The FDA-approved Alzheimer's drug lecanemab (Leqembi) may provide significantly less benefit to female patients compared to males, according to a new analysis published in The Journal of the Alzheimer's Association on January 29, 2025.
Researchers from McGill University, led by PhD candidate Daniel Andrews and neuroscientist Professor Louis Collins, conducted extensive simulations based on data from lecanemab's Phase 3 CLARITY AD trial, revealing that the drug's effectiveness appears to vary substantially between genders.
Gender Disparity in Drug Response
The original Phase 3 trial data showed lecanemab slowed cognitive decline by 27% overall compared to placebo over 18 months. However, when broken down by gender, the results revealed a striking difference: male patients experienced a statistically significant 43% slowing of cognitive decline, while females showed only a non-significant 12% improvement.
To investigate whether this 31% gap between genders represented a true biological difference rather than statistical noise, the McGill team ran 10,000 simulated trials using the same demographics and constraints as the original study. Their analysis found that such a large gender difference occurred randomly in only 12 out of 10,000 simulations.
"Known differences in brain aging between males and females could only account for a fraction of the observed gap in drug effect," explained Andrews. "While we cannot conclude that lecanemab is completely ineffective in females, our results suggest the drug has either no or limited effectiveness in this population."
Clinical Implications
Since receiving FDA approval in 2023, lecanemab has gained traction in clinical practice, with sales reaching $87 million USD in the last quarter of 2024. As the second Alzheimer's-modifying drug to receive regulatory approval, it represents an important treatment option for a disease that has seen decades of failed drug development efforts.
However, these new findings raise important questions about prescribing practices, especially considering that approximately two-thirds of Alzheimer's patients are female. The drug also carries risks of serious side effects in some patients, further complicating the risk-benefit analysis.
"These findings should better prepare clinicians to decide whether the potential benefits of lecanemab outweigh the potential harms in female patients," said Professor Collins. "This information may also inform future consideration of the drug's approval in other countries."
Mechanism of Action and Sex Differences
Lecanemab targets amyloid protein plaques in the brain that are associated with Alzheimer's disease. However, the exact mechanism by which clearing these plaques translates to clinical improvement remains incompletely understood.
Recent evidence suggests that sex hormones and sex chromosomes may play crucial roles in how amyloid plaques form and are cleared from the brain, potentially explaining why certain amyloid-targeting drugs might function differently in females and males.
"The biological basis for this apparent sex difference requires further investigation," noted Andrews. "Future work should examine possible links between the drug's action mechanism and sex differences in amyloid clearing and clinical efficacy."
Broader Implications for Research
The study highlights a persistent problem in medical research: the insufficient consideration of sex differences in clinical trials. Until recently, trial recruitment and data analysis often failed to adequately account for potential sex-based variations in treatment response.
"This case underscores why trials should make assessing sex-related differences in responses a priority," said Marina Lynch, a neuroscientist from Trinity College not involved in the study. "The extreme male bias in brain aging research has grave consequences for wellbeing and places a disproportionate burden on female health."
The researchers recommend that future Alzheimer's drug trials be designed with sufficient statistical power to detect sex differences and that drug developers share trial data to accelerate research into potential mechanisms.
Future Directions
As the field continues to evolve, these findings may influence how new Alzheimer's treatments are developed and prescribed. The researchers suggest that personalized approaches to Alzheimer's treatment may be necessary, taking into account not only a patient's sex but potentially other factors that might influence drug response.
"Understanding why female brains may respond differently to these medications is crucial for developing more effective treatments for all patients," concluded Collins. "This study represents an important step toward more personalized and effective Alzheimer's care."
