Efficacy of Nonhormonal Treatment for Patients With VMS Considered Unsuitable, Unwilling to Take Hormone Therapy
In this video, Nanette Santoro, MD, discusses the efficacy of nonhormonal treatment for patients with vasomotor symptoms (VMS)—also called hot flashes or night sweats—in subgroups of patients considered unsuitable for or unwilling to take hormone therapy based on hormonal therapy history, the efficacy of the nonhormonal treatment for patients with VMS in menopause according to time of day, and pooled safety data over 52 weeks of the nonhormonal treatment for patients with VMS in menopause. These topics were also presented at The Menopause Society 2023 Annual Meeting.
Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of Fezolinetant in moderate to severe vasomotor symptoms associated with menopause: a phase 3 RCT. J Clin Endocrinol Metab. 2023 ;108(8):1981-1997. doi:10.1210/clinem/dgad058
Nanette Santoro, MD: Hello, I'm Nanette Santoro, professor and E. Stewart Taylor Chair of Obstetrics and Gynecology at the University of Colorado School of Medicine. I have been a lifelong researcher in menopause and the menopause transition, and in particular in menopausal symptoms.
Consultant360: Please provide an overview of the data examining the efficacy of nonhormonal treatment for VMS in subgroups of patients considered unsuitable for or unwilling to take hormone therapy based on hormonal therapy history presented at the The Menopause Society 2023 Annual Meeting.
Dr Santoro: In this recent presentation, we wanted to look at women in different groups who might or might not have taken hormone therapy, to see if we could break down the effectiveness of fezolinetant, which is a new first in class, what we call, neurokinin-3 receptor antagonist. To make that simple, it's something that bypasses the estrogen receptor and does a similar action to estrogen to relieve hot flashes. And that's important because estrogen is our most effective treatment, and it is one of two FDA-approved treatments for hot flashes, fezolinetant is now the third.
So, these are the trials that went into the use of fezolinetant, called SKYLIGHT 1 and 2, and those trials included a substantial number of women, that you need to prove effectiveness for the FDA, and from that group, we looked at women who would never be able to take hormones because medically they're contraindicated. We looked at women for whom there might be a caution or a reason that we might be able to give them hormones, but we would have to monitor them closely. Women who stopped hormones for medical reasons developed a contraindication, or they had another reason to stop it. Women who did not want to take it, and said, no way will I ever take this. And women who were naive had not taken hormones but would be willing to try them. We separated the women into groups that were unsuitable for hormone therapy, and those would be the top groups, contraindicated, caution, stopped, or averse, and looked at naive willing.
When you look at all of those groups, we looked at the two doses of fezolinetant that were used in the SKYLIGHT studies, 30 milligrams a day and 45 milligrams a day, and we found very similar evidence that it seemed effective in all of those groups. So the punchline is that whether or not you can take hormones, or you want to take hormones, or you're willing to take hormones, it seemed to have similar efficacy. So, all of the average relief fell on the side favoring the use of fezolinetant, which is very good news because there are many women who cannot take hormones, who do not get relief from the other FDA-approved compound, and who may be very good candidates for fezolinetant. Importantly, we looked at two doses in this study, but the only FDA-approved dose is the higher of the two, which is 45 milligrams.
C360: Please provide an overview of the poster presentation exploring efficacy of the nonhormonal treatment for VMS due to menopause according to time of day.
Dr Santoro: In this second study which was presented as a poster at The Menopause Society, we looked at whether the time of day made a difference in terms of fezolinetant use, and whether or not it was effective. This was important because, in the initial dose-finding studies, some of the regimens included twice-a-day dosing. And if you take medications by prescription, you know that twice-a-day dosing is just about twice as inconvenient as once-a-day dosing. So, when you have a compound that might run out or might not be as effective because you're going to clear it over the course of the day, there is a concern that it'll be less effective over the full 24 hours, and that might influence the time of day that you would take the medication.
So, for example, hot flashes typically are most disruptive when they're at night and they disrupt sleep. So if we did find a day/night difference, a woman might want to take it at nighttime to get the best effect when she needs it the most. The punchline of this study was, we looked at time of day differences and we actually didn't see any. So that's again, very good news because it doesn't matter when you take it, you're pretty much going to get that 24 hours of relief at the FDA-approved 45-milligram dose of fezolinetant.
C360: Please provide an overview of the poster presentation featuring pooled safety data over 52 weeks of the nonhormonal treatment for VMS in menopause.
Dr Santoro: We also looked at the safety data from both the SKYLIGHT 1 and 2 studies, both of those had been reported separately. And there have been concerns as these compounds have begun to be tested because there are some that are coming after fezolinetant, this is the first in class to be FDA-approved. There was another compound that preceded it that was stopped in development because of concerns about liver toxicity. So, the FDA, you can be sure, took a very, very careful look at liver changes and the side effect profile of the medication. And what we saw in that study is, when you pull the studies together, you don't see any specific effect. So, there are always symptoms that some people will have, adverse events, headache, and nausea, and those things seem to be similar in all the groups. For the women who were randomized to placebo, women who were randomized to 30 milligrams, and women who were randomized to 45, there was no dominant effect.
And if you do think you have a drug effect, typically you see it at the lower dose and then you'll see more of it at the higher dose. We didn't see any of that. Other clinical endpoints that were looked at that, that the FDA required, even though fezolinetant is not a hormone, they wanted to be sure that it had no changes in the lining of the uterus, so there was an endometrial safety study. Women had endometrial biopsies at the beginning and end of the study. There was no sign or signal that there was any problem with endometrial safety as well. So that was all reassuring data.
C360: How do the results of these studies impact clinical practice?
Dr Santoro: I think at this point in terms of using it in practical clinical use, we have about the best data that we can have, we have a compound that seems effective, almost as effective as estrogen, which is a big plus. It can be used in people who cannot take estrogen, which is a big plus. It doesn't matter the time of day you take it, so it's overall a fairly convenient medication to be able to give to patients, and I think that's very good news in clinical practice. We do have to monitor patients for liver enzymes, and there is one important contraindication with fezolinetant that the FDA felt was important to avoid medications that are metabolized by a specific liver enzyme called CYP1A2. So, if anyone is taking a medication that's a CYP1A2 inhibitor, they cannot take that with fezolinetant.
This is something that needs to be figured out with a patient and her physician or practitioner because you actually need to look at every single medication a woman is taking to be sure this is not a specific class of drugs that makes it easy to figure out. Liver enzymes need to be checked regardless, at baseline, three, six, and nine months for the time being, until we get more safety data. And of course, once something gets from FDA approval out into clinical practice, there are always other things that may emerge.
There are also, I think at this point with thousands of women studied to date, we know that there doesn't seem to be anything serious and relatively common, but as you get into tens of thousands or hundreds of thousands of women who may use this medication, which is actually quite likely because of how prevalent hot flashes are, more than three-quarters of the population of menopausal women have them, we may see other things emerge. So, it's very important to keep an eye on oddball side effects, and that people report them to their doctors, their practitioners, and that those get reported back to the FDA.
C360 What knowledge gaps remain and what is next for research on nonhormonal treatment for VMS in menopause?
Dr Santoro: The whole class of these NK3 receptor antagonist compounds has really opened up an entirely new line of investigation. For years and years, we knew that there was a thermostat in the brain, and the midbrain, called the hypothalamus, and that thermostat was very sensitive to estrogen. And when estrogen is withdrawn, or when estrogen is bouncing up and down, it triggers hot flashes. And that was about all we knew, that thermostat area of the brain was kind of a black box. So, the knowledge of how this NK3 pathway works has opened up an entirely new area, where we can look at some of the things, not just the NK3 pathway itself, but some of the things that interact with it. And if we can get compounds that interrupt that pathway or adjacent pathways in a way that might synergize, we may be able to get some new, very, very effective treatments for hot flashes so that women will have a choice of which kinds of treatments and we may be able to target a particular patient to a particular medication.
C360: What are the overall take-home messages from our conversation today?
Dr Santoro: I think probably the biggest take home is that there's a new kid on the block for hot flashes so women really should know if they are menopausal and they're having symptoms and they feel like they don't know if they should go see someone for this, they're afraid to take hormones, they're afraid the doctor's only going to give them a prescription for hormones, they have other options.