Fezolinetant Shows No CNS Safety Signal in Pooled Analysis of 3100 Women, With Marla Shapiro, CM

A pooled analysis of the phase 3 SKYLIGHT 1, 2, and 4 trials found low rates of central nervous system (CNS) adverse events with fezolinetant (Veozah), a selective neurokinin 3 (NK3) receptor antagonist approved for moderate to severe menopausal vasomotor symptoms (VMS).

Presented at the Endocrine Society (ENDO) Annual Meeting 2026 by Marla Shapiro, C.M., CCFP, MHSc, FRCPC, FCFP, MSCP, Professor in the Department of Family and Community Medicine at the University of Toronto, the analysis included > 3100 women followed for up to 52 weeks.

Rates of CNS adverse events were low and generally similar between fezolinetant and placebo, with no signal for depression, memory impairment, somnolence, abuse liability, or suicidal ideation or behavior. The findings help address questions about CNS safety that have accompanied fezolinetant since its introduction as the first non-hormonal, non-gabapentinoid treatment for VMS, given its central action within the hypothalamus.

The HCPLive content team spoke with Shapiro about the findings, their clinical relevance, and what they mean for women who cannot or choose not to use menopausal hormone therapy.

HCPLive: Can you provide a brief overview of your study and its findings?

Shapiro: What this looked at was the central nervous system safety effect of this NK3 antagonist, fezolinetant. Looking at all the data that we have out there, we looked at several things in terms of treatment-emergent adverse events, which were things like headache, dizziness, fatigue, and somnolence. I'm often asked about things like brain fog, which is a very popular term, but not a term that we actually can tease out — that may come in under things like effect on memory, which is another CNS safety adverse event that we looked at.

When we looked at these treatment-emergent adverse events, be they headache, dizziness, fatigue, or somnolence, what we found was that compared to our placebo group, or our 45 mg treatment — that's our on-label dose, which came to North America and everywhere all over the world — there was really no significant differences in the drug-related treatment-emergent adverse events in each of those categories. For example, if you look at things like headache in our placebo group, of about the 7.5 to 8% that we saw, about less than 3% were thought to be related to the drug as adjudicated by our adjudicators. If you look at fezolinetant, you see the exact same thing — the same treatment-emergent adverse events of headaches were about 8.2%, but only 2.3% were thought to be related to the drug. The same is true for dizziness, fatigue, and somnolence.

One thing that's really important is that the incidence of these effects — whether they're fatigue or dizziness or headache or somnolence or mood changes — they really did not lead to treatment withdrawal. We also did the Columbia Suicide Severity Rating Scale, and there was really no treatment effect of fezolinetant on suicidal ideation or behavior. So really, when we look at the safety-reported events in any of the treatment arms, including the 30 mg that didn't come to market, what we saw was a remarkable similarity between all of them. There really was nothing that we saw in any of the exposure-adjusted incidence rates in these particular areas that were identified as so-called central nervous system safety concerns.

HCPLive: Fezolinetant represents a different therapeutic approach for vasomotor symptoms, targeting neurokinin 3 receptors rather than estrogen pathways. What motivated the need to specifically examine central nervous system safety, and what were the key concerns clinicians had when this mechanism was introduced?

Shapiro: Whenever this is our first on-label, non-hormonal option, understanding what hot flashes and vasomotor symptoms are — we now understand the relationship between stimulation and antagonism of both estrogen and neurokinin B at the level of the KNDy neuron. We now understand that when estrogen is withdrawn in menopause, you get overstimulation of the KNDy neuron because of the neurokinin impact in terms of the receptor. So the notion of developing a drug with a targeted mechanism of action is very exciting for women who cannot, will not, or do not want to use menopausal hormone therapy, which typically has been used as the on-label gold standard.

This represents novel science and on-label new therapeutics. And I think that when a new therapeutic comes, everybody wants to know the same thing: does it work? Is it safe? Does it work? Yes — we saw marked reductions as early as one week in both the frequency of hot flashes and, of the residual hot flashes, the severity. So now you want to know, what about safety? And people say, well, this is a brain mechanism, this is working in the brain. So are there CNS safety signals we should be aware of, because we're talking about the hypothalamus and the medial preoptic nucleus, which is where these receptors are. So it was important to be able to do the data work to look at the typical CNS safety signals that one would expect — things like fatigue, dizziness, headache, and somnolence. We wanted to make sure there was no signaling or alarm telling us that there are CNS events here that are impacting these women, particularly when it comes to, for example, next-day somnolence, or next-day fatigue, or dizziness, or headache. And it's very reassuring that, particularly in the placebo and the fezolinetant 45 mg, which is the dose that came to market, we really do not see any treatment-emergent adverse events related to the medication versus placebo.

HCPLive: This pooled analysis of SKYLIGHT 1, 2, and 4 included more than 3,000 women and found similar rates of CNS adverse events across groups. Which findings do you consider most clinically meaningful?

Shapiro: I think what's clinically meaningful is all of it. If we look at things like effect on memory — women often talk about brain fog, and that's one of the things they worry about. You want to make sure that the medication you're using is not exacerbating what one typically associates with menopause, and even late perimenopause. The fact that there was no change in depression, no change in dizziness or headache, or next-day fatigue or somnolence — these are critical for us to be able to say to women that the things you're concerned about, in terms of quality of life, are not going to be exacerbated by the medication you're using.

We know this medication will separate out very quickly in terms of responders. As early as week one, we saw a 61% reduction in the frequency of hot flashes, and then of the residual hot flashes that remain, we saw marked decreases in severity. So being able to answer the questions about safety is very important for women. They want to know: does it work? Is it safe? Those are the two big questions that everybody has.

HCPLive: How do these safety findings affect your approach when considering fezolinetant for women who cannot or prefer not to use menopausal hormone therapy?

Shapiro: The elegant science behind the NK3 antagonist is just so exciting, because it allows us to understand the mechanism of action of what a hot flash and a night sweat actually is. We never knew that before. By having this very elegant science — recognizing that when estrogen is removed, the agonist activity on the KNDy neurons means that having antagonists at the NK3 receptors blocks this overstimulation, and therefore makes a difference in hot flashes and night sweats — is just so exciting.

For many women who are either a hormone caution or a hormone contraindication, but also women who see themselves as not wanting menopausal hormones as their therapeutic option, this opens the doorway to an effective medication. And having safety data allows us to say safe and effective — which is the goal of any new therapeutic.

HCPLive: Are there particular patient populations — such as women with a history of mood disorders, sleep disturbances, or sensitivity to CNS-active medications — where these data are especially relevant?

Shapiro: One would imagine that when you identify that population, you want to make sure you're not going to give them a medication that's going to exacerbate something that may be pre-existing. These are not contraindications to using the medication, and the fact that these were not exclusion criteria for women who entered into the study is meaningful. Given the large number of women in the study and the randomization, you often have women with these concerns already represented. It's very difficult to tease them out because they're non-entrance criteria.

So one would imagine that if we do not see a difference in any of these red-flag events in either the placebo group or the pooled analysis of SKYLIGHT 1, 2, and 4 — which is a very large, representative sample of women in that age group — I think that we can be very reassured.

HCPLive: In clinical practice, many menopausal symptoms overlap with mood changes, sleep disruption, and cognitive concerns. How should clinicians distinguish underlying menopausal symptoms from potential treatment-related effects when evaluating these patients?

Shapiro: The first question before that question is, how do we evaluate women to know whether something is related to a menopause symptom or is it comorbid and pre-existing — and often that's very difficult to do. For many women who come in with multiple symptoms, many of which may or may not be exacerbated by menopause, what we talk about is: what is our goal of treatment? Our goal of treatment is usually, in women who are having 30, 40, 50 hot flashes, to reduce the frequency and the severity so that they can be in the workplace, not be disrupted in their activities of daily living.

So I think that's what we focus on, and to be able to say to them that we don't have any evidence that this medication will exacerbate any of these underlying symptoms. We'll have to see — as your hot flashes and night sweats get better, does your mood get better? We know from the PROMISE data that there is improvement in sleep. Does the improvement in sleep improve some of these other symptoms, or are they really comorbid conditions that merit treatment in and of themselves, separate from their hot flashes and sweats?

Editor’s Note: Shapiro reports relevant disclosures with Astellas Pharmaceuticals and others.

References

1. Shapiro M. Central Nervous System Safety of Fezolinetant From Pooled Analysis of 52-Week, Phase 3 Studies (SKYLIGHT 1, 2, and 4). Presented at: ENDO 2026; June, 2026; Chicago, IL.

2. Kagan R, Cano A, Nappi RE, et al. Safety of Fezolinetant for Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause: Pooled Analysis of Three Randomized Phase 3 Studies. Adv Ther. 2025;42:1147-1164. doi:10.1007/s12325-024-03073-8.