CEimpact Podcast

Fezolinetant for Vasomotor Symptoms in Menopause

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Menopausal vasomotor symptoms occur in about 80% of women and have a significant impact on quality of life. Hormone replacement therapy works well; however, it is often underused. Join host, Geoff Wall, as he evaluates Fezolinetant, a new medication to treat 'hot flashes.'

The GameChanger
HRT is vastly underused in menopausal women. Gabapentin and SNRIs may help with some vasomotor symptoms. Fezolinetant is effective for hot flashes and seems to be well tolerated.
 
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023 Apr 1;401(10382):1091-1102. doi: 10.1016/S0140-6736(23)00085-5. Epub 2023 Mar 13. PMID: 36924778.

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00085-5/fulltext
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CPE Information
 
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Discuss the pros and cons of hormone replacement therapy in women with vasomotor symptoms.
2. Discuss the role of fezolinetant for treatment of vasomotor symptoms. 

0.05 CEU/0.5 Hr
UAN: 0107-0000-23-365-H01-P
Initial release date: 11/27/2023
Expiration date: 11/27/2024
Additional CPE details can be found here.

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Speaker 1:

Welcome to the Game Changers podcast, where we have clinical conversations that impact your pharmacy practice. Let's listen in as our team discusses this week's clinical practice game changer.

Speaker 2:

Hello and welcome again to Game Changers clinical conversations. I am Jeff Wall, your host. I'm a professor of pharmacy practice at Drake University. Today we are going to talk about a. We're talking about menopause, so that's the first thing we can kind of talk about that. What triggered this is a paper that was just published looking at Desalinotent, which is a brand brand new medication with a brand brand new mechanism of action for the treatment of a vasomotor symptoms associated with menopause. And so I'd actually had a couple of people in our couple of questions about this in the drug information center that people ask hey, are these new drugs for menopause is coming out? You know what's it like and do you know if it'll work and how expensive it is and all this other stuff. And so with all that and this paper coming out, which was a phase three study that got is going to get the drug FDA approved, I'm sure we thought it was worth kind of talking a little bit about menopause.

Speaker 2:

Now you know it is worth noting that that menopause is is a fairly large morbidity, that I think you know. Certainly we tend to not give the do it is do, and I think that's you know partially because it's kind of thought well, you know, this is just part of the aging process and you know, and you know all that sort of you know, you know women are just going to have to deal with it and all that. And you know, I always think that's kind of funny because certainly, you know, if something like that were to happen to any other population, including men, we just wouldn't go. Oh well, I mean too bad, you know so, especially when, when you know vasomotor symptoms have been shown now in study after study after study, that significant impacts on quality of life, it blocks postmenopausal women from doing, you know, social things and having personal relationships. It's even actually associated with depression, it's associated with anxiety, it substantially affects sleep, as you might imagine, and so that leads to fatigue and leads to things like, like difficulty, you know, sometimes driving a car or some other complex things along those lines. And, interestingly, there's even been some retrospective studies and core studies have suggested that there is a link between severe vasomotor symptoms and things like cardiovascular disease, bone turnover and bone loss. Now, of course, is that just because you know the people have severe vasomotor symptoms, have the lowest level of estrogen, and so because of that, we know, low levels of estrogen are associated with that. That might be the reason why. But the bottom line is that the vasomotor symptoms themselves associated with menopause are exactly significant toll and on it cannot on everyone, but most women will develop it and many women will have symptoms they consider moderate to severe. And in the study we're going to talk about, women had postmenopausal symptoms at least 10 times a week. So again, that's pretty significant in my opinion.

Speaker 2:

So we know that the treatment and what we'll talk a little bit about the treatment as we go along here is has what was long hormone replacement therapy and we'll kind of discuss, you know why you know that was kind of abandoned largely and how we've gone to other medications that have some effect, medications such as SNRIs, gabapetnoids, clonidine. I've all, in some small studies, shown that they help reduce symptoms but that none of them are nearly as good as as hormone replacement therapy treating days and motor symptoms. Hormone replacement therapy also deals with other things such as sexual health and bone loss, and we know that estrogen can improve and help prevent, though not treat, osteoporotic osteoporosis in patients as well. So you know we do have some treatments for hot flashes, but on the whole the treatment of choice is largely not even offered by physicians anymore and is often not considered by patients much anymore. So the need for something else and different certainly kind of makes sense. And so, you know that brings us to, you know, the treatment of menopause. And to find this out I actually looked up. There's, as you might imagine, several guidelines out there and I tried my best to kind of combine all the guidelines.

Speaker 2:

To talk a little bit about Bayes, you know how to treat Bayes, motor symptoms. For mild hot flashes, which are considered, you know, less, less than two a week or not very severe, they, as always, recommend lifestyle changes by keeping the core body temperature cool, especially at night, light clothes, you know, keeping the air conditioning on and stuff like that, avoiding alcohol intake and cigarette smoking. Smoking in particular seems to be associated with an increased severity of postmenopausal Bayes and motor symptoms, and so that's something they, you know. Reason 5,312 you should quit smoking, following a healthy diet, of course, and stress psychological stress, does seem to magnify the symptoms, and so using cognitive behavioral therapy can actually really help, not only with things like depression, but can help with symptoms like hot flashes and stuff like that. So then that brings us to what the guidelines recommend for moderate severe high flashes and, as I said before, they're very clear that hormone replacement therapy is the gold standard of literally quoting this, the gold standard in best therapy for reduction of age and motor symptoms, followed by non hormonal up prescription medications such as GABA, petanoids and antidepressants, and then cognitive behavioral therapy can be helpful. So what happened? I mean, when I came out of school in the early 90s.

Speaker 2:

You talk to any pharmacists who'd been out, then they would tell you that premmarin, which was the estrogen that almost all postmenopausal women were on, was one of our fast movers. It was one of the drugs that flew off the shelves. Many, many women were on it, and at the time there was emerging retrospective evidence that suggested that postmenopausal women taking hormone replacement therapy not only had improvements in vasomotor symptoms, they not only had improvements in sexual health, but they also had a decreased risk of coronary disease, they had decreased risk of stroke, they had a decreased risk of osteoporosis. And again, these were all large retrospective studies. And then, in 2002, the Women's Health Initiative study was published, and this was the largest study ever done looking at postmenopausal women and the use of hormone replacement therapy, and the vast majority of these women did have intact uteruses and so they did receive both estrogen and progesterone. And so, again, those of you who are a little more veteran may remember that when we had women who had uteruses, if they had to be on hormone replacement therapy to prevent cancer, you needed to be on both estrogen and progesterone. And again, some of the more veteran pharmacists out there remember that when a lot of people were on premarin, a lot of women were on premarin. They were also on concomitant provera or methamedroxyprogesterone. Because of that, this study looked at that.

Speaker 2:

The Women's Health Initiative study looked at the combination of estrogen and progesterone and it was a huge prospective study and it really turned the use of hormone replacement therapy on its head and created really kind of a media fire norm, because it included that the use of conjugated estrogens and metroxyprogesterone in post-metal positive women was associated with a small but significant increase in risks of breast cancer and coronary disease and strokes. So pretty much the opposite of what we thought with coronary disease and stroke. And after that the use of hormone replacement therapy was largely abandoned. In fact, wyatt, the company that made premarin, was basically sued into oblivion after that, and so they basically disappeared as a company. So the Women's Health Initiative is one of those mega vanguard studies that, if you're working in the world of hormone replacement therapy, there was before the Women's Health Initiative study and after the Women's Health Initiative study Though like many things in medicine, especially those that are kind of latched onto by the media when they did reanalysis of the study they actually found that in women who only took estrogen so again, the majority of these patients took both estrogen and progesterone that when they did a subgroup analysis looked at only women who took estrogen they actually found that the overall risk there actually was not a significant risk of increase of coronary disease and stroke.

Speaker 2:

It was higher than the base limit in recidivical significance and that the risk of breast cancer was smaller than they thought as well. So it's seemed like it was the combination of estrogen and progesterone that seemed to have the highest risk for coronary disease, stroke and breast cancer. But kind of the damage has been done and I think most postmenopausal women have either read some stuff about this online or been counseled by their providers to say, huh, there's this risk. I'm not really sure it's really worth the risk. And women I think quite rightly are terrified of breast cancer. Just those men are terrified of prostate cancer and I think even a small increase in risk in that possibility is going to be enough for women to say no thanks, I'll either try and live through it or could we try something else.

Speaker 2:

So, based on that, the guidelines that I read and again there's two or three guidelines out there, there's the American menopausal society and there's a couple other, the American obstetrics and gynecology group, and there's been a couple of guidelines out there and they basically say that especially in women who no longer have uteruses, it's very appropriate to recommend estrogen without progesterone in those patients and counseling them that the overall risk for those patients is lower than we thought. It is reasonable if we sit down and explain and do kind of a joint decision making thing. It's reasonable to offer hormone replacement therapy with progesterone in patients who do have a uterus. That's reasonable to do. It's even reasonable to consider the combined use of low dose oral contraceptives in perimenopausal women and more recent evidence has suggested that those combination low dose oral contraceptives can help with postmenopausal symptoms but don't seem to have the higher risk of stroke or breast cancer. So if a woman was kind of on the fence about things you could say well, we could certainly try a combination low dose oral contraceptive and see if it helps with the hot flashes.

Speaker 2:

So the guidelines all agree on what the contraindications are. So you would probably not want to offer estrogen-based hormone replacement therapy in somebody with unexplained vaginal bleeding, with someone with acute liver dysfunction, anyone who has a history of estrogen-dependent cancer, so largely breast cancer, people who have a history of coronary disease or stroke or any thromboma and bokeh disease and again, that's not unique to this. We don't give oral contraceptives usually to patients who have a history of of dbt's or p's, so that doesn't really really surprise me. And they note that that the benefit is probably relatively low in women after the age of 60 or after 10 years of post-menopause and they do know that's kind of a relative contraindication but the benefit seems to go down. You get to see more benefit in the late 40s and 50s than you do in the 60s. They do also note the contraindications to progesterone unexplained vaginal bleeding, again breast cancer. And they note that in some preparations of micronized progesterones that peanut oil is used as a preparation agent and new year's order to peanut. You probably shouldn't be on those.

Speaker 2:

So you know again, I think as primary care clinicians I think that we need to realize that, while the women's health initiative study was an important study and it really did help us figure out you know what we were doing with hormone replacement therapy and a lot of the claims we were making, and a lot of those claims did not come out to be actually, you know, true, there is still a real place for hormone replacement therapy in the right patient and I've long said that this is one of the most important patient sharing decisions that a clinician can make with a patient who is suffering from Bayes and motor symptoms. And I think you know, I think sitting down and saying, okay, here's our risk, you can easily calculate never needed to treat, never needed to harm. I think that gives people an idea of a number to look for and just make sure that patients who have contraindications, you know, say look, I'm afraid you're not a candidate for these medications for all the reasons that we've kind of talked about. So you know the first part of this. I just didn't want to mention that.

Speaker 2:

I think, even though we've largely abandoned hormone replacement therapy, I think that it was, you know, kind of throwing the baby out with the bathwater there, and I think that you know the hormone replacement therapy, estrogen in particular, can be very beneficial in the right patient and I think we need to be doing a better job of considering to offer that to patients. And if they want more information, we can sit down and talk with them. And again, I know how hard that is to do. If you're a busy family medicine doctor, you're a busy OBGYN, you're a busy pharmacist, to take 10 minutes and kind of explain the women's health initiative study is challenging. I know some OBGYN practices have kind of come up with a nice little, you know professionally made kind of handout about it to kind of laze it, everything out that they can actually give to the patients. Hey, read this, take your time, do your research, let's come back and talk about it, sort of thing. Anything that I think would help. You know, get that conversation going is a good idea, because I do believe that that estrogen is underused for vasomotor symptoms, but there's a lot of women who are not kind of want to take it, there's a lot of women who can't take it, and so, you know, are there any other therapies we can take a look at? And the answer is yes with this brand new drug, falsalititin, and this drug is an interesting medication. So you know, the drug itself comes from the fact that we know the reason women have soaking, you know hot flashes at night, whether they soak through their bedsheets and stuff is.

Speaker 2:

There's a, there's the thermal regulars authority center and the hypothalamus of the brain is actually affected by estrogen. But it's also affected by other things and one of them is the key and the KNDY neuron and that stands for chisopeptin, neurokinin B, dinorphin, and I'm never going to say that again, I'm just going to say KNDY neurons. These neurons are stimulated by neuropeptide, neurokinin B at the neurokinin three receptors and that's what's inhibited by estrogen. Declining in variable estrogen levels during menopausal transition basically lead to neurokinin through receptor mediated activation. That results in hypertrophy of these KNDY neurons and dysregulation of the thermoregulatory center. So basically, because these are are how the thermo thermoregulatory center is innervated with these neurons, when estrogen levels drop, those neurons get large and it leads to dysregulation and again this is the symptoms of hot flashes. So again, for this elizotant is a selective neurokinin three receptor antagonist that blocks the binding of their kind of B to the KNDY neurons to restore a normal sensitivity of the third of the regulatory center. So basically they kind of act. As you know, if estrogen levels hadn't variable, hadn't gone variable and decreased, none of this would happen. They basically block that receptor to kind of get everything back in line and reach kind of a homeostatic norm. So this study the study that looked at fozilizotent was called the Skylight One study we'll have a link to the study in our show notes was a randomized double blind placebo control phase three study in women ages 40 to 65.

Speaker 2:

And they had to have an average of seven or more moderate severe hot flashes per day before they could be randomized and put in the study. All the women had spontaneous amenorrhea for at least 12 consecutive months, or for at least six months with biochemical criteria of menopause. They also looked at things like follicle stimulating hormone if that's high, that point you was thinking that you that you've reached menopause or they had a bilateral oophorectomy for at least six weeks before the screening visit. They also had to have a BMI of someone between 18 and 38, which may limit some of the generalizability of the study and a couple of other inclusion, but those are kind of the big ones. As with a lot of these studies they excluded patients who basically had any other disease. So they really wanted basically just healthy women who were in menopause. So patients who had significant cardiovascular disease cause, significant liver disease, significant kidney disease, they were all excluded. Again, I get why they did that, but that does sometimes limit some of the generalizability of the study.

Speaker 2:

It was done in 97 facilities across many countries, mostly in Europe, canada, the UK and the United States. They collected a whole bunch of information at screening and SUCS was self-reported and the inclusion criteria was someone who was born female, basically. So then once people were randomized, they were randomized in a one-to-one-to-one ratio to receive, as a lit of 1030 once daily there's a lit of 1045 milligrams once daily or placebo for 12 weeks, according to how they randomized the patients. They did stratify patients by smoking status cause. As I said, smoking does play a role in amount and severity of post-mroposal hot flash symptoms.

Speaker 2:

The investigators, project team members, were all blinded to the data at, blinded who received what, and the tablets and the placebo were indistinctly Englishful and in appearance and shape. Patients took the assigned study drug orally once per day for up to for 12 weeks, and then those who had completed the trial were offered the opportunity to do a 40 week continuation extension period, even if they received placebo, which I thought was kind of interesting. Usually in these studies they just go on 40 weeks for people who did well on the active therapy and now they actually allow people, even who had improvement, even if they're on placebo, to continue therapy, which I thought was kind of interesting and probably a good way to look at things. So the primary and objective of the Scholar1 study was to evaluate the efficacy of Pesilizotent versus placebo on the frequency and severity of moderate severe vasomotor symptoms. Because of that they had to use basically subjective scales and things like that, cause I mean, the patient is gonna have to tell you, yeah, my symptoms are better, or no, they're not.

Speaker 2:

So they used a wide variety of survey instruments to kind of figure out what was going on here, but a lot of them were just surveys that just said, okay, after 12 weeks are your symptoms much better, moderately better, a little better, or there was no change, and basically gave those kind of diaries to electronic diaries to basically have them mark that sort of thing as they were going along.

Speaker 2:

So the biggest outcome they looked at was improvement in symptoms that was captured by basically an electronic diar or where women just listed their own symptoms as well. The key secondary endpoint was a mean change in the patient reported outcomes. Measurement information system sleep disturbances short form 8B, which is shortened to the Promise SDSF 8B I don't know who comes up with the names of these things, but in any event it is a validated instrument, survey instrument to kind of look at not just how many hours did you sleep, but the perceptions of I got restless sleep, I'm not satisfied with my sleep, I don't feel like I got refreshed in sleep, et cetera, et cetera, et cetera. So it sounds like a kind of a complex survey, but I do appreciate the fact that they just didn't say, gee, is your sleep better?

Speaker 2:

They kind of did more of a deep dive into the characteristics of somebody's sleep, which I thought was a good thing, Other secondary endpoints included mean change in frequency and severity of just moderate to severe symptoms from baseline up to week 12, and then percentage of reductions of at least 50% and at least 75% in symptoms at week 12 as well. The statistics were actually pretty straightforward. They used a mixed model with repeated measures for the treatment group and then they stratified again by group, week and smoking status, which they divided as either current, former or never smokers as factors. They did the least square means response, which would be pretty standard in any type of study like this, and they estimated that they would need about 530 patients to show a significant improvement in symptoms with a Pesilizotend compared to placebo. So the study was conducted between 2019 and 2021.

Speaker 2:

They recruited and screened 2,500 women and 520 actually were randomly assigned to treatment groups. Again, remember they were looking at pretty much only healthy women, so I suspect a lot of women were excluded just because they had hypertension or they had dyslipidemia or something like that. So 522 women received at least one dose of the study drug and were included in the safety analysis set. One patient was randomly assigned a Pesilizotend 45 and error received another dose that they were dropped out. So in the end, the full analysis set consisted of 175 patients in the placebo arm, 173 in the Pesilizotend 30 arm and 174 in the Pesilizotend 45 arm. What did they find? What were the results of the study? Well, we're going to talk about that right after a message from our sponsor, ce Impact.

Speaker 1:

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Speaker 2:

So we're back discussing menopause and an important women's health issue that you know. I know our own program has probably not done as good a job as we should at shining a light on, but we're talking right now about an interesting new medication with a brand new mechanism, action called tazolizatant and its ability to improve symptoms in postmenopausal hot-flag symptoms. In the study that we've been discussing, the average age was 54, mean body mass index was 28, 75 percent of patients were white and they did have, as I said, mentioned a significant number of hot flashes. In fact, the median number of hot flashes per day was 10. So I think that's pretty severe. It certainly counted as severe. They all rated in their electronic diary that they had a severe effect on sleep and they felt like they did not get very restful sleep or and had fatigue very commonly, and less than 5 percent of anybody on any group had been on hormone replacement therapy. Again speaking to what we talked about earlier in the women's health initiative study. So what did they find with the tazolizatant? Well, when they took a look at women who rated their symptoms either much better or moderately better, that percentage was 48 percent in the tazolizatant 45 milligram group. It was 36 percent in the tazolizatant 30 group and it was 30 in the placebo arm. So we just take a look at the 45 milligram arm. That was 48 percent compared to 30 percent in the placebo arm and that did reach statistical significance. When they took a look at their problems associated with basal motor symptoms in their diaries, again they found pretty much the same numbers that patients on the tazolizatant arm found that the activities that they did were greatly improved when they took the medication compared to placebo, and this was true at week 12 as well as the end of the study at week 40.

Speaker 2:

They then break down, as you might imagine, into a wide variety of different subcategories and they looked at, like, the improvement in symptoms based on numbers. If we were to scale the symptoms on one to ten, how would that do and stuff. So I think there's much point talking about it, because the numbers really don't mean a lot to me. But when women themselves are saying my symptoms are either significantly better, much better or somewhat better compared to placebo, I think that in the end that's the practical, clinically relevant endpoint that you're really looking at Now. Interestingly, they found that even though early on the drug arms did have an improvement in sleep quality that actually disappeared by the end of the study. So interestingly, even though initially women did say, yeah, my mom, without these hot flashes of sleeping a lot better, that actually did not continue. So now, and I think that's one of the things that authors were surprised about, because it's like, well, hold it, if your hot flash symptoms are better, how come you're not sleeping better? So that was kind of interesting. Other quality of life secondary outcomes all improved across the board and the improvement in types of symptoms was similar, depending on patients smoking history as well, which was great.

Speaker 2:

When they took a look at side effects, earlier drugs in this class had had some concern about liver function abnormalities and in fact they didn't find any of that in the study. But keep in mind that they only had 500 patients in this study and I suspect that something we're going to have to watch out for if this drug makes it to market. So when you add everything up, when you add the percentage of women who felt like they had, you know, significantly increase in, increase, improvement in their symptoms compared to placebo, you know, but the number needed to treat them only six. So I think that's that. That speaks to the effect sides here and I think that that you know it seems to have a significant benefit in a significant number of women who take this take medication. So the authors, you know, in their discussion note that you know their study found that that Pesilisotans seem to improve the frequency and severity of vasomotor symptoms both at week 12 and week 40. They note that when you look at the Kaplan-Meier plots their symptoms improved as early as week one and had continued benefit throughout the throughout the study. They know that that same number of patients had at least a 50% approval of their symptoms and severity of their hot flashes. But they also kind of puzzled a bit over the fact that, even though that was true, that sleep quality did not seem to really improve over time but other points of quality of life did as well. So they kind of walked away from the sky.

Speaker 2:

One saying study saying you know, yes, I think this is a drug that seems to improve symptoms, it seems to be relatively safe it you know we need to do a little more deep diving into you know why it didn't seem to prove sleep. But overall women who are in the study seem to be very satisfied with the improvement in symptoms and there didn't seem to be significant adverse effects. Now the this was the skylight one study. There's another ongoing study called skylight to that will have more than 1000 women in it and that may give that'll give us more information, particularly about safety, which which again I think is something that will have to kind of keep an eye out here.

Speaker 2:

So I mean the big issues, I think, with the drug or adverse drug reactions, especially liver function abnormalities, and, of course, as it always does, with the new drug cost. You know, I suspect this is not going to be an inexpensive medication, especially compared to GABA, penton or a bit of a vaccine or hormone replacement therapy in and of itself. So you know, I suspect that this may be something to offer women who have failed all those therapies and and are, you know, their insurance can, will be willing to try that. But again, as I said at the beginning of the pod I I, the other piece I really want to want listeners to walk away from is that, you know, don't dismiss hormone replacement therapy for these patients out of hand. You know well, we just don't do that anymore. I think it really does require assessing patients risk, telling them about the risk and then share decision making in this area is more crucial than a lot of other disease states that I know of, and and so I think that's that's certainly worth thinking about.

Speaker 2:

So keeps, keep, to keep, stay tuned for as the patent. My guess is that it probably will be approved, unless something very weird shows up in the skylight to study, and again, where we place it in the treatment of postmenopausal hot flashes will be pretty interesting. So that's it for this week of game changers. Thanks again for listening. We will see you next week, but until then, remember time flies.

Speaker 1:

I don't know where it's going for all the CE resources you need Become a Pharmacist by Design member today to access it all for free, including CE, for this podcast. Thanks for listening. We'll talk to you next week on Game Changers Clinical Conversations.