Lecanemab Rolling Submission for Alzheimer Disease Initiated by Eisai, Biogen

The investigational antiamyloid beta (Aß) protofibril antibody previously known as BAN2401 is being submitted to the FDA under the accelerated approval pathway for the treatment of Alzheimer disease.

Eisai and Biogen have announced that they have begun the process of completing a rolling biologics license application (BLA) submission for their investigational Alzheimer disease (AD) treatment, lecanemab. The therapy, previously known as BAN2401, has been submitted to the FDA under the accelerated approval pathway.1

Previously, in June 2021, lecanemab was granted a breakthrough therapy designation, and Eisai noted that after all portions of the BLA are submitted to the FDA and the agency accepts the BLA, the Prescription Drug User Fee Act (PDUFA) action date will be set. The application will be supported by data from the phase 2b clinical trial, known as Study 201 (NCT01767311), which 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 

In Study 201, senior author Jeffrey L. Cummings, MD, ScD, director, Chambers-Grundy Center for Transformative Neuroscience, 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, identifying 10 mg/kg biweekly as the effective dose 90%. 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.

"The Alzheimer's community welcomes scientific innovation that creates more treatment options for people living with this terrible neurodegenerative disease," Cummings said in a statement.1 "Based on the efficacy and safety results of the phase 2b study and preliminary results from the open-label extension study, I am optimistic about the potential lecanemab may have as a treatment choice for patients with early Alzheimer's to ameliorate the otherwise inevitable decline they face."

READ MORE: Emphasizing Gender and Genetic Differences in Alzheimer Disease Trials

Investigators also conducted conventional analyses of Study 201, which showed a dose-dependent reduction in change from baseline in ADCOMS over 18 months in the 10 mg/kg biweekly lecanemab group, with 30% (= .034) less decline than placebo. A 26% less decline on Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) was observed in the same dosed group (= .125), along with a 47% less decline on Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14).2

As well, the 10 mg/kg biweekly lecanemab dose reduced brain amyloid by 0.306 standardized uptake value ratio units (baseline mean, 1.37), and more than 80% of subjects became amyloid negative by visual read. Additionally, the rate of amyloid-related imaging abnormalities-edema/effusion (ARIA-E) for the 10 mg/kg biweekly dosing was 9.9%.1,2

In July 2021, the details of the phase 3 Clarity AD study (NCT03887455) were presented by Michelle Gee, PhD, director, neuroscience product creation unit, Eisai, at the 2021 Alzheimer’s Association International Conference, where design, end points, and comparison to the phase 2 study population were explored. Clinical efficacy and safety of the investigational antiamyloid ß protofibril antibody will be evaluated in a placebo-controlled, double-blind, parallel-group assessment including adults with early AD. As of March 2021, Clarity AD had enrolled its goal of 1795 participants; as of the January 6, 2021, cutoff the median participant age was 72 years, with patients ranging in age from 50 to 90 years, 81% of whom were over 65 years.1 Results showed mean baseline values for clinical end points of 3.2 points (Standard deviation [SD], 1.3) on CDR-SB, 0.4 points (SD, 0.1) on ADCOMS, 25.4 points (SD, 7.3) on ADAS-Cog, 25.6 points (SD, 2.2) on Mini-Mental State Exam (MMSE), and 0.6 points (SD, 0.2) on Global CDR.3

The FDA has agreed that the completed results of Clarity AD can serve as the confirmatory study to verify the clinical benefit of lecanemab post-accelerated approval. Blinded safety data from Clarity AD will also be included, but to support the BLA.1

"With the worldwide population growing and aging, the number of people living with AD is on the rise. AD imposes an enormous burden on not only people living with AD and their families but also for society. We recognize the strong and urgent expectations from stakeholders to further advance a treatment system for this disease. For many years, Eisai has endeavored to understand the anxieties of people living with AD and has been conducting research and development of novel therapies," Haruo Naito, chief executive officer, Eisai, said in a statement.1 "The lecanemab rolling BLA submission marks a new milestone toward the advancement of a treatment system for AD. As part of our human health care mission, we are committed to bringing new medicines to people living with AD and their families as early as possible."

1. Eisai Initiates Rolling Submission to the U.S. FDA for Biologics License Application of Lecanemab (ban2401) For Early Alzheimer’s Disease Under the Accelerated Approval Pathway. Eisai. News release. September 28, 2021. Accessed September 28, 2021. https://eisai.mediaroom.com/2021-09-27-Eisai-Initiates-Rolling-Submission-To-The-U-S-FDA-For-Biologics-License-Application-Of-Lecanemab-BAN2401-For-Early-Alzheimers-Disease-Under-The-Accelerated-Approval-Pathway
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. 2021;13(80). doi:10.1186/s13195-021-00813-8
3. Lynch SY, Irizarry MC, Dhadda S, et al. Baseline characteristics for Clarity AD: a phase 3 placebo-controlled, double-blind, parallel-group, 18-month study evaluating lecanemab (BAN2401) in early Alzheimer’s Disease. Presented at 2021 AAIC Annual Meeting; July 26-29. Poster 543331.