through neuroimaging, are more common in patients with the APOE4 gene variant, a known genetic risk factor for late-onset Alzheimer’s.
Results showed that amyloid reductions in people treated with 10 mg/kg of lecanemab, every other week, in the core study were sustained for up to two years after treatment discontinuation within the gap period before entering the extension phase.
Amyloid drops during the extension also appeared to be dependent on placement in the core study, with patients initially assigned to placebo showing the greatest reductions.
Among those switching from placebo to lecanemab, the therapy “rapidly reduced brain amyloid, with effects noted as early as three months,” Swanson said.
Patients given lecanemab in the core study showed less pronounced drops in amyloid levels over the first year of the extension phase, with those showing higher levels at its start having greater reductions. Patients who were treated with the intermediate dose of 10 mg/kg every month during the core study showed greater amyloid drops in the extension.
A total of 14 (7.8%) patients in the extension phase experienced ARIA-E. Among the placebo-to-lecanemab group, this adverse event occurred in 8.9% of patients, “which is consistent with the ARIA incidence of 9.9% observed in the core study” in the highest dose group, Swanson said.
Notably, all who experienced an ARIA-E after switching to lecanemab in the extension phase carried the APOE4 gene variant.
Most ARIA-Es occurred in the first three months of treatment, and were resolved within one to three months, consistent with findings from the core study. Some patients with mild or moderate ARIA-E were able to resume treatment, and six are still receiving lecanemab.
These preliminary findings highlighted that 10 mg/kg of lecanemab, given once every two weeks, “rapidly reduced brain amyloid in Core placebo-treated subjects as early as 3 months in the [extension phase], with continued reduction over 12 months of treatment,” the researchers wrote.
Findings also suggest that this lecanemab regimen “can be initiated at treatment onset to elicit rapid reduction of brain amyloid with relatively low incidence of ARIA-E,” Swanson said.
Lecanemab is also being tested in two ongoing Phase 3 trials: Clarity AD (NCT03887455) and AHEAD 3-45 (NCT04468659). Clarity AD is enrolling adults with early stage Alzheimer’s, who show disease symptoms, in China. AHEAD 3-45 is recruiting at multiple sites worldwide people who are clinically normal, but have intermediate or elevated amyloid levels on PET scans.