Lecanemab (BAN2401) Reduces Amyloid in Alzheimer Disease Across 18-Month Study

NeurologyLive, June 2021, Volume 4, Issue 3

SAP Partner | <b>Cleveland Clinic</b>

Findings on multiple cognitive end points and biomarkers support lecanemab’s therapeutic concept for the targeting of specific oligomeric species in the process of pathophysiological amyloid generation in Alzheimer disease.

Data from Study 201 (NCT01767311), a phase 2b proof-of-concept clinical trial, showed that treatment with BAN2401, now known as lecanemab (Eisai and Biogen), demonstrated a reduction in brain amyloid accompanied by a consistent reduction of decline across several clinical and biomarker end points in patients with mild cognitive impairment (MCI) due to Alzheimer disease (AD) or Alzheimer dementia.1,2

Original results from Study 201 were reported by Eisai and Biogen at the 2018 Alzheimer’s Association International Conference (AAIC) in Chicago, Illinois.

Senior author Jeffrey L. Cummings, MD, ScD, director emeritus, Lou Ruvo Center for Brain Health, Cleveland Clinic; and vice chair, Department of Brain Health, University of Nevada-Las Vegas, and colleagues conducted a Bayesian design clinical trial randomizing patients to lecanemab (2.5 mg/kg biweekly, 5 mg/kg monthly, 5 mg/kg biweekly, 10 mg/kg monthly, 10 mg/kg biweekly) or placebo.

They identified 10 mg/kg biweekly as the effective dose 90% (ED90), defined as the simplest dose that achieves greater than or equal to 90% of the maximum treatment effect at the 12-month final Bayesian analysis. At 18 months, 10 mg/kg biweekly lecanemab had a 76% probability of achieving 25% less decline on the primary end point, the change on the Alzheimer’s Disease Composite Score (ADCOMS), than placebo.2

Achievement of primary end point required 80% probability, though additional prespecified Bayesian analyses indicated a 97.6% and 97.7% probability of the 10-mg/kg lecanemab being superior to placebo by any magnitude at both 12 and 18 months, respectively.

All dose-dependent reductions in amyloid positron emission tomography (PET) standardized uptake value ratio (SUVr) measures were observed using florbetapir as the imaging agent and whole cerebellum as reference region. At 18 months, the least squares (LS) mean changes from baseline to whole cerebellum mask were –0.306 for 10 mg/kg biweekly lecanemab.

"Amyloid beta aggregates are thought to be more toxic than monomers, and we hypothesized that reducing these could represent an effective treatment approach in early stages of Alzheimer disease,” Cummings said in a statement.1 “These results from lecanemab’s phase 2b clinical trial are encouraging and the scientific community is looking forward to learning more in the phase 3 studies, Clarity AD and AHEAD 3-45, currently underway.”

The aforementioned Clarity AD phase 3 clinical trial (NCT03887455) is a placebo-controlled, double-blind parallel-group, 18-month study with an open-label extension phase that will confirm the safety and efficacy of lecanemab in individuals with early AD. In March, the company completed enrollment for the study, with 1795 symptomatic patients included.

Eisai and Biogen, in conjunction with the Alzheimer’s Clinical Trials Consortium (ACTCT) launched their other study, AHEAD 3-45, in July 2020.3 It aims to enroll 1400 participants with preclinical AD who will be treated with lecanemab for 216 weeks A common screening period will be conducted, after which patients will be randomized to 1 of 2 trials: A3 and A45.

In the conventional analyses of Study 201, 10 mg/kg biweekly treatment showed dose-dependent reduction in change from baseline in ADCOMS over 18 months, with 30% (P = .034) less decline than placebo. Additionally, the same dosed group had 26% less decline on Clinical Dementia Rating-Sum-of-Boxes (CDR-SB; P = .125) and 47% less decline on Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14).

Numerical differences from placebo were noted as early as 6 months and were maintained over the 18 months of treatment. Researchers also noted a marginally greater hippocampal volume reduction (7.56% increased volume decline) was observed at 10 mg/kg biweekly compared to placebo without nominal significance. An increase in cerebrospinal fluid (CSF) amyloid ßeta-42 (Aß-42) and decrease in p-tau relative to placebo were observed in the 10 mg/kg dose arm, whereas inconsistent results were noted at 12 months and 18 months for total tau.

Amyloid-related imaging abnormalities-edema/effusion (ARIA-E) rates were below 10% at the highest doses for the overall population and at 14.3% for apolipoprotein E4-positive subjects. Other than ARIA-E, the most common treatment-emergent adverse events (TEAEs) were infusion reaction. Aside from ARIA-Es, the incidence rates of adverse events (AEs), serious AEs, and TEAEs were consistent with those expected for this population and similar across placebo and lecanemab groups.

"These supportive findings from the lecanemab phase 2b study and the initiation of 2 phase 3 studies are exciting for the field and provide the opportunity to further explore the key role of the amyloid beta pathway in the pathophysiology of Alzheimer disease," Michael Irizarry, MD, vice president, deputy chief clinical officer, Neurology Business Group, Eisai, said in a statement.

REFERENCES
1. 18-month, pre-specified analysis showing consistent reduction in clinical outcome measures from a lecanemab (BAN2401) phase 2b clinical trial in early Alzheimer disease published in peer-reviewed journal, Alzheimer’s Research and Therapy. News release. Eisai. Biogen. April 19, 2021. Accessed May 5, 2021. https://www.prnewswire.com/news-releases/18-month-pre-specified-analysis-showing-consistent-reduction-in-clinical-outcome-measures-from-a-lecanemab-ban2401-phase-2b-clinical-trial-in-early-alzheimers-disease-published-in-peer-reviewed-journal-alzheimers-research-an-301271976.html
2. Swanson CJ, Zhang Y. Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer disease with lecanemab, an anti-Aß protofibril antibody. Alzheimers Res Ther. doi:10.1186/s13195-021-00813-8
3. Initiation Of New Phase III Clinical Study (AHEAD 3-45) Of BAN2401 Preclinical (Asymptomatic) Alzheimer's Disease. News release. Eisai. Biogen Inc. July 13, 2020. Accessed May 5, 2021. eisai.mediaroom.com/2020-07-13-Initiation-Of-New-Phase-III-Clinical-Study-AHEAD-3-45-Of-BAN2401-Preclinical-Asymptomatic-Alzheimers-Disease.