Canadian Study Finds That Alzheimer Drug Leqembi May Work Less Effectively in Women Than Men

Medical News: Lecanemab, marketed under the name Leqembi, has been hailed as a breakthrough in the treatment of Alzheimer’s disease, particularly since it became only the second disease-modifying drug to receive approval from the U.S. Food and Drug Administration (FDA) in 2023. The drug is designed to slow cognitive decline by targeting beta-amyloid plaques in the brain, a hallmark of Alzheimer’s pathology. Its approval followed data from the CLARITY AD Phase 3 trial, which showed a statistically significant 27% reduction in cognitive decline for patients treated with lecanemab compared to those receiving a placebo.


Canadian Study Finds That Alzheimer Drug Leqembi May Work Less Effectively in Women Than Men

However, new findings from a Canadian research team led by McGill University are casting a shadow over the enthusiasm surrounding the drug. In a newly published study, researchers have raised concerns that lecanemab may be significantly less effective in women than in men - a finding that could have broad implications for how the drug is prescribed and evaluated in the future.
 
Sex-Based Differences in Drug Effectiveness
The McGill research team, which includes lead PhD candidate Daniel Andrews and senior neuroscientist Professor Louis Collins from the Montreal Neurological Institute at McGill University, conducted an in-depth analysis using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). This Medical News report reveals that their simulations mirrored the demographics and clinical criteria of the CLARITY AD trial in order to investigate whether the apparent sex-based discrepancies in lecanemab’s efficacy were due to natural variations in Alzheimer’s disease progression between men and women - or if they represented a genuine disparity in how the drug functions based on biological sex.
 
Their results were striking. The researchers discovered that the 31% greater effectiveness observed in male participants in the original CLARITY AD trial could not be explained by pre-existing sex differences in the rate of cognitive decline. In simulations, men did show a slightly slower rate of decline than women, but the difference was only 7.9% - far too small to account for the 31% gap seen in the original trial.
 
Furthermore, when 10,000 simulated trials were run, a difference as large as 31% between male and female groups occurred in only 0.12% of cases. This strongly suggests that the sex-based disparity in drug efficacy observed in the original trial was not a statistical fluke, but rather a meaningful biological difference.
 
Clinical Implications and Future Trials
While the researchers were cautious not to conclude that lecanemab is entirely ineffective in women, their data strongly suggest it is less effective in female patients. The implications of these findings are significant. With approximately two-thirds of Alzheimer’s patients being female, the diminished efficacy of lecanemab in this group could affect millions of potential users. It also raises concerns about how clinical trials are currently designed and evaluated, especially when they are not adequately powered to assess subgroup differences.
 
Interestingly, other Alzheimer’s drugs targeting beta-amyloid plaques - such as aducanumab and donanemab - have shown similar trends, though no statistically significant sex differences have been reported in their trials. These patterns hint that amyloid-clearing therapies may, in general, work more effectively in men than in women, possibly due to hormonal or genetic factors, or differences in brain structure and metabolism between the sexes.
 
CLARITY AD also showed a greater benefit in males than females on two out of three non-primary endpoints and trends favoring males on several quality-of-life measures. The possibility that lecanemab's sex difference in efficacy may be linked to differences in amyloid clearance or how amyloid pathology impacts cognition in each sex is being increasingly considered. However, sex-disaggregated data on amyloid reduction from clinical trials remain unavailable, limiting further insights.
 
Toward Personalized Alzheimer’s Therapies
The McGill researchers emphasized the need for more personalized approaches in Alzheimer’s treatment and clinical trial design. Future trials should not only include balanced sex representation but also be designed with enough statistical power to evaluate treatment effectiveness in men and women separately. Stratifying patients based on menopausal status, hormone profiles, and education levels could provide a deeper understanding of how these variables influence drug response.
 
Additionally, researchers suggested leveraging more advanced trial designs, including digital twin models and cohort enrichment strategies, to reduce participant numbers while increasing the precision of results. They also recommended greater transparency from pharmaceutical companies regarding sex-disaggregated data from Alzheimer’s trials, as this could expedite the development of more equitable and effective therapies.
 
Conclusion
This new study from McGill University provides strong evidence that lecanemab, despite its overall promise, may not deliver equal benefits to all patients. Women, who make up the majority of those living with Alzheimer’s, appear to gain less from the treatment than men. While the drug is not entirely ineffective in females, the reduced clinical benefit calls for a more cautious and personalized approach to prescribing it. Future clinical trials must prioritize sex-specific analyses and include sufficient sample sizes to detect real differences. Moreover, regulators and healthcare providers need to consider these discrepancies when approving and recommending therapies. Only by addressing these gaps can the medical community ensure that advancements in Alzheimer’s treatment benefit all patients equally, regardless of sex.
 
The study findings were published in the peer reviewed journal: Alzheimer’s and Dementia.
https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.14467
 
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