Leqembi: Promising Alzheimer's Drug May Not Benefit Men and Women Equally

Researchers have analyzed the effectiveness of lecanemab, an Alzheimer’s drug, and found that it reduced cognitive decline by 27%. However, the results suggest that the effect may be less in women than in men. Simulations indicated that this difference did not occur by chance, but it is not yet possible to conclude that the drug is ineffective in women. More studies are needed to better understand this variation.

Alzheimer’s disease (AD) affects men and women differently. About two-thirds of patients diagnosed are women, and the lifetime risk of developing the disease is approximately twice that of men.

Researchers believe that genetic, hormonal, and other biological differences may influence both the progression of the disease and the effectiveness of treatments.

In light of this, experts recommend that new clinical trials analyze the results separately for men and women. Although this has not yet been done specifically for Alzheimer’s disease, many clinical trials already perform subgroup analyses, evaluating whether a particular drug works better in one group than in another.

However, these analyses are not intended to prove the effectiveness of each subgroup in isolation, but rather to raise hypotheses for future research.

A common way to present this data is through graphs called “forest plots,” which show the impact of the drug on different subgroups. However, interpreting these graphs correctly requires statistical knowledge, as they can lead to misleading conclusions if the data is not analyzed carefully.

This may have been the case in the CLARITY AD study, a phase 3 clinical trial that evaluated the effectiveness of lecanemab, a new Alzheimer’s drug.

Lecanemab (sold as Leqembi) is a drug developed to treat early-stage Alzheimer’s. It works by attacking a protein called beta-amyloid, which builds up in the brain and forms plaques associated with the progression of the disease.

The drug is a monoclonal antibody, a type of protein designed to identify and remove these plaques. Studies show that Lecanemab can slow cognitive decline by about 27%, helping patients maintain their memory and reasoning skills for longer.

However, it is not a cure and can cause side effects, such as swelling and bleeding in the brain, requiring close medical monitoring.

The CLARITY AD study demonstrated that lecanemab reduced disease progression by an average of 27% compared to placebo. However, when analyzing the effects of the drug separately in men and women, a significant difference was observed: in men, the reduction in cognitive decline was 43%, while in women it was only 12%, a difference of 31%.

This apparent variation has raised questions about whether lecanemab actually works for women. However, it is important to note that CLARITY AD was not designed to evaluate the efficacy of the drug separately by gender.

In other words, the sample of participants may have been too small to draw definitive conclusions on this aspect. In addition, it is known that women with Alzheimer's tend to have a faster progression of the disease than men, which may have influenced the results.

Another possibility is that the observed difference occurred by chance due to the way in which the participants were distributed between the groups. To clarify this issue, researchers from McGill University, Canada, performed computer simulations using data from a large database on Alzheimer's (Alzheimer's Disease Neuroimaging Initiative – ADNI).

They compared the rate of natural cognitive decline between men and women and looked at whether the 31% difference in the CLARITY AD study could have been due to chance.

The results showed that such a large difference occurred randomly in only 12 out of 10,000 simulations, suggesting that this variation was unlikely to be due to chance. This means that lecanemab may be less effective in women than in men.

However, the data do not support the conclusion that the drug is completely ineffective in women. More studies are needed to better understand these differences and ensure that treatments are effective for all patients.

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

Daniel Andrews, Simon Ducharme, Howard Chertkow, Maria Pia Sormani and D. Louis Collins for the Alzheimer’s Disease Neuroimaging Initiative, 

Alzheimer’s & Dementia. Volume21, Issue1, January 2025. e14467

DOI: 10.1002/alz.14467

Abstract: 

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. 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. 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). 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.