Clinical Pearls & Morning Reports
Published January 4, 2023
Van Dyck et al. conducted a double-blind, placebo-controlled phase 3 trial that assessed the safety and efficacy of lecanemab in participants with early Alzheimer’s disease. Read the NEJM Original Article here.
Q: Are there any approved anti-amyloid therapies for Alzheimer’s disease in the U.S.?
A: Current therapeutic agents for Alzheimer’s disease–related dementia temporarily improve symptoms but do not alter the underlying disease course. Some evidence suggests that amyloid removal slows the progression of disease. One anti-amyloid antibody (aducanumab) has received accelerated approval from the Food and Drug Administration.
Q: What is lecanemab?
A: Lecanemab is a humanized monoclonal antibody that binds with high affinity to soluble amyloid-beta (Aβ) protofibrils, which have been shown to be more toxic to neurons than monomers or insoluble fibrils. A phase 2b, dose-finding trial involving 854 participants with early Alzheimer’s disease did not show a significant difference between lecanemab and placebo in a Bayesian analysis of 12-month change in a composite score (primary end point). However, analyses at 18 months showed dose- and time-dependent clearance of amyloid with lecanemab, and the drug was associated with less clinical decline on some measures than placebo.
A: The primary efficacy end point was the change in the score on the Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) from baseline at 18 months. The CDR-SB score is a validated outcome measure used in clinical trials of Alzheimer’s disease that is obtained by interviewing patients and their care partners and captures cognition and function. The mean CDR-SB score at baseline was approximately 3.2 in both the lecanemab and placebo groups, findings consistent with early Alzheimer’s disease (score of 0.5 to 6). The adjusted mean change from baseline at 18 months in the CDR-SB score was 1.21 in the lecanemab group and 1.66 in the placebo group (difference, ₋0.45; 95% confidence interval [CI], ₋0.67 to ₋0.23; P<0.001). Note that a definition of clinically meaningful effects in the primary end point of the CDR-SB score has not been established. Results for secondary clinical end points were in the same direction as those for the primary end point.
A: The most common adverse events (affecting >10% of the participants) in the lecanemab group were infusion-related reactions (26.4% with lecanemab and 7.4% with placebo); ARIA with cerebral microhemorrhages, cerebral macrohemorrhages, or superficial siderosis (ARIA-H; 17.3% with lecanemab and 9.0% with placebo); and ARIA with edema or effusions (ARIA-E; 12.6% with lecanemab and 1.7% with placebo). Events of ARIA-E with lecanemab were mostly asymptomatic (78%), occurred during the first 3 months of the treatment period (71%), and resolved within 4 months after detection (81%). Longer trials are warranted to determine the efficacy and safety of lecanemab in early Alzheimer’s disease.