The higher benefit of lecanemab in males compared to females in CLARITY AD is probably due to a real sex effect

INTRODUCTION: The phase 3 trial CLARITY AD found lecanemab slowed cognitive decline by 27%. However, subgroup analyses indicated a significant 31% sex difference in the effect and suggested no or limited effectiveness in females. We used simulations constrained by the trial design to determine whether that difference reflects a pre-existing sex difference in Alzheimer's disease progression or was a random event. METHODS: Simulations were generated using linear mixed models of cognitive decline fit to data from Alzheimer's Disease Neuroimaging Initiative participants satisfying CLARITY AD inclusion criteria. RESULTS: The statistically non-significant 7.9% smaller cognitive decline rate in our cohort's males versus females does not explain CLARITY AD's 31% sex difference in lecanemab's effect. A ≥ 31% difference occurred randomly in only 12 of our 10,000 simulations (0.0012 probability). DISCUSSION: CLARITY AD's sex difference was probably not random. Lecanemab is likely less effective in females than males, but we cannot conclude the drug is ineffective in females. HIGHLIGHTS: Lecanemab is more clinically effective in males than in females. Forest plots should only report subgroup-specific effects in well-powered subgroups. Trial simulations based on real data enable investigation of subgroup drug effects. We cannot conclude that lecanemab is clinically ineffective in females. A sex difference in lecanemab's efficacy could be linked to its action mechanism.