Hot flush drug fezolinetant

On this week’s podcast, Dr Louise is joined by Dr Ashley Winter, a urologist and sexual medicine specialist, and Dr Sarah Glynne, a GP and menopause specialist who is a member of the research team at Newson Health and chairs a working party that promotes access to evidence-based menopause care for patients with breast cancer.

They discuss Fezolinetant – brand name Veoza – a new drug recently approved in the UK and other countries to treat moderate to severe hot flushes in menopausal women aged 45 to 60 years.

You can read an article about fezolinetant on the balance website here.

Related articles

Lederman S., Ottery F.D., Cano A., Santoro N., Shapiro M., Stute P., et al. (2023) ‘Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study’, Lancet, 401(10382):1091-102. doi.org/10.1016/S0140-6736(23)00085-5

Johnson K.A., Martin N., Nappi R.E., Neal-Perry G., Shapiro M., Stute P., et al. (2023), ‘Efficacy and safety of fezolinetant in moderate to severe vasomotor symptoms associated with menopause: a Phase 3 RCT’, J Clin Endocrinol Metab, 108(8):1981-97. Doi:10.1210/clinem/dgad058

Douxfils J., Beaudart C., Dogne J.M. (2023), ‘Risk of neoplasm with the neurokinin 3 receptor antagonist fezolinetant’, Lancet, 402(10413):1623-5. doi.org/10.1016/S0140-6736(23)01634-3

Follow Dr Ashley Winter on X and Instagram @ashleygwinter

Follow Dr Sarah Glynne on Instagram @sarahglynne

Click here to find out more about Newson Health 

Transcript

Transcript 

Dr Louise: [00:00:11] Hello, I’m Dr Louise Newson, I’m a GP and menopause specialist, and I’m also the founder of the Newson Health Menopause and Wellbeing Centre here in Stratford-upon-Avon. I’m also the founder of the free balance app. Each week on my podcast, join me and my special guests where we discuss all things perimenopause and menopause. We talk about the latest research, bust myths on menopause symptoms and treatments, and often share moving and always inspirational personal stories. This podcast is brought to you by the Newson Health Group, which has clinics across the UK dedicated to providing individualised perimenopause and menopause care for all women. So today on the podcast, I’ve got two guests, one who works geographically close to me and one who geographically doesn’t work close to me. So I’ve got Dr Sarah Glynne, who does a lot of academic work with me in Newson Health, and Ashley Winter, who some of you might know, did a podcast recently with me, who’s a urologist in the US. So welcome both of you to the podcast. [00:01:23][72.5] 

Dr Sarah Glynne: [00:01:24] Hi. Thank you for having me. [00:01:25][0.8] 

Dr Ashley Winter: [00:01:25] Yeah, thanks so much for having me. [00:01:26][0.5] 

Dr Louise Newson: [00:01:27] Uh, no. It’s great. It’s really good. And I love meeting kindred spirits. And Sarah and I have known each other for a little while, but we’ve become very close over sort of academic papers. There’s not many people that salivate over academic papers the way that Sarah and I do. And we’re often Whatsapping to say, have you read this? Have you read that? What do you think of this study? And sometimes our conversations get quite heated if we don’t always agree. But I love it. I think it’s absolutely great. And through your social media, Ashley, I’m hearing a lot of your sort of academic brain, the way it’s been lit up in different ways. And I think, you know, it’s one of the reasons we went into medicine was because we’ve got this curiosity, we’ve got a sort of thirst for knowledge really that I think the older I get, the more I want to know. And we never stop learning. I always say to my children, every day is a learning day, really. And it’s very true in medicine, isn’t it? [00:02:16][49.2] 

Dr Ashley Winter: [00:02:16] Oh, absolutely. I think the further we get in our careers, the more we understand that, you know, what we learned in medical school was so reductionist, and a lot of the way information was presented to us was really a choice by the establishment of medicine and the history of medicine. And there’s so many layers to everything, to the knowledge that we have and the way that it makes itself to patients. So I absolutely love when, you know, a concept in medicine is presented to me. And then you say, okay, well, I want to know everything about this and look at the papers and look at the quality of the evidence and, you know, all the nitty gritty. So I completely agree with you, and it’s a very exciting pursuit. [00:03:00][44.1] 

Dr Louise Newson: [00:03:01] Yeah. And I think, well I know, that medicine is an art as well as a science. So the science we absolutely need but the art is individualising care as well, and everyone is different. But also using our clinical experience, which we have more and more, the more medicine that we do in practice, is really, really important with everything that we do. And I think it’s sometimes misunderstood how much we learn from our patients, actually, and how much we experience different things with our patients. And I was just talking to a GP recently, well actually just a couple of hours ago, who also specialises in psychiatry, and she reached out to me because she said, Louise, a lot of the patients I see are on antipsychotics. They have really high prolactin levels, but they’re all menopausal as well. They’re not having periods and how should I be managing them? And the few that I have given hormones to, it’s been transformational. And why aren’t we doing more about this? And I think this is a great conversation because it’s something I was never taught about in psychiatry, and we were talking about how our hormones, oestradiol, testosterone and progesterone, are produced in our brain, not just our ovaries. And I feel really cross that no one taught me that 30 years ago. And she was saying the same, you know, why aren’t we taught these things that are really, actually important to our clinical work? [00:04:19][77.5] 

Dr Ashley Winter: [00:04:20] Yeah. No, it’s a fascinating concept. I mean, yeah. [00:04:23][3.0] 

Dr Louise Newson: [00:04:24] So the other thing that obviously we’re going to talk about this new drug that’s coming out, but when I was taught menopause, which hardly was anything, it’s always been about flushes and sweats. Sometimes it’s about vaginal dryness. But the vaginal dryness, as we’ve talked about before, Ashley is never… no one talks about urinary symptoms, it’s always the dryness of the vagina, which I think is really actually very disparaging to women. But it’s also the menopause as I’ve mentioned many times before, it’s not just about flushes and sweats. And I know Sarah in your clinic, I’m sure you would agree with me, it’s not the most common symptom that women talk about, is it? [00:05:00][36.2] 

Dr Sarah Glynne: [00:05:01] No, not at all. I think fatigue, brain fog, mood, anxiety, loneliness, flat mood, lack of confidence, motivation, that I would say that all, look I mean there’s evidence that tells us they’re more common than hot flushes and night sweats and even women that do get hot flushes and night sweats, they’re not usually the most debilitating symptom. They can be, they can be really debilitating for some women. But no, they’re definitely not the most common symptom. The problem is that some women, probably up to about half of the women that do get hot flushes and night sweats, get them badly, moderate to severe severity. And women that do get hot flushes and night sweats, that has a negative impact on their mood, their sleep, their ability to work. And it’s also linked with later cardiovascular disease and dementia. So you know they’re not a minimum symptom, you know, and there’s lots of things you can do about hot flushes and night sweats and that’s what we’re here to talk about today is the latest option. But there are both hormonal and non-hormonal options that can be used to treat women who are having problems with them. [00:05:52][50.8] 

Dr Louise Newson: [00:05:52] Absolutely. And for some women, I have seen some women that literally have to have a shower every 30 minutes. I remember years ago speaking to a lady who just sleeping on the bathroom floor because it was the only place she could cool down with the tiles on her bathroom, and she said every 20 minutes she just changed from one side to the other because she just burnt up so much. So there are people it’s really, really negatively affecting. But I just went into work earlier and I was talking to some of the staff, some of my admin staff saying, you know, which is the main symptom that people phone up about. They said it’s always about mood, memory, concentration, sleep, which is what we see. I mean, 98% of women who come to our clinic have psychological symptoms and about 70% have vasomotor symptoms. So you’re obviously right. They are there, but they, I have not actually ever, that I’m aware of, seen a lady who’s only had vasomotor symptoms. There’s always other symptoms as well, because our hormones go all around our body and affect us in so many ways, don’t they? [00:06:48][55.6] 

Dr Ashley Winter: [00:06:48] You know, it’s so interesting just putting together, you know, the dots from my own personal life experiences, listening to these stories and thinking, last time I was on your podcast and we were talking about how postpartum is, you know, in a way, a mini menopause with the plummeting of the hormones. And I remember in the first month after having my daughter, I would wake up completely drenched and I would think that I had wet the bed and you know, and then I would realise that it didn’t smell like urine and it was everywhere and, but yeah, I hadn’t been prepared for that at all. You know, you’re told that, you know, childbearing can give you stress leakage, right? Leakage with cough and sneeze. But, you know, here I was just completely confused. And I’m a physician with a particular interest in hormones. So it was, you know, a very interesting place to be and certainly one that was connected with my mood, you know, and definitely, you know, what people called baby blues, but, you know, sadness, irritability, you know, and not so much just connected to loss of sleep. So yeah, all very interesting. [00:07:54][65.5] 

Dr Louise Newson: [00:07:55] Yes. And it would have been all related obviously to your hormones but not addressed probably in a hormonal way. So we’ve got this new drug that we’ve been knowing about for ages and in fact, I think it was about 3 or 4 years ago, the drug company Astellas phoned me up and wanted to work with me on this drug. And I don’t do any paid work with pharma. And I told them that, and I said, I’m happy to advise without being paid but I can tell you straight up, I’m not sure that it’s going to really be a drug that the majority of women will want to take, knowing what I do about the way it works and the one specific symptom, as in the vasomotor symptoms that it’s addressing, isn’t going to address all the other symptoms. So they sort of sent me on my way and weren’t very happy to engage anymore. So fast forward, we’ve got this drug, which is a very long name that it’s very difficult to pronounce, isn’t it? So it’s fezolinetant, which works on neurokinin receptor in our brain. And it’s been out in the US and now it’s come out to the UK, currently only available privately. But I just, we’ve all been reading the evidence and trying to unpick the evidence, which is what we do as clinicians any time a new drug comes to market. I’ve older and wiser now and I would never just rush and prescribe something just because it’s on my formulary or because someone says it’s good. You always have to go back to the evidence and work out what it’s doing. What are the benefits? What are the risks? What are the limitations of the study? So Sarah if I to start with you, can you just give a brief overview as to what this drug actually does and what this, this neurokinin receptors is in our brain. [00:09:30][95.5] 

Dr Sarah Glynne: [00:09:31] Sure, so the neurokinin receptors are in the thermoregulatory centre in the hypothalamus. And essentially the mechanism is very poorly understood. But we think that the reason women get hot flushes and night sweats is related to the fall in oestrogen levels and fluctuating oestrogen levels across the menopause transition. And it’s these, they’re called KNDy neurons that the neurokinin binds to. They are related, they’re linked to basically how we perceive temperature and how we respond to it. So essentially what happens is that our bodies register a small change in core temperature. This is what I understand. And then there’s an exaggerated response. So our body reacts by trying to cool us down even though actually we’re not that hot. So we get these hot flushes which are caused by vasodilation, which is when the capillaries under the skin dilate, so when they go red and flushed and lose heat by radiation, and it makes us sweat and the night sweats, that’s obviously to lose heat by evaporation and behaviours that cool us down, you know taking off layers, etc. And so the neurokinin receptor blockers such as the fezolinetant block those neurons and essentially they’re kind of dialling down the thermostat mechanism in the thermoregulatory centre in the brain. So the idea is if you block those neurons, if you dial down that activity, you’ll prevent the hot flushes and night sweats that are an exaggerated response to something that actually we wouldn’t normally be responding to. [00:10:51][80.1] 

Dr Louise Newson: [00:10:52] So it makes sense, if you see what I mean, targeting an area of the brain where our temperature regulation is. But Ashley, how effective is it, this drug for, just looking at the vasomotor symptoms, the flushes and sweats, because they’ve done studies, but they’ve only compared with placebo, which is basically a dummy pill haven’t they. They haven’t compared with standard treatment. And we know that the, you know, first line treatment still is HRT. So they didn’t do any. I’ve not seen any head-to-head comparison trials of HRT with this drug. [00:11:22][29.8] 

Dr Ashley Winter: [00:11:22] Yes. Correct. So they have not done the head-to-head studies comparing to HRT. And you know, it is interesting just circling back briefly to the mechanism of action, to remember that our brains have a lot of overlap, right. And so this thermoregulatory centre of the brain is also a part of the brain, the hypothalamus, where something called GnRH is made. And that’s gonadotropin releasing hormone. So that is a hormone that leads to the production of other hormones that lead to the production of oestrogen. Right. So the part of the reason why, when you have higher oestrogen levels in your body before menopause, that you, you know, kind of have an effect on your temperature regulatory centre is because the oestrogen is leading to this negative feedback right on that part of the brain. When oestrogen levels are going down, you don’t have the same level of feedback. So the long reason kind of I’m bringing this up, and a very interesting thing is that what is shown in some animal studies about this medication, and also in some studies of this medication on women with polycystic ovarian syndrome, is that this medication actually does have the potential at certain doses to affect the hormones in the brain that function on the ovary. Okay. So basically this can suppress production of something called LH. And that works on the ovary. And I think it’s an interesting thing to keep in the back of your mind, just because the ovary still has the potential to function after menopause, predominantly in the production of androgens. So testosterone. Yeah, I don’t know. It’s just it’s just very fascinating. And I think, you know, something that will probably be teased out in the years of post-market study on women taking this medication is, what is the consequence of that? A colleague who has reached out to the pharmaceutical company that makes the medication has said that in the trials, even though it’s not published in the major publication on the phase three studies, has said that there wasn’t a major change in sex steroids in women taking this relative to placebo, but I would be interested in to see what those actual numbers are and and how that effect pans out in women’s bodies over time. So I know that was a a big digression, but I think it’s a really fascinating thing because, you know, we talk about this medication as being this purely non hormonal solution for people who are scared of hormones, which, you know, I wish we focused on correcting misinformation about hormones instead of helping people stay away from hormones. But you know, the idea is ultimately that there is a potential for a hormone modification. Right. Even in a non hormonal treatment. And there’s just this such intrinsic overlap in this part of the brain between sex steroid regulation and temperature. And you know, it’s hard to say that this targets that without any other effect. End of my diatribe. [00:14:29][186.8] 

Dr Louise Newson: [00:14:31] And it’s very interesting actually, because one of the side effects from the drug is actually hot flushes, isn’t it? And so you wonder whether it’s actually causing some symptoms because of switching off oestradiol and testosterone or reducing levels. And we don’t know enough. And as we talked about before, sometimes hormone levels can be quite unreliable as well. So unless they’re monitored very regularly you won’t know. You won’t see changes. And certainly the study looking with polycystic, women with polycystic ovarian syndrome, they often have a higher testosterone level anyway. That’s part of their condition if you like, but they often miss testosterone as well. So it is interesting to see that there is possibly a reduction in those hormones.[00:15:14][42.9] 

Dr Sarah Glynne: [00:15:15] Yeah, I was just gonna say just, while we’re talking about testosterone, it’s really interesting because a lot of menopausal symptoms are probably related to testosterone deficiency as well. It’s not all about oestrogen. And this drug, if you say, in higher doses it’s been shown to suppress testosterone levels, so it’s being explored in women with PCOS who have high testosterone levels. But one of the problems in menopause is low testosterone. So that potentially could exacerbate, it that may be one of the reasons why some of the side effects include things like insomnia, low mood, anxiety, etc. because it could be related to a fall in testosterone levels. And it’s interesting, I think, that many of the doctors who are using and promoting fezolinetant at the moment are also denying women access to testosterone therapy because they’re saying there’s a lack of long term safety data, but actually the randomised controlled trials, there’s a lot more data about testosterone generally, but the randomised controlled trial data in particular, we’ve got twice, it’s twice as long. We’ve got randomised controlled trials of up to two years duration for testosterone, whereas the fezolinetant clinical trials are only one year. So there’s a real double standard because on the one hand, they’ve got one year’s worth of data about fezolinetant and I think there are some serious concerns with some of the data, versus two years plus a lot of observational study data about testosterone. And it seems to be much safer. And yet we’re being told we can’t give women testosterone for their symptoms of testosterone deficiency, but we can give them this drug called fezolinetant that we don’t know very much about. Just wanted to inject that. [00:16:36][81.3] 

Dr Louise Newson: [00:16:36] Yes. It’s actually, I think, really important when we think about this, because there is this whole debate, as you said, Ashley, about non-hormonal treatment. And we should remember what hormones are. They are just biologically active substances that go around our body. And we know, even though we haven’t got really big studies in really long duration for testosterone, we know physiologically how it works in our body. We know mechanisms of action. We know that it’s a natural hormone that we produce. Now fezolinetant is not a natural substance. So we can’t even speculate or extrapolate just basic science with this. And as you say as well, Ashley the brain isn’t just like one part of the brain does one thing and one part does something else. Our brain is obviously the most amazing organ we have, but we also have lots of neurotransmitters, so chemical. A lot of our new transmitters are hormones, but they work and send messages to other areas of the brain and also obviously the body as well, but they work in conjunction with others. So I’ve already spoken many times before about if we have low oestradiol levels, we also have low serotonin levels or low dopamine levels and our noradrenaline can change. And there is some concern actually, that this drug might adversely affect serotonin and dopamine levels as well, mightn’t it? [00:17:58][81.5] 

Dr Ashley Winter: [00:17:59] Yeah. And something that’s much harder to measure the blood test of sex steroids. So yeah. I mean and I’m not sure but was anything ever… related to psychological state in any way recorded in the trials? [00:18:13][13.9] 

Dr Sarah Glynne: [00:18:14] Yeah, there’ve been headaches, insomnia, mood change have all been reported as side effects as well as abnormal liver function tests, so quite significant abnormal liver function tests up to sort of 3 to 5 times the upper limit of normal, although reversible on stopping the drug. So yes, there definitely have been some mental health side effects that could be related to serotonin. Could be oestrogen, could be testosterone. There are lots of things that could account for it. Yeah. [00:18:35][21.3] 

Dr Ashley Winter: [00:18:35] And then the interesting thing would be to say, right, if you had randomised in relation to standard of care with hormone replacement as opposed to placebo and looked at, you know, psychological and neurocognitive side effects, where would the two groups, you know, compare? And I think that would be the more interesting question, and of course one that you don’t have the answer to. [00:18:58][23.2] 

Dr Sarah Glynne: [00:18:59] I think that’s one of the problems is it’s just that the data is so limited. It’s been I think, you know, across the three Skylight trials, there were about 2,000 women, I think, in the trials that have been randomised for fezolinetant for one year. So one of the main problems is that we don’t have much data. And I think the risk of adverse effects has probably been underreported, partly because there’s not much data. And partly I think there have been some trials that haven’t demonstrated benefit, but they haven’t been included. So when the FDA in the States and the Medicines Regulatory Healthcare Agency in the UK, looked at and reviewed the data regarding fezolinetant, they only looked at the positive studies, they didn’t look at the negative ones. So I think the benefit would have been overestimated. And I think there’s lots of reasons why things have been understated. So, I said you know, the fact that there’s not much data for women in the safety analysis of the 12-month trial, the Skylight 4 trial, they were included in the safety analysis if they took just one dose of fezolinetant. So clearly there were, we don’t know. There was no information about adherence. How many women took the drug, how often they took the drug. Clearly women who aren’t taking the drug aren’t going to get side effects, but they were still included in the safety analysis. About 14% of the women that were in that trial discontinued the drug we didn’t know how long they took it for before they discontinued it. Again, they’re not going to report side effects if they’re not taking the drug, but they were still included. So I think the benefits have been overstated, possibly. I think the risks are being understated and the major risk to my, I think at the moment, is that there this flag, this signal, possibly for increased risk of cancer in women who take fezolinetant. And that’s not being reported in the early Skylight trials. It’s been mentioned, there’s a mention of cancer in the Skylight 4 trial, but the authors conclude that it’s nothing to do with the drug, they didn’t need to worry about it. I’ve got, I don’t know if you know mind me sharing Louise, but I printed this off because there’s a clinical pharmacologist in Belgium who went, so any randomised controlled trial has to be registered at the clinical trials registry otherwise I can’t get published later on. So this clinical pharmacologist, this is published in The Lancet, it’s freely available. So anybody that Googles neoplasia, fezolinetant, and Lancet will be able to find it. A professor of clinical pharmacology called Jonathan Douxfils in Belgium, and he went to the original clinical trials registry and looked at the cancer data basically, and essentially in the placebo group so broadly speaking, let’s just say for argument’s sake, there were about 1,000 women in each group. And in the placebo group, there were two cases of cancer in women aged 50 to 59. So that’s what you’d expect. Obviously, some women are going to develop cancer if you follow them over a year. But in the group that were taking the recommended dose of fezolinetant for menopause, which is 45mg per day, there were 16 cases of cancer. And that’s a statistically significant 4.25-fold increased risk of cancer in the fezolinetant group. Now, clearly, probably you know, we don’t know whether it causes cancer or not. We don’t have enough data because there’s been such limited numbers. But that’s a signal, that’s a risk. And I think there’s two things that are very concerning about that. One is that there’s a risk that needs to be further evaluated, and it hasn’t been further evaluated. And yet we’re being told that it’s safe to prescribe that we can go ahead and give it potentially to women who’ve had breast cancer, who actually the drug hasn’t been tested on. So I think that’s a major cause of concern. And the other thing that really concerns me is that data is not freely available. Clinicians, doctors aren’t talking about it. Women aren’t being told about it. And women can’t make an informed choice about whether they want to have this drug or not if they don’t know about it. And I think that a lot of women would probably look at that and say, you know what, I think I’ll wait until there’s more data available and I’ll try something else at the moment. So I think that’s really concerning. [00:22:24][205.6] 

Dr Ashley Winter: [00:22:25] It’s so interesting what you bring up about the cancer, because one of the main comments or, you know, reasons to use it is people saying, I want to give my patients options if they are scared of oestrogen. Right? And the reason why people are scared of oestrogen is perceived cancer risk primarily. Right? I mean, that is primarily the concern, even though we know that oestrogen therapy alone, if you don’t have a uterus, has never been shown to cause any sort of cancer. And yeah, I just wonder to what extent this potential signalling regarding, you know, increased cancer rates, which certainly should be reported and studied in the long term, you know, presenting that data in front of people alongside really robust evidence on the cancer risks associated with oestrogen therapy. You know, what would women choose? And I think that is really the question that people have to keep in the back of their mind. And, you know, if that is not being presented, are patients really having the opportunity to have a real correct choice about what’s best for their health, right? [00:23:39][73.5] 

Dr Sarah Glynne: [00:23:40] Absolutely. [00:23:40][0.0] 

Dr Louise Newson: [00:23:41] And it is really concerning. The other thing is, is that there’s lots of people who are told they can’t have HRT, but actually can. I met someone at an event last night who said, oh, I had a polyp diagnosed two years ago. My gynecologist has told me I can never have HRT. Well, of course she can have HRT. Lots of people who’ve had clots in the past who told they can’t have HRT. Of course they can have transdermal oestradiol with natural progesterone and testosterone. But the group of women where we haven’t got robust data, are women who’ve had an oestrogen receptor positive breast cancer, and that’s a very individualised choice that we’ve spoken about before on other podcasts. But actually this is potentially a drug that would be used for those women. But we don’t have any studies do we? None of the studies included women who’ve had breast cancer. And I have read things on various social media forums saying yes, but they will do studies. Now, if I had breast cancer, I wouldn’t want to take a drug that hadn’t been tested on a similar person to me. And we know that at the minute, the studies have only been done between the ages of 45 and 60. So if I start at 59, do I stop at age 60 or what? I don’t know, we haven’t got evidence, but if I’ve had breast cancer, though, I’m not aware, are you, of any studies that have included women who’ve had oestrogen receptor positive breast cancer? [00:24:56][75.0] 

Dr Sarah Glynne: [00:24:56] Not with fezolinetant, no. Only healthy people have been recruited into the trial. [00:25:00][3.3] 

Dr Louise Newson: [00:25:00] Yeah. And actually, one of the things I was thinking about last night, actually, about this drug is when I read about the oestradiol levels reducing, so we know, don’t we, that women who are diagnosed with a oestrogen receptor positive breast cancer, or any breast cancer who have been taking HRT actually have a better outlook, they have a better prognosis. And we know that oestrogen is very anti inflammatory. As you’ve already said Ashley, women who take oestrogen have a lower future risk of breast cancer anyway. But women who’ve had cancer might have a better prognosis because of them having had some oestrogen in their body. We don’t know. But actually if you’re giving a drug that’s blocking it, we don’t know whether that’s going to make the overall prognosis worse or not. And we can’t answer. There’s lots in medicine, of course we can’t answer. But I do worry when we’ve got so little data to actually be able to guide patients on this drug.[00:25:53][52.5] 

Dr Ashley Winter: [00:25:53] Yeah. I think another, just to kind of round out our conversation, another thing to keep in the back of our mind, which is an overarching conversation regarding, you know, the ethics of the way we treat midlife women is that menopause causes so much symptoms, many symptoms. And when you silo and compartmentalise those symptoms and use each one of those symptoms to target for pharmaceuticals, right, there is a great opportunity to have people on a myriad of medications, right? And I’m constantly thinking of this, wearing my hat as a urologist, because as I have shared with you in email exchanges, a very direct symptom of, for example, low oestrogen state is overactive bladder, for example. And there are, you know, probably, you know, over a dozen medications of various different pharmaceutical classes to address that. And very commonly, those medications receive FDA approval by being studied in postmenopausal women, because there’s a high prevalence of those symptoms in that population, but almost never is usage of low dose vaginal oestrogen a prerequisite for studying those medications or the comparator as opposed to placebo. Right. And that is really important because truly, the hormone intervention, right, a low dose topical vaginal oestrogen, is actually the safest way and the least invasive way to treat overactive bladder in a postmenopausal population. And certainly if somebody fails that medication regimen, then moving on to an oral medication is appropriate. But nowhere in our guidelines, in our counselling of patients, in our societal awareness, is the use of oestrogen considered first and foremost, even though physiologically that makes sense as the first treatment. And I feel like this is just so prominently an issue for midlife peri and postmenopausal women that we create a basket for a new pharmaceutical class by sectioning off, you know, all of these symptoms and creating a new medication for them. And we have to be really cognizant of that in terms of ethically treating this population of patients. [00:28:14][140.3] 

Dr Louise Newson: [00:28:14] Yeah, I think that’s such an important point because many people we see are on several medications by the time they certainly come to us in the clinic, you know, they might be on painkillers for their muscle and joint pains. They might be on migraine tablets, they might be on bladder tablets, like you say, they might be on tablets for their palpitations. Now they might be on medication for their vasomotor symptoms. But actually we have to take a step back and think. There’s one thing about symptoms. And as you say, there’s one treatment, treating the underlying cause, giving the appropriate hormones that will improve the symptoms if they’re caused by a hormonal deficiency. But the other thing is thinking about long term health risks of not having our hormones. And we know many people also want to take HRT to keep their bones strong, to reduce their risk of cardiovascular disease, probably reduce their risk of dementia as well. Now, I’m not aware of any, well, there’s only been one year study data we know, but I can’t imagine and try and comprehend how this drug is going to give us long term health benefits. Someone was saying, oh, um, sleep might improve, therefore overall health might improve. Yes, I get that. But actually it’s not just the hormones don’t work by improving sleep, they work because they’re very anti-inflammatory in our body. And so to deny women a treatment that will halve their risk of heart disease, even if they’re only having minimal symptoms, in my mind, is wrong actually. [00:29:37][83.3] 

Dr Sarah Glynne: [00:29:38] And actually we haven’t said yet, actually that the benefit is very modest in terms of the clinical trial data. It was only two and a half hot flushes a day less in the women that took the fezolinetant compared with the placebo group. So yes, there was a benefit and obviously that’s an average, so some women may get a more noticeable benefit, but the average reduction of 2.5 hot flushes per day actually is less than the minimum clinically important difference. So it’s arguable as to whether that’s even clinically significant. [00:30:05][26.8] 

Dr Louise Newson: [00:30:06] Yeah. Are you going to be prescribing it Ashley? [00:30:08][1.7] 

Dr Ashley Winter: [00:30:09] I mean this is a tough situation, right. Because I think the pharmacologic discovery behind it is very fascinating. And I think that there is a potential role for certain patients. But in an ideal world, the data I would have would be one, compared to HRT and two, studying a population with true contraindications to hormone replacement therapy, because that is the population that you would be consider using it in right. So, you know, I don’t want to say inherently it’s not possible. But before I would consider using it in my clinical practice, I would like to see those things. And I think a very reasonable approach that any clinician should be keeping in the back of their mind is exactly that. And I don’t think from an ethical standpoint that prescribing this medication because somebody is afraid of oestrogen, if it won’t be harmful to them, is the right approach. And I think when we start talking that way, we have to say, why is somebody afraid and what is the education we can give them that will allow them to have the best health outcomes with the treatment choices they have. So that is my long answer to that question right now. [00:31:20][70.6] 

Dr Louise Newson: [00:31:20] Yeah, I think you’re absolutely right. And it goes back to what we were saying at the beginning. When we have professional curiosity and academic curiosity as well, we always will look at the evidence. So although certainly I wouldn’t prescribe it at the moment based on the evidence that I’ve read and understand, and certainly I’ve made a decision for my clinic that no one in my clinic will be prescribing it for our patients, if the evidence changes, if I read more studies, we’ve got more data, then I can change my mind. You’re allowed to change your mind as a doctor and we do quite a lot. So I think it’s absolutely fine to look at what we’ve got now, look at, as you say, safety of our patients is paramount. We’ve made a decision. Doesn’t mean others are going to make that. That’s absolutely fine. So I’m really grateful for your time and actually for you to have, you know, taken on board, read so much of the evidence. It’s great to be able to talk it through, and I hope it’s been helpful for those people that are listening. Now, before we end, I always ask for three take home tips. Now I can’t ask you for one and a half each, so I’m going to break some rules and ask for two tips each. So I was just going to ask you one reason why you think we shouldn’t be prescribing this drug at the moment. And the other reason is why women should maybe not feel quite so scared about hormones. I know we’ve alluded to it. So I just be really grateful if, if I go with you, Sarah first. So two tips please. [00:32:44][83.6] 

Dr Sarah Glynne: [00:32:44] So one reason why I wouldn’t prescribe it yet is just that I don’t think there’s enough data, I think are some red flags that I think need further evaluation. And until that data is available, I think we’ve got plenty of alternative treatment options that we can use. So there’s no urgency. We can wait for that data. And the second question related to hormones, I just think it’s really worth speaking to somebody, a menopause specialist who, you know, knows a little bit about it. I completely agree with what you were saying earlier – a lot of women believe they can’t have HRT when actually they can. I’m doing a lot of work in breast cancer with you and with Newson Health, and even with women who’ve had a history of oestrogen receptive positive breast cancer. If the benefits are quite significant of having oestrogen and HRT and the risks are very small, which they often are these days because breast cancer these days for most women has an excellent prognosis. I think it comes down to the individual. It’s not up to me or to you or to any other doctor to sit there and say you can or can’t have it. It’s up to us to give women the information about the risks and benefits of both HRT, and fezolinetant, which means that clinicians have to be much more aware of what the risks and benefits are because, like I said, I don’t think the cancer potential risk has been talked about yet. And then they can make an informed decision. And it’s a woman’s choice, isn’t it? So so I would say you just need to find someone that can talk to you about it knowledgeably. [00:33:53][68.8] 

Dr Louise Newson: [00:33:54] Absolutely. What about you, Ashley, your two tips here? [00:33:56][2.6] 

Dr Ashley Winter: [00:33:57] Yeah, I would say one reason to not prescribe it is that my concern is that it would lead to potentially a delay in initiation of HRT or a lack of initiation of HRT. And we know that HRT, particularly when started at a younger age, has very important health benefits. And I just don’t want people to miss out on those health benefits. And, you know, a reason to not be scared of oestrogen. Well, I mean, I’m sure the people who listen to your podcast know all about why not to be scared of oestrogen. It’s a wonderful treatment, and it’s far less scary than most people would believe. And they definitely should talk to somebody who has specialisation in menopause or, you know, hormone use. And it will allow, circling back to one of my previous comments, it will potentially allow you to be on far fewer medications. So again, this concept of non-hormonal being less, it’s actually possible that a hormonal treatment will lead to less medicalisation in your life by a dramatic extent. So those would be my two comments. [00:35:07][69.7] 

Dr Louise Newson: [00:35:08] Excellent. Really really important and lots to think about. And I’m very grateful for your time and let’s see what happens. I think the other thing I would just add is that if someone is prescribing it for you, I would certainly be very direct and ask if they do have any potential conflicts, if they’ve been paid by the drug company, because that is something that I feel quite strongly about. We shouldn’t have any conflicts that change our judgment about any treatment. So thank you very much for your time today, and I’m sure both of you at different times will come back onto my podcast, because there’s so much that we need to talk about going forward. But thank you ever so much today. [00:35:44][36.3] 

Dr Ashley Winter: [00:35:44] Yes. Thank you. [00:35:45][0.8] 

Dr Sarah Glynne: [00:35:45] Thank you. [00:35:46][0.3] 

Dr Louise Newson: [00:35:50] You can find out more about Newson Health Group by visiting www.newsonhealth.co.uk, and you can download the free balance app on the App Store or Google Play.[00:35:50][0.0] 

ENDS