The biologics license application includes data from the pivotal phase 2b proof-of-concept trial, its open-label extension, and the ongoing phase 3 Clarity AD study, which includes almost 1800 participants.
After beginning their process in September 2021, Eisai and Biogen have officially submitted a biologics license application (BLA) for lecanemab (BAN2401), an investigational agent for the treatment of mild cognitive impairment (MCI) because of Alzheimer disease (AD) and mild AD. The anti-amyloid-ß (Aß) protofibril antibody was submitted under the accelerated approval pathway, with an expected Prescription Drug User Fee Act (PDUFA) date still being determined.1
The application is 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 MCI because of AD or Alzheimer dementia. Additionally, the agency agreed that the completed results of the phase 3 Clarity AD study (NCT03887455), an ongoing trial, can serve as a complementary study to verify the clinical benefit of lecanemab post accelerated approval.
"With Alzheimer disease, patients and their loved ones don’t have the luxury of time. There is an enormous unmet need in this space, and we continue to make progress in advancing additional treatment options for people living with this devastating disease," Michel Vounatsos, chief executive officer, Biogen, said in a statement.1 "Antiamyloid antibodies are a new wave of important medicines, which could provide patients and their physicians more options in addressing this complex disease."
Lecanemab was granted breakthrough therapy and fast track designations by the FDA in June and December 2021, respectively. In Study 201, investigators conducted a Bayesian design clinical trial randomizing 856 patients with early AD with a confirmed presence of amyloid pathology 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%.2
At the end of the 18-month treatment period, 10 mg/kg biweekly lecanemab reduced brain amyloid by a mean of 0.306 standardized uptake value ratio (SUVr) units from a baseline mean of 1.37. Additionally, this treated group had a 76% probability of achieving 25% less decline on the primary end point, the change on the Alzheimer Disease Composite Score (ADCOMS), than placebo. Developed by Eisai, ADCOMS combines items from the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog), Clinical Dementia Rating (CDR), and the Mini-Mental State Examination (MMSE) scales to enable a sensitive detection of changes in clinical functions of early AD symptoms and changes in memory.
In conventional analyses, treatment with lecanemab 10 mg/kg biweekly resulted in a dose-dependent reduction in change from baseline in ADCOMS over 18 months, with 30% (P = .034) less decline than placebo. Additionally, a 26% less decline on CDR-sub of boxes was observed in the same dosed group (P = .125), along with a 47% less decline on ADAS-Cog scales as well. Amyloid-related imaging abnormalities-edema/effusion, a concern for patients with AD, was found in 9.9% of patients on 10 mg/kg biweekly dosing in Study 201.
Clarity AD, a phase 3, placebo-controlled, double-blind, parallel-group study, had design details presented at the 2021 Alzheimer’s Association International Conference by Michelle Gee, PhD, director, neuroscience product creation unit, Eisai. Following the cutoff date of January 6, 2021, the trial had enrolled 1536 participants of its 1795 intended goat. At baseline, the values for clinical end points were 3.2 points (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 MMSE, and 0.6 points (SD, 0.2) on Global CDR.3
When compared with the phase 2 study, investigators found similar aggregate baseline characteristics, with a median patient age of 72 years and an age range of 50 to 90 years, and clinical end points identified mean scores of 3.0 points (SD, 1.4) on CDR-SB, 0.4 points (SD, 0.2) on ADCOMS, 22.2 points (SD, 7.4) on ADAS-Cog, 25.6 points (SD, 2.4) on MMSE, and 0.6 points (SD, 0.2) on Global CDR. Investigators compared additional study demographics, as 52% of participants in phase 3 were women, compared to 50% in phase 3, and 75% of participants in phase 3 were Caucasian, compared to 90% in phase 2.