Fezolinetant: un tratamiento no hormonal para los sofocos

Jamie DePolo: Hello, thanks for listening. If you've been diagnosed with breast cancer before menopause, some of your treatments, including chemotherapy and hormonal therapy, can bring on menopause earlier and more abruptly than expected. Hot flashes and night sweats are common symptoms of menopause, and the hot flashes and night sweats that accompany menopause caused by breast cancer treatment can be more intense and last longer.

For some women, these symptoms can be severe and dramatically affect their quality of life. In search of relief, some women consider using hormone replacement therapy, also called HRT, which can help ease hot flashes and night sweats. But because HRT contains hormones — estrogen or a combination of estrogen and progesterone, which can make breast cells grow — it's not recommended for women who've been diagnosed with breast cancer.

Our guest today is Dr. Genevieve Neal-Perry, the Robert A. Ross Distinguished Professor and chair of the department of obstetrics and gynecology at the University of North Carolina School of Medicine. Part of her research program focuses on menopause. At the 2022 annual meeting of the Endocrine Society, Dr. Neal-Perry presented research on fezolinetant, an experimental medicine that doesn't contain hormones, to treat hot flashes. The results have exciting possibilities for women with a history of breast cancer, and Dr. Neal-Perry joins us to explain the findings. Dr. Neal-Perry, welcome to the podcast.

Dr. Genevieve Neal-Perry: Good morning. I'm happy to be here.

Jamie DePolo: So, to begin, could you tell us how you started studying fezolinetant? What made you think it might be helpful for hot flashes?

Dr. Genevieve Neal-Perry: You know, it's two-fold. One is, as part of the type of care I provide, which is reproductive endocrinology, I often took care of women with a diagnosis of breast cancer in terms of helping them preserve their fertility, but then I would also see them afterwards regarding their hot flashes and how to manage those hot flashes. And so that's kind of my clinical entry point. And then, I have a lab where most of my research is focused on understanding the biological mechanisms that contribute to how the brain ages and the impact of hormones.

And so it really is a convergence of the two that led me to the work with fezolinetant, being involved in some research that helped us understand why hot flashes happened, and our understanding of why hot flashes happen has really only been truly revealed over the last five to 10 years. And so it was through that work and that foundation that I began to collaborate with Astellas [Pharma] and looking at this particular drug, fezolinetant, as something that could actually prevent hot flashes and that was not hormonal.

Jamie DePolo: Okay. So, how does fezolinetant work to ease hot flashes? And if I could just say, if you could explain it in terms that we all might understand, and if there's something I don't understand, you know I'll ask about it.

Dr. Genevieve Neal-Perry: Oh, that's perfectly great. 

Again, we've only recently started to understand how and why hot flashes happen, although we know it's been around for as long as we can probably remember. So, hot flashes, what it is is the sense of overwhelming warmth that causes sweats, and it may also cause you to feel a little bit anxious, depending on who you are. But basically, all of a sudden, you start sweating. You feel hot, and it's not because there's been a change in the temperature of the room, okay?

So this is independent of a change of the temperature in the room, and so, what we now understand is that the hot flashes that are associated with menopause are certainly related to the loss of estrogen. And what the loss of estrogen does, it affects certain neurons that are located in a region of the brain that's called a hypothalamus. The hypothalamus holds these neurons that are important for reproduction, important for general maintenance of life, as well as neurons that are important for a regulation of the body's temperature.

So, these neurons, in the absence of estrogen, become hyperactive. This neurons are called KNDy neurons — and they're called KNDy neurons because they have these neurotransmitters, which are these chemicals that communicate with other cells, called kisspeptines, neurokinin, and dynorphin — and they become really hyperactive, and they're releasing these peptides, and these peptides are stimulating the neurons that are located in the thermoregulatory region of the brain.

And they were triggering this sensation that, you know, your body should respond because it's hot, and so, your body responds to this perceived neurochemical change, and it responds by causing you to sweat and doing things to help cool you down. And so that's what we understand now in terms of the biology that we didn't understand. 

And fezolinetant is a neurokinin-3 receptor antagonist. So, what does that mean?

Jamie DePolo: That is a big word.

Dr. Genevieve Neal-Perry: I know. The neuron that I talked about, the KNDy neuron, one of the peptides it releases is neurokinin, okay. And that peptide is the peptide that's stimulating and causing these neurons to think that we're overheated and we need to cool down. 

And so, what this antagonist — and basically, an antagonist is something that blocks the action of the drug or the chemical. What this antagonist does is it blocks the action of the neurokinin in the brain region that causes the trigger of thermoregulation. The other thing it does is it actually reduces the activity of these KNDy neurons. So, it's two-fold. It reduces the activity of the KNDy neurons, and it reduces the activation of the neurons that are regulating your body temperature. So, fezolinetant is a neurokinin-3 receptor antagonist, and it blocks the KNDy neurons, and it reduces the activation of those neurons that regulate heat.

Jamie DePolo: Okay. Thank you. So, I'm going to paraphrase that a little bit, and you tell me if I'm understanding this correctly. So, basically, we now understand that hot flashes happen in the brain, in a region of the brain, and fezolinetant works in two ways. In one way, it's sort of calming down these neurons, these molecules that are overactive and can trigger hot flashes when they put too much stuff out, and then it also is kind of blocking other molecules from hooking into their receptors and starting a hot flash. In a very basic way, am I understanding that right?

Dr. Genevieve Neal-Perry: That is a very basic way. So, if you're a hockey player, right, and you have your goalie and the goalie is kind of blocking those pucks, that's what fezolinetant is doing, is blocking the puck [from] entering the goal on a KNDy neuron. So, it is blocking the entry or the activation of those cells.

Jamie DePolo: So, could you summarize the results of the SKYLIGHT 2 study that you presented at ENDO 2022? Because, to me, they sounded very exciting.

Dr. Genevieve Neal-Perry: Yeah, they are very exciting. This has been such an unmet need for individuals with a diagnosis of breast cancer or hormone-responsive cancers, and their not being able to have a really effective therapy to treat hot flashes. 

And so what SKYLIGHT 2 demonstrated were a couple of things. You know, it's a study that was done across several areas — United States, Canada, and several countries in Europe — and it was what we call a placebo-controlled crossover study. There were a couple of doses of the medicine fezolinetant and a placebo. Placebo being no medication, the dose of fezolinetant being 35 and 45 milligrams. 

And what the primary outcomes of interest were was the reduction in the number of frequency of hot flashes, a reduction in the intensity of hot flashes, and then also looking at some sleep parameters. Many individuals who experience hot flashes often have sleep disruption, and so a drug that can impact both hot flashes as well as sleep, improved sleep, is an amazing need for many affected individuals.

We looked at a couple of time points. We looked at 4 weeks, 12 weeks of the drug compared to placebo, and what we saw was, within a week, you actually see a significant reduction in frequency as well as intensity of hot flashes for both doses and that that reduction continues out to 12 weeks as compared to placebo. And it is a significant difference. At that point, what we did was, for individuals who were using the placebo, we then randomized them to either 35 or 45 milligrams of the fezolinetant, and then we followed people out to 52 weeks of treatment.

And what we were able to see is that, in the individuals who were using a placebo and started the drug, they continued to have a reduction in their hot flashes, frequency and intensity, to the point that they looked like the individuals who had already been on the drug from the very beginning of the study. And for both groups of individuals, their reduction in hot flashes and reduction in severity was sustained throughout the entire study, which was great.

In addition, we did also see some improvement in sleep within the first 12 weeks of treatment, and then that improvement in sleep continued throughout the 52 weeks. So, both from the perspective of hot flashes, frequency and severity, we saw improvement with fezolinetant, and we also saw some improvement with sleep. We'll need to do some additional studies to understand a little bit more about the benefits for sleep.

Very exciting data. It's really encouraging to know that women have opportunities to use a drug that is highly effective with very few side effects, because that's the other important thing, is that there are some other non-hormonal therapies. They're not as effective in that there are some disparities in that, in particular, the serotonin receptor inhibitors, the SSRIs that are used as an alternative therapy for women or individuals with breast cancer, don't always work as well in women of color, and it has to do with how they metabolize the drug. So, it is not the ideal drug for everyone. 

With fezolinetant, we had women who were obese. We had women of color, and we were able to see great outcomes in all of the groups. And so that is really exciting.

Jamie DePolo: Oh, that is. I'm curious, for any of the women in this study, had they been diagnosed with breast cancer? Did you know that, or was that not something you asked?

Dr. Genevieve Neal-Perry: No, that was actually an exclusion. You know, this is the first trial. So, in the initial trials, you want to have… you know, you don't have people who have other known morbidities. So, people that were generally healthy. We did have some smokers, which you often don't have in the hormone therapy trials, and we did have obese women, and obesity is often an exclusion. So, those are the two things that were a little bit different than what you typically see.

We are revving up to do some additional studies, and my focus and goal has always been about how do we help women or individuals with a diagnosis of breast cancer or hormone-responsive treatments that have hot flashes? That's always kind of been at the core of why I've been involved, and so now that we see such great safety profiles in healthy individuals, we feel that we can now move to other groups who have other morbidities who could benefit. So we're actually revving up to do those studies.

Jamie DePolo: Oh, great. That is very exciting. Now, you said there were two different doses of fezolinetant in the study. Did one work better than the other, or I guess, what was the reason for that?

Dr. Genevieve Neal-Perry: The reason for it was there have been some other studies where we used twice daily dosing and looking at the reduction in hot flashes and the severity in terms of reduction of frequency and severity. And so it worked with the two-daily dosing, and we had two different doses, and so we wanted to go to one pill a day, right? No one really wants to take two pills a day. And so we just reduced it to one pill a day with the same dosing that we had with the other studies. So, to answer your question about whether one worked better than the other, they were both highly effective, but there may be some advantages with the higher dose than with the lower dose.

Jamie DePolo: Okay, and you mentioned the safety profile. What about the side effects? You said they were mild. Can you talk about that?

Dr. Genevieve Neal-Perry: Yeah. Yes, I can. So, keep in mind that the study was done during COVID, which was no small task, you know, to get this done. So, one of the things that we did see, we saw COVID, but it wasn't different when you compare to placebo. We also saw some headaches, again, a small group of individuals that had headaches, but that was really the most common side effect that we saw. It didn't vary across the different groups, meaning placebo was similar to the different treatment arms.

Jamie DePolo: Oh, that sounds very exciting, too. I mean, that's a pretty mild side effect, and the drug was effective. I want to ask, too, so your study, you had women taking it for 12 weeks. You evaluated, and then if anybody was taking a placebo, they could switch over to fezolinetant, and the people who were taking fezolinetant kept taking it. So, in all total, it sounds like the study lasted for a year. So, I'm wondering, would a woman take fezolinetant for as long as she was having hot flashes or just for a year, or is that something you still need to study?

Dr. Genevieve Neal-Perry: Yeah, that's a great question, and it is something that we still need to study. So, if you look at some studies from the study of women across the nation and some studies from Australia where they just kind of looked at the timing, duration of hot flashes, the average woman will have hot flashes for five to seven years.

The question is whether they're bothersome, and so typically when we treat hot flashes, it's because they're disruptive. You're not sleeping. You know, you're breaking out in a sweat in the middle of a meeting, which is just really uncomfortable. It's very disruptive. So, if one assumes that the average woman has hot flashes five to seven years, someone may need to use it.

Really, the goal would be to use it as long as someone needs to. You know, that would be kind of the message at this point. You may have the question of if we withdraw the medication, do hot flashes come back? We haven't quite done those studies yet, but we do know, over time, they do go away, and so one would anticipate that the biology isn't any different with or without the use of fezolinetant.

Jamie DePolo: Okay. Well, that sounds very promising. And then I guess, finally, I'm kind of wondering if we could put the results in perspective for women with a history of breast cancer. Is the manufacturer going to apply for FDA approval for this use? Does more research need to be done first, and I'm also wondering if fezolinetant is approved for any other conditions?

Dr. Genevieve Neal-Perry: Yeah, so, it's not approved for any other conditions. So the initial approval will be just for individuals that have bothersome hot flashes. Will Astellas look to get approval for breast cancer? That is my hope. That is something that I am lobbying for, because I feel that there is such a great need.

That's why I've been involved with the study, you know, just because I know, as a clinical provider, that there really are not many options for individuals who've been diagnosed with breast cancer, and the treatment itself triggers hot flashes, right, and that's not necessarily true with some other treatments, and I mean, it is immediate, right? If you use the anastrozole, you use the Lupron, I mean, you're right.

You said at the beginning of your talk that they could be really severe, and they are, and they're severe in young individuals, right? You know, my advocacy and my kind of personal goal is to see this approved for individuals with hormone-responsive cancers as well as individuals who have blood disorders that cause clotting, because they also can't use estrogen.

Jamie DePolo: Oh, okay. Okay. So, it sounds like, then, the final message is kind of stay tuned, because we need a little bit more research, and we need to wait and see what's going to happen, but still, very, very exciting to know that this is out there and the work is being done.

Dr. Genevieve Neal-Perry: Oh, yeah, it is very exciting, and at least from the data so far, there is nothing that indicates that it would be a contraindication. You know, the things that we look at with breast cancer, we look at does the medication cause anything like bleeding, right, uterine bleeding? Like, tamoxifen is one that's used in breast cancer, and we have to monitor for risk for endometrial cancer. We did look at endometrium as part of the study.

And we don't see an effect on the endometrium, which is another important finding, and that'll be reported out at NAMS this year, and so we have a lot of information that tells us and really suggests to us that it will be safe. But obviously, you want to do the study, and that is the plan, and those were the conversations that we've having now. You know, what's the next step, and which groups do we now look at to provide more information around safety?

Jamie DePolo: That sounds very exciting, and I am going to keep in touch with you because we are going to want to know these results as soon as you're ready to announce them. So, thank you so much for joining us today.

Dr. Genevieve Neal-Perry: Thank you. This was a pleasure, and thank you for your work and for your advocacy as well.