Questions remain about new drug for hot flashes
In May, a new drug, Fezolinetant, was approved by the FDA to treat hot flashes associated with menopause.
Vascomotor symptoms (VMS) is the medical term for hot flashes associated with menopause. You are going to hear a lot more about it because a company has a new drug to sell. Here is what you need to know.
Menopause marks the end of a woman’s reproductive capacity. Normal hormonal production associated with that monthly cycle becomes erratic and finally ceases. For some women the transition can be relatively brief with only modest symptoms, while for others the body's “thermostat” in the brain is disrupted and they experience hot flashes and other symptoms that can disrupt daily activity. Lifestyle modification and drugs such as hormone therapy can provide some relief, but women at risk for cancer are advised not to use them and other women choose not to do so.
Fezolinetant, sold by Astellas Pharma Inc. under the product name Veozah™, was approved by the Food and Drug Administration (FDA) on May 12 to treat hot flashes associated with menopause. It is the first in a new class of drugs called neurokinin 3 receptor antagonists, which block specific neurons in the brain “thermostat” that trigger VMS. It does not appear to affect other symptoms of menopause. As with many drugs targeting a brain cell receptor, it must be taken continuously for a few days to build up a good therapeutic response, rather than working as a rescue product such as an asthma inhaler to immediately treat that condition.
Hot flashes vary greatly and naturally get better or resolve completely with time. That contributes to a placebo effect and makes it more difficult to judge the outcome of any intervention. Early this year, a meta analysis of 17 studies of drug trials for hot flashes found an unusually large placebo response in those types of studies; the placebo groups had an average of 5.44 fewer hot flashes and a 36 percent reduction in their severity.
In studies of fezolinetant, the drug recently approved by the FDA, the placebo benefit was strong and persistent. The drug group bested the placebo response to a statistically significant degree but, “If people have gone from 11 hot flashes a day to eight or seven in the placebo group and down to a couple fewer ones in the drug groups, how meaningful is that? Having six hot flashes a day is still pretty unpleasant,” says Diana Zuckerman, president of the National Center for Health Research (NCHR), a health oriented think tank.
“Is a reduction compared to placebo of 2-3 hot flashes per day, in a population of women experiencing 10-11 moderate to severe hot flashes daily, enough relief to be clinically meaningful?” Andrea LaCroix asked a commentary published in Nature Medicine. She is an epidemiologist at the University of California San Diego and a leader of the MsFlash network that has conducted a handful of NIH-funded studies on menopause.
Questions Remain
LaCroix and others have raised questions about how Astellas, the company that makes the new drug, handled missing data from patients who dropped out of the clinical trials. “The lack of detailed information about important parameters such as adherence and missing data raises concerns that the reported benefits of fezolinetant very likely overestimate those that will be observed in clinical practice," LaCroix wrote.
In response to this concern, Anna Criddle, director of global portfolio communications at Astellas, wrote in an email to Leaps.org: “…a full analysis of data, including adherence data and any impact of missing data, was submitted for assessment by [the FDA].”
The company ran the studies at more than 300 sites around the world. Curiously, none appear to have been at academic medical centers, which are known for higher quality research. Zuckerman says, "When somebody is paid to do a study, if they want to get paid to do another study by the same company, they will try to make sure that the results are the results that the company wants.”
Criddle said that Astellas picked the sites “that would allow us to reach a diverse population of women, including race and ethnicity.”
A trial of a lower dose of the drug was conducted in Asia. In March 2022, Astellas issued a press release saying it had failed to prove effectiveness. No further data has been released. Astellas still plans to submit the data, according to Criddle. Results from clinical trials funded by the U.S. goverment must be reported on clinicaltrials.gov within one year of the study's completion - a deadline that, in this case, has expired.
The measurement scale for hot flashes used in the studies, mild-moderate-severe, also came in for criticism. “It is really not good scale, there probably isn’t a broad enough range of things going on or descriptors,” says David Rind. He is chief medical officer of the Institute for Clinical and Economic Review (ICER), a nonprofit authority on new drugs. It conducted a thorough review and analysis of fezolinestant using then existing data gathered from conference abstracts, posters and presentations and included a public stakeholder meeting in December. A 252-page report was published in January, finding “considerable uncertainty about the comparative net health benefits of fezolinetant” versus hormone therapy.
Questions surrounding some of these issues might have been answered if the FDA had chosen to hold a public advisory committee meeting on fezolinetant, which it regularly does for first in class medicines. But the agency decided such a meeting was unnecessary.
Cost
There was little surprise when Astellas announced a list price for fezolinetant of $550 a month ($6000 annually) and a program of patient assistance to ease out of pocket expenses. The company had already incurred large expenses.
In 2017 Astellas purchased the company that originally developed fezolinetant for $534 million plus several hundred million in potential royalties. The drug company ran a "disease awareness” ad, Heat on the Street, hat aired during the Super Bowl in February, where 30 second ads cost about $7 million. Industry analysts have projected sales to be $1.9 billion by 2028.
ICER’s pre-approval evaluation said fezolinetant might "be considered cost-effective if priced around $2,000 annually. ... [It]will depend upon its price and whether it is considered an alternative to MHT [menopause hormone treatment] for all women or whether it will primarily be used by women who cannot or will not take MHT."
Criddle wrote that Astellas set the price based on the novelty of the science, the quality of evidence for the drug and its uniqueness compared to the rest of the market. She noted that an individual’s payment will depend on how much their insurance company decides to cover. “[W]e expect insurance coverage to increase over the course of the year and to achieve widespread coverage in the U.S. over time.”
Leaps.org wrote to and followed up with nine of the largest health insurers/providers asking basic questions about their coverage of fezolinetant. Only two responded. Jennifer Martin, the deputy chief consultant for pharmacy benefits management at the Department of Veterans Affairs, said the agency “covers all drugs from the date that they are launched.” Decisions on whether it will be included in the drug formulary and what if any copays might be required are under review.
“[Fezolinetant] will go through our standard P&T Committee [patient and treatment] review process in the next few months, including a review of available efficacy data, safety data, clinical practice guidelines, and comparison with other agents used for vasomotor symptoms of menopause," said Phil Blando, executive director of corporate communications for CVS Health.
Other insurers likely are going through a similar process to decide issues such as limiting coverage to women who are advised not to use hormones, how much copay will be required, and whether women will be required to first try other options or obtain approvals before getting a prescription.
Rind wants to see a few years of use before he prescribes fezolinetant broadly, and believes most doctors share his view. Nor will they be eager to fill out the additional paperwork required for women to participate in the Astellas patient assistance program, he added.
Safety
Astellas is marketing its drug by pointing out risks of hormone therapy, such as a recent paper in The BMJ, which noted that women who took hormones for even a short period of time had a 24 percent increased risk of dementia. While the percentage was scary, the combined number of women both on and off hormones who developed dementia was small. And it is unclear whether hormones are causing dementia or if more severe hot flashes are a marker for higher risk of developing dementia. This information is emerging only after 80 years of hundreds of millions of women using hormones.
In contrast, the label for fezolinetant prohibits “concomitant use with CYP1A2 inhibitors” and requires testing for liver and kidney function prior to initiating the drug and every three months thereafter. There is no human or animal data on use in a geriatric population, defined as 65 or older, a group that is likely to use the drug. Only a few thousand women have ever taken fezolinetant and most have used it for just a few months.
Options
A woman seeking relief from symptoms of menopause would like to see how fezolintant compares with other available treatment options. But Astellas did not conduct such a study and Andrea LaCroix says it is unlikely that anyone ever will.
ICER has come the closest, with a side-by-side analysis of evidence-based treatments and found that fezolinetant performed quite similarly and modestly as the others in providing relief from hot flashes. Some treatments also help with other symptoms of menopause, which fezolinetant does not.
There are many coping strategies that women can adopt to deal with hot flashes; one of the most common is dressing in layers (such as a sleeveless blouse with a sweater) that can be added or subtracted as conditions require. Avoiding caffeine, hot liquids, and spicy foods is another common strategy. “I stopped drinking hot caffeinated drinks…for several years, and you get out of the habit of drinking them,” says Zuckerman.
LaCroix curates those options at My Meno Plan, which includes a search function where you can enter your symptoms and identify which treatments might work best for you. It also links to published research papers. She says the goal is to empower women with information to make informed decisions about menopause.
Too much of this ingredient leads to autoimmune diseases, new research shows. Here's how to cut back.
Scientists are looking at how salt affects our cells, and they're finding more reasons to avoid htoo much of it.
For more than a century, doctors have warned that too much salt in your diet can lead to high blood pressure, heart disease and stroke - and many of the reasons for these effects are well known. But recently scientists have been looking deeper, into the cellular level, and they are finding additional reasons to minimize sodium intake; it is bad for immune cells, creating patterns of gene expression and activity seen in a variety of autoimmune diseases such as multiple sclerosis, lupus, rheumatoid arthritis, and type-1 diabetes.
Salt is a major part of the ocean from which life evolved on this planet. We carry that legacy in our blood, which tastes salty. It is an important element for conducting electrical signals along nerves and balancing water and metabolites transported throughout our bodies. We need to consume about 500 milligrams of salt each day to maintain these functions, more with exercise and heavy sweating as that is a major way the body loses salt. The problem is that most Americans eating a modern western diet consume about 3400 milligrams, 1.5 teaspoons per day.
Evidence has been accumulating over the last few years that elevated levels of sodium can be harmful to at least some types of immune cells. The first signal came in monocytes, which are immune cells that travel to various tissues in the body, where some of them turn into macrophages, a subset of white blood cells that can directly kill microorganisms and make chemical signals that bring other types of immune cells into play.
Two years ago, Dominik N. Müller from the Max-Delbrueck-Center in Berlin, Germany and Markus Kleinewietfeld, an immunologist at Hasselt University in Belgium, ran a study where they fed people pizza and then measured their immune cell function. “We saw that in any monocytes, metabolic function was down, even after a single salty meal,” Kleinewietfeld says. It seemed to be the cellular equivalent of the sluggish feeling we get after eating too much. The cells were able to recover but more research is needed to answer questions about what dose of sodium causes impairment, how long the damage lasts, and whether there is a cumulative effect of salt toxicity.
Kleinewietfeld and his colleagues have hypothesized that too much salt could be a significant factor in the increased number of autoimmune diseases and allergies over the last few generations.
The latest series of experiments focused on a type of T cell called T regulatory cells, or Tregs. Most T cells release inflammatory mediators to fight pathogens and, once that job is done, Tregs come along to calm down their hyperactive brethren. Failure to do so can result in continued inflammation and possibly autoimmune diseases.
In the lab, Kleinewietfeld and his large team of international collaborators saw that high levels of sodium had a huge effect on Tregs, upregulating 1250 genes and downregulating an additional 1380 genes so that they looked similar to patterns of gene expression seen in autoimmune diseases.
Digging deeper, they found that sodium affected mitochondria, the tiny organelles inside of cells that produce much of its energy. The sodium was interfering with how the mitochondria use oxygen, which resulted in increased levels of an unstable form of oxygen that can damage cell function. The researchers injected those damaged Tregs into mice and found that they impaired the animals' immune function, allowing the inflammation to continue rather than shutting it down.
That finding dovetailed nicely with a 2019 paper in Nature from Navdeep Chandel's lab at Northwestern University, which showed in mice that inhibiting the mitochondrial use of oxygen reduced the ability of Tregs to regulate other T cells. “Mitochondria were controlling directly the immunosuppressive program, they were this master regulator tuning the right amount of genes to give you proper immunosuppression,” Chandel said. “And if you lose that function, then you get autoimmunity.”
Kleinewietfeld's team studied the Treg cells of humans and found that sodium can similarly decrease mitochondrial use of oxygen and immunosuppressive activity. “I would have never predicted that myself,” Chandel says, but now researchers can look at the mitochondria of patients with autoimmune disease and see if their gene expression also changes under high salt conditions. He sees the link between the patterns of gene expression in Tregs generated by high salt exposure and those patterns seen in autoimmune diseases, but he is cautious about claiming a causal effect.
Kleinewietfeld and his colleagues have hypothesized that too much salt could be a significant factor in the increased number of autoimmune diseases and allergies over the last few generations. He says a high salt diet could also have an indirect effect on immune function through the way it affects the gut microbiome and the molecules made by microbes when they break down food. But the research results are too preliminary to say that for sure, much less parse out the role of salt compared with other possible factors. “It is still an exciting journey to try to understand this field,” he says.
Additionally, it is difficult to say precisely how this research in animals and human cell cultures will translate into a whole human body. Individual differences in genetics can affect how the body absorbs, transports, and gets rid of sodium, such that some people are more sensitive to salt than are others.
So how should people apply these research findings to daily life?
Salt is obvious when we sprinkle it on at the table or eat tasty things like potato chips, but we may be unaware of sodium hidden in packaged foods. That's because salt is an easy and cheap way to boost the flavor of foods. And if we do read the labeled salt content on a package, we focus on the number for a single serving, but then eat more than that.
Last September, the U.S. Food and Drug Administration (FDA) began a process to update labels on the content of food, including what is meant by the word “healthy” and how food manufacturers can use the term. Many in the food industry are resisting those proposed changes.
Chandel cautions against trying to counter the effects of salt by reaching for foods or supplements full of antioxidants, which, in theory, could reduce the harmful effects on mitochondria caused by a heavy hand with the salt shaker.
Until labels are updated, it would be prudent to try to reduce sodium intake by cutting down on packaged foods while making your own food at home, where you know just how much salt has been added. The Mayo Clinic offers guidance on how to become more aware of the sodium in your diet and eat less of it.
Chandel thinks many people will struggle with minimizing salt in their diets. It’s similar to the challenge of eating less sugar, in that the body craves both, and it is difficult to fight that. He cautions against trying to counter the effects of salt by reaching for foods or supplements full of antioxidants, which, in theory, could reduce the harmful effects on mitochondria caused by a heavy hand with the salt shaker. “Dietary antioxidants have failed in just about every clinical trial, yet the public continues to take them,” Chandel says. But he is optimistic that research will lead us to a better understanding of how Tregs function, and uncover new targets for treating autoimmune diseases.
In this week's Friday Five, new research that could help prevent Alzheimer's. Plus, why you should care about smart senior towns, how to reverse being drunk, money can make you happier if you're this type of person, and personalized anxiety medicine.
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five, featuring interviews with Dr. Christopher Martens, director of the Delaware Center for Cogntiive Aging Research and professor of kinesiology and applied physiology at the University of Delaware, and Dr. Ilona Matysiak, visiting scholar at Iowa State University and associate professor of sociology at Maria Grzegorzewska University.
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