Lecanemab Shows Benefit in Early Alzheimer Disease in Phase 3 Trial

Lecanemab significantly reduced brain amyloid levels associated with cognitive decline compared with placebo in patients with early Alzheimer disease (AD) after 18 months. However, the drug caused increased adverse events (AEs) in the treatment group, and has been associated with a second death. The study was published in the New England Journal of Medicine¹.

The drug, lecanemab (BAN2401, Biogen/Eisai), is a humanized monoclonal antibody that binds strongly to amyloid-beta soluble protofibrils. Studies have shown that amyloid-beta levels correlate with progression of AD, suggesting that lecanemab may potentially slow AD progression.

Researchers conducted an 18-month, multicenter, double-blind, randomized, placebo-controlled, phase 3 trial, A Study to Confirm Safety and Efficacy of Lecanemab in Participants With Early Alzheimer’s Disease (Clarity AD; ClinicalTrials.gov Identifier: NCT03887455), at 235 sites across North American, Asia, and Europe from March 2019 to March 2021. They analyzed the efficacy and safety of lecanemab in individuals with early AD or mild dementia due to AD between the ages of 50 and 90 years. Positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing confirmed early AD in these participants.

The researchers randomly assigned 898 people to the treatment group and 897 to the placebo group, with 729 people in the lecanemab group and 757 in the placebo group completing the trial. Individuals in the treatment group received 10 mg of intravenous lecanemab per kg of body weight every 2 weeks for 18 months.

Participants underwent serial blood testing for plasma biomarkers and could choose to participate in 1 of 3 substudies assessing amyloid burden on PET scans, AD biomarkers through CSF testing, or brain tau pathologic features on PET scans.

The main outcome measure included the Clinical Dementia Rating–Sum of Boxes (CDR–SB) at 18 months compared to baseline. Secondary outcomes included the change in brain amyloid burden on PET scans, and scores on the Alzheimer’s Disease Assessment Scale (ADAS-14), the Alzheimer’s Disease Composite Score (ADCOMS), and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL). Higher scores in all but the ADCS-MCI-ADL indicated greater cognitive impairment.

After 18 months, patients with early AD in the lecanemab group demonstrated lower average scores on the CDR-SB than the placebo group (mean difference: -0.45; 95% CI, -0.67 to -0.23; P <.001).

Similarly, patients in the lecanemab group demonstrated scores indicating reduced cognitive impairment compared with the placebo group on the following:

• ADAS-14 (mean difference: -1.44; 95% CI, -2.27 to -0.61; P <.001),
• ADCOMS (mean difference: -0.050; 95% CI, -0.074 to -0.027; P <.001), and
• ADCS-MCI-ADL (mean difference: 2.0; 95% CI, 1.2 to 2.8; P <.001) scales.

Regarding AEs, deaths occurred in both patient groups (0.7% of patients in the lecanemab group; and 0.8% of patients in the placebo group). Although the researchers in the NEJM study did not attribute the deaths to the drug or occurrence with ARIA, an article published by the journal Science² on November 27 highlighted a second death potentially caused by lecanemab. A 65-year-old woman who received the drug as part of the clinical trial died from a massive brain hemorrhage “that some researchers link to the drug,” according to the article. In a summary of the case report, the woman was described as having “amyloid deposits surrounding many of her brain’s blood vessels.” The article’s author stated that lecanemab contributed to her brain hemorrhage after biweekly infusions of the drug “inflamed and weakened the blood vessels.”

In CLARITY AD, serious AEs occurred in 14% of patients in the lecanemab group and 11.3% of patients in the placebo group. The most common serious AEs in the treatment and placebo groups included:

• infusion-related reactions (1.2% vs. 0%, respectively),
• amyloid-related imaging abnormalities with edema or effusions (ARIA-E; (0.8% vs. 0%, respectively),
• atrial fibrillation (0.7% vs. 0.3%, respectively),
• syncope (0.7% vs. 0.1%, respectively), and
• angina pectoris (0.7% vs. 0%, respectively).

Compared with the placebo group, patients treated with lecanemab experienced more infusion-related reactions (26.4% vs. 7.4%), ARIA with cerebral microhemorrhages/macrohemorrhages or superficial siderosis (ARIA-H; 17.3% vs. 9%), and ARIA-E (12.6% vs. 1.7%) with infusion-related reactions and ARIA-E reaching statistical significance between groups.

Study limitations included the relatively short-term follow-up duration, obstacles due to the COVID-19 pandemic, a 17.2% dropout rate significantly impacted by missed doses due to the COVID-19 pandemic, use of a modified intention-to-treat analysis without representation of missing data, and ARIA-E adverse events potentially cluing patients into group allocation.

“Lecanemab reduced markers of amyloid in early Alzheimer’s disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months but was associated with adverse events,” the researchers noted.

They concluded, “Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.”

Disclosures: The study was partially funded by industry. Please see the original reference for a full list of disclosures.

Editor’s note: This article was updated on December 5, 2022 to include the second death potentially linked to lecanemab.

This article originally appeared on Neurology Advisor