2023-08-20 08:26:16
Approximately 60 von 100 People with Alzheimer’s dementia are female. A drug once morest Alzheimer’s should therefore also benefit the women affected. At the very least, one might expect a world-renowned medical journal like the New England Journal of Medicine (NEJM) to point out gender differences.
At the Study on the Alzheimer’s drug lecanemab, which the US Food and Drug Administration in July 2023 allowed, but the authors do not say a word regarding it. The information that lecanemab was significantly less effective in women than in men can only be found in the «supplementary appendix» to the study in «New England Journal of Medicine».
Gender differences are hardly examined
That was “disappointing”, commented three scientists in “Jama Neurology» and pointed out that this information had already been presented in hidden form in the case of the Alzheimer’s drug aducanumab. For a third compound in clinical trials, Gantenerumab, the effect on women was also worse. Out of four active ingredients that have already been approved or are being tested, three performed worse in women than in men.
The three commentators criticize possible gender differences in Alzheimer’s research: in a sample of 118 studies on dementia, only eight studies reported the results when broken down by gender. The authors of the lecanemab study at least did that in the appendix.
“The clinical study found that the drug slowed down cognitive decline in men. […] For men, the data on efficacy seems compelling,” writes Johns Hopkins University medical professor and author Marty Makary on the blog “Sensible Medicine» on lecanemab. “But nobody talked regarding the results in women.”
In contrast to the authors of the study – and to the majority of the media who reported on the study – Makary goes into the gender differences in more detail: In women, the active ingredient slowed mental deterioration by only 12 percent, in men by 43 percent.
In women, the disease is often more advanced when it is diagnosed
It is still unclear whether this finding is statistical coincidence or has a biological reason. Women with Alzheimer’s dementia are usually able to conceal the onset of mental decline for longer than men thanks to their often better verbal skills. The women affected are often misjudged as “depressed” at first, says the Alzheimer’s researcher Antonella Santuccione. She has worked at Swissmedic, at the University of Zurich for various pharmaceutical companies and is now director of the “Women’s Brain Project”, a non-profit initiative. Its sponsors also include several companieswho are developing Alzheimer’s drugs.
Lecanemab is intended to break down the so-called amyloid deposits in the brain of Alzheimer’s patients and prevent new ones from forming. On average, women are diagnosed with Alzheimer’s later than men, at a time when there are already more abnormal deposits in the brain, explains Santuccione. “You might have to start treatment earlier for women, or with a different dose,” she suspects. Whether this would benefit women or result in more side effects is also uncertain.
The published data from the lecanemab study does not reveal whether the women already had more pathological deposits in their brains or whether the Alzheimer’s tests performed differently than the men.
After 18 months there is hardly any noticeable effect
Only people with mild Alzheimer’s dementia took part in the approval study for lecanemab. According to an article in «Neurology» these antibodies, injected into a vein every two weeks, slowed mental decline by an average of regarding a year and a half over the course of a year and a half four to five monthscompared to people who received a placebo.
One must discuss “how relevant the effect is clinically,” said Stefan Teipel, professor at the German Center for Neurodegenerative Diseases in Rostock/Greifswald, to the “Science Media Center». The patient “probably hardly notices anything” regarding this effect. However, if the positive effect continued over time, then this difference to the placebo group would become more significant over time.
Side effects were not broken down by gender
The downside of as «moderate» drug classified as effective: 13 out of 100 people treated with lecanemab – the gender is not broken down here in the study – experienced brain swelling, compared with around two out of 100 in the placebo group. Brain haemorrhages (usually minor) were found in around 17 out of 100 people treated, compared to nine out of 100 in the placebo group.
In view of the risk-benefit ratio, he would not have recommended such compromises to his aunt, who recently died of Alzheimer’s, Makary sums up. It is time to focus more on how Alzheimer’s can be prevented, to invest more in prevention research, “and not just to push pharmaceuticals indiscriminately”.
Alzheimer’s researcher Antonella Santuccione disagrees. “Even if a healthy lifestyle is as effective as the new medicines, it is difficult to get people to adopt it. Many feel patronized when you try to encourage them to lead a healthier lifestyle,” says Santuccione. “Second, many people underestimate how serious, long-lasting, and deadly Alzheimer’s disease is.” In the event of illness, Santuccione would therefore start lecanemab treatment, even if it is currently unclear whether women benefit from it. “This disease is so bad that I would be willing to take that risk.”
Annual costs of more than $25,000 – plus examinations
The question is whether insurers should also take this risk. In addition to the approximately $26,500 annual cost (in the US) for lecanemab, there are costs for initial and follow-up examinations, such as special tomography, which can run into the thousands. In the study, these examinations were initially carried out every three months. In the USA, for example, anyone who is insured with “Medicare” and is eligible for treatment has to pay $7,000 for the medication themselves each year, reports Makary in the blog “Sensible Medicine».
The manufacturer Eisai emphasizes that “the results for all results were in favor of lecanemab.” Gender was “not a statistically relevant covariate” with regard to effectiveness. He relies on the spread in estimating the effectiveness. She is tall. Due to the statistical inaccuracy, in extreme cases it might be that lecanemab does almost nothing for women – or that it works for them as well as for men. Somewhere between these extremes lies the true effect.
The US Food and Drug Administration (FDA) is now demanding so-called post-marketing studies from the lecanemab manufacturers Eisai and Biogen. They should clarify within the next few years whether women benefit from lecanemab and how great this is. However, these are observational studies that are more likely than the so-called randomized studies before approval to deliver distorted results (Infosperber reported).
Antonella Santuccione considers this approach – allowing the drug now and conducting follow-up studies – reasonable. “We need data on how lecanemab works outside of the approval studies. If, in a few years, it turns out that women really don’t benefit, then health insurers should stop paying for this group of patients.”
Even with a new heart drug, it is unclear whether it will benefit women
Something similar happened recently with the drug colchicine for heart failure. The US Food and Drug Administration approved the drug even though colchicine did not bring any measurable benefit to the women in the authoritative studies.
There, too, the “NEJM” only referred to this gender difference in the appendix to the studies. The cardiologist and gender researcher Catherine Gebhard from the Inselspital Bern responded to this in a letter to the editor «NEJM” attentive.
Since colchicine quickly becomes toxic in the event of an overdose and women excrete this active substance more slowly than men, it cannot be ruled out that colchicine does more harm than good in women – however, as with lecanemab, the side effects were not broken down by gender there.
Demand: motivate more women to take part in the study
The reason colchicine had a significant effect only in men may be because women were included in the two main studies of colchicine heavily underrepresented were: Not even every fifth person taking part was female. This small number of subjects reduced the validity of the studies in relation to women. In the case of lecanemab, on the other hand, around half of the study participants were female.
Although both drugs have already been approved in the USA, neither women with heart failure nor those with mild Alzheimer’s disease nor their treating physicians know whether this treatment would make sense for them – or possibly even harm them.
“If we don’t start recruiting enough women for clinical trials, we will never be able to close this alarming gender gap»summarizes Gebhard on «LinkedIn». Physicians and scientists should raise awareness “that sex and gender really play a role in clinical trials!”
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