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.