Lecanemab in Early Alzheimer's Disease.
Level 2 - randomized trial
Individual double-blind randomized controlled phase 3 trial
PubMed 36449413 · doi:10.1056/NEJMoa2212948
What was done
An 18-month, multicenter, double-blind, phase 3 randomized controlled trial enrolled 1,795 participants aged 50 to 90 years with early Alzheimer's disease (mild cognitive impairment or mild dementia) and confirmed amyloid pathology by PET or cerebrospinal fluid testing. Participants were randomly assigned 1:1 to receive intravenous lecanemab (10 mg/kg every 2 weeks; n = 898) or placebo (n = 897). The primary outcome was change from baseline at 18 months in the Clinical Dementia Rating-Sum of Boxes (CDR-SB; range 0–18). Key secondary outcomes included change in amyloid burden on PET (substudy n = 698), ADAS-cog14, ADCOMS, and ADCS-MCI-ADL.
What was found
Baseline CDR-SB was approximately 3.2 in both groups. At 18 months, adjusted least-squares mean change in CDR-SB was 1.21 with lecanemab versus 1.66 with placebo (difference, -0.45; 95% CI, -0.67 to -0.23; P < 0.001). Brain amyloid burden was substantially reduced with lecanemab (difference, -59.1 centiloids; 95% CI, -62.6 to -55.6). Significant differences favoring lecanemab occurred across secondary outcomes: ADAS-cog14 difference of -1.44 (95% CI, -2.27 to -0.61; P < 0.001), ADCOMS difference of -0.050 (95% CI, -0.074 to -0.027; P < 0.001), and ADCS-MCI-ADL difference of 2.0 (95% CI, 1.2 to 2.8; P < 0.001). Infusion-related reactions occurred in 26.4% and amyloid-related imaging abnormalities with edema or effusions in 12.6% of lecanemab recipients.
Why it matters
This phase 3 trial demonstrates that clearing amyloid protofibrils with lecanemab modestly slows cognitive and functional decline over 18 months in early Alzheimer's disease.
Limits
The trial was limited to 18 months of follow-up, leaving long-term efficacy and safety unknown. Enrollment was restricted to individuals aged 50–90 with biomarker-confirmed amyloid and early-stage disease, so results cannot be extrapolated to moderate-to-severe dementia. Lecanemab carried notable safety risks (12.6% ARIA with edema/effusions, 26.4% infusion reactions), and the absolute difference in CDR-SB (0.45 points on an 18-point scale) represents a modest clinical effect.
Cited by
- contradicts Lecanemab lowered phosphorylated tau by 23% in clinical trials over nearly 7 years.