2 Blood Biomarkers May Be Used to Monitor Lecanemab’s Efficacy
The blood levels of two biomarkers of Alzheimer’s disease are significantly associated with changes in brain beta-amyloid deposits and cognitive function in early Alzheimer’s patients treated with lecanemab (BAN2401), according to a new analysis of data from a Phase 2b clinical trial.
The results suggest that these blood biomarkers — p-tau181 and beta-amyloid fragments — may be used to monitor lecanemab’s efficacy and help determine treatment dosages.
These findings, along with additional data supporting the therapy’s potential, were presented by Eisai and BioArctic in six oral presentations at the 14th Clinical Trials on Alzheimer’s Disease conference, held Nov. 9–12 in Boston and online.
Lecanemab was originally the result of a partnership between Eisai and BioArctic, and is now being jointly developed by Eisai and Biogen.
The newly-presented data “and the progress in the broad ongoing clinical trial program, gives deeper insight into the uniqueness of lecanemab and its potential to help patients with early Alzheimer’s disease,” Gunilla Osswald, PhD, BioArctic’s CEO, said in a press release.
“We are looking forward to the continued development of this potentially disease-modifying treatment,” she added.
Lecanemab, administered directly into the bloodstream, is an antibody designed to bind specifically to soluble aggregates of the beta-amyloid protein, while leaving single proteins unharmed. These soluble clumps progressively form larger structures called fibrils that together generate the toxic plaques that contribute to Alzheimer’s.
By binding to these harmful beta-amyloid clumps, the antibody is designed to promote their clearance before they generate toxic plaques, potentially slowing Alzheimer’s progression.
The international Phase 2b Study 201 clinical trial (NCT01767311) is evaluating the therapy’s safety and efficacy in 856 patients with mild cognitive impairment or dementia, and a confirmed presence of beta-amyloid deposits in the brain.
In the first part of the trial (core study), participants were randomly assigned to receive either one of five lecanemab treatment regimens — 2.5, 5, or 10 mg/kg every other week, or 5 or 10 mg/kg monthly — or a placebo for 18 months (1.5 years).
Patients completing the core study had the option to enter the trial’s open-label extension (OLE) phase, in which all are receiving the investigational therapy, at the highest dose (10 mg/kg every other week), for up to five years.
A mean average of two years (range of nine months to five years) separated the completion of the core study and the initiation of its OLE (gap period).
Previous core study data showed that 18 months of lecanemab treatment at its highest dose significantly reduced beta-amyloid levels in the brain, as assessed by positron emission tomography (PET), and slowed cognitive decline, compared with a placebo.
Also, reduced levels of beta-amyloid in the brain were sustained within the gap period in patients given the highest dose in the core study, suggesting that the therapy has disease-modifying effects.
The therapy resulted in significant drops in brain beta-amyloid as early as three months during OLE, with more than 80% of participants achieving beta-amyloid negative status by visual read after one year. Greater brain beta-amyloid drops were observed in patients switching from a placebo to lecanemab.
Study 201’s new data were shared in a presentation, titled “Clinical, Biomarker, and Safety Update from the Lecanemab Phase 2 Study.”
Updated results showed that the therapy remains generally well-tolerated, with a less than 10% rate of amyloid-related imaging abnormalities — edema, a type of brain swelling often associated with amyloid-targeting therapies, and with less than 2% of patients showing symptoms of such swelling.
In addition, two blood biomarkers — p-tau181 and the ratio between two common beta-amyloid protein fragments (Aβ42 and Aβ40) — were significantly associated with PET-measured brain beta-amyloid and cognitive function during the trial.
This suggests that “monitoring of treatment effects using [blood] biomarkers may allow simple dose modification following rapid and thorough amyloid removal (e.g., less frequent and/or lower dose),” the researchers wrote.
They also provided data supporting the robustness of Study 201’s efficacy results in the presentation “Consistency of Efficacy Assessments Across Various Statistical Methods from the Lecanemab Phase 2 Proof-of-Concept Study, BAN2401-G000-201, in Subjects with Early Alzheimer’s Disease.”
A consistent effect on cognitive function was observed after 1.5 years of treatment with lecanemab’s highest dose relative to a placebo for all three evaluated measures: the Alzheimer’s Disease Composite Score, the Clinical Dementia Rating-Sum-of-Boxes, and the Alzheimer’s Disease Assessment Scale–Cognitive Subscale.
This high dose was associated with a significantly slower cognitive decline from six months of treatment onward across all measures and statistical methods.
During the conference, Lars Lannfelt, MD, PhD, BioArctic’s co-founder, also presented data on the binding abilities of the three most advanced beta-amyloid-targeting antibodies: lecanemab, Biogen’s Aduhelm (aducanumab) — conditionally approved in the U.S. in June — and Roche’s gantenerumab.
In his presentation, titled “Binding profiles to different amyloid-beta species for lecanemab, aducanumab and gantenerumab,” Lannfelt noted that lab studies showed all three antibodies preferentially bind to beta-amyloid clumps, instead of the single protein.
However, lecanemab showed the highest selectivity to oligomers and protofibrils, the soluble aggregates believed to be the most neurotoxic, while the other two antibodies preferred non-soluble fibrils.
“These binding profiles might reflect differences in clinical outcome and also side-effects,” Lannfelt noted.
In a separate presentation, “Introduction of plasma biomarker screening for the AHEAD 3-45 Study,” the Aβ42/Aβ40 ratio was shown to accurately predict the levels of brain beta-amyloid and is now being used for screening participants for the global Phase 3 AHEAD study (NCT04468659).
The trial seeks to test the therapy against a placebo in up to 1,400 adults, ages 55–80, without Alzheimer’s symptoms, but who have intermediate to high levels of beta-amyloid clumps in the brain.
Screening patients through blood tests could “substantially reduce the number of PET scans needed to fully enroll the study saving both time and money,” and has the potential to be critical to identify patients at high risk and “most likely to benefit from early intervention,” the companies stated in the release.
The companies are also confirming Study 201’s findings in a larger, placebo-controlled Phase 3 clinical trial, called Clarity AD (NCT03887455). The study is evaluating the safety, pharmacodynamics (the effects of a treatment on the body), and efficacy of lecanemab, given at 10 mg/kg every other week, in 1,795 adults with early Alzheimer’s.
Top-line data are anticipated by the end of September 2022.