What data is available to support the use of neurokinin 3 (NK3) receptor antagonists for the management of vasomotor symptoms related to menopause?

Introduction
In North America, the average age of menopause is approximately 51 years of age.^1,2 Defined as 12 consecutive months without menses, menopause is the natural and permanent cessation that occurs as a result of the loss of ovarian hormone production. Following the onset of menopause, women may experience a constellation of symptoms including sleep disturbances, mood changes, impaired memory and concentration, genitourinary syndrome of menopause, and vasomotor symptoms (VMS).

Vasomotor symptoms, commonly referred to as hot flashes or night sweats, are the most prevalent menopausal complaint, affecting up to 80% of women.^1-3 Many of these women experience daily VMS, which may persist for an average of 7 to 9 years, and in one-third of women, can last more than 10 years. Vasomotor symptoms result in a substantial negative impact on quality of life, resulting in physical and psychosocial impairment affecting work performance, social activities, and personal and social relationships.

The pathophysiology surrounding VMS is not fully understood, and likely multifactorial.^1,2 The reduction in reproductive hormones (estrogen and progesterone) appear to play a role in the thermoregulatory zone of the hypothalamus. Additionally, the thermoregulatory zone may adapt and become more sensitive to changes in core body temperature, which may cause the sensation of a hot flash. There are several neurons and neurotransmitters hypothesized to play a role in VMS including serotonin, adrenal system, noradrenergic, and neurokinin (NK)-1 and NK-3 receptors.⁴ During the transition to menopause, alterations occur to some of these neurons, leading to thermoregulatory system disruptions and the development of VMS.

Standard of care for VMS
The overall goal for the treatment of menopausal related VMS is to reduce the frequency and severity, as well as improve the overall quality of life.^1,2 For women who have mild VMS, nonpharmacological treatment options alone can be considered. However, in women experiencing moderate to severe VMS, systemic hormone therapy (HT) with estrogen alone or in combination with progestin is regarded as the most effective treatment option. Some women may choose not to use HT or have contraindications to its use, such as history of an estrogen-sensitive cancer, coronary heart disease, myocardial infarction, stroke, venous thromboembolism, or inherited high risk of thromboembolic disease.³ For these women, nonhormonal pharmacologic evidence-based options may be useful to avoid HT for the treatment of VMS.

The North American Menopause Society published a position statement on nonhormone therapy in 2023.³ The guideline states only 2 medications were Food and Drug Administration (FDA) approved for reduction of VMS in menopause at the time of publication: paroxetine mesylate 7.5 mg daily (a selective serotonin reuptake inhibitor [SSRI]) and fezolinetant 45 mg daily (an NK-3 receptor antagonist), both with level I recommendations (defined as good and consistent scientific evidence). Fexolinetant, approved in 2023, was the first of its class.⁵ Off-label alternative medication classes include SSRIs other than paroxetine, serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin, and oxybutynin, all with level I recommendations.³ There is limited comparative data between nonhormone therapies.

The American College of Obstetrics and Gynecology published a practice bulletin on the management of menopausal symptoms in 2014.¹ Recommended nonhormonal medications for VMS included SSRIs, SNRIs, clonidine, and gabapentin. At the time of publication, NK receptor antagonists were not yet available. Since the publication of both guidelines, a dual NK-1 and NK-3 receptor antagonist, elinzanetant, was approved in 2025 for treatment of menopausal VMS.⁶

NK3 receptor antagonists
Neurokinin-3 receptor antagonists provide a novel and targeted nonhormonal approach for treating VMS.² Neurokinin B peptides bind to kisspeptin/neurokinin B/dynorphin (KNDy) neurons located in the hypothalamus, which play a role in regulating the thermoregulatory pathway. With the onset of menopause, declining estrogen levels lead to increased neurokinin B binding to the KNDy neurons, increasing signaling in the thermoregulatory center, resulting in symptoms of VMS. Through blockade of the NK-3 receptor, neurokinin B binding to KNDy neurons is reduced, leading to the decreased frequency and severity of VMS. Unlike hormone therapy, NK-3 receptor antagonists act independently of estrogen pathways, providing an effective treatment option for those who cannot or prefer not to use HT. The available evidence to support the use of NK-3 receptor antagonists for the management of VMS due to menopause is summarized below.

Clinical trial overview
Fezolinetant
The key clinical trials leading to the FDA-approval of fezolinetant included the SKYLIGHT 1 and SKYLIGHT 2 trials, which demonstrated a statistically and clinically significant decrease in moderate to severe VMS due to menopause compared to placebo after treatment for 4 and 12 weeks.⁵ AlBarakat et al (2025) published a systematic review and meta-analysis of 6 randomized controlled trials (RCTs), including the SKYLIGHT trials, evaluating the efficacy and safety of fezolinetant for VMS in postmenopausal women.⁷ Eligible studies compared fezolinetant with placebo and had a primary outcome investigating the change in frequency and severity of moderate to severe VMS. Secondary outcomes included quality of life scores reported using the Menopause-Specific Quality of Life (MENQol) score, various symptom scores, and adverse events.

Across these studies, 3657 participants were randomized to fezolinetant (up to 180 mg daily) or placebo.⁷ The mean age of participants was 54 years. Five of the studies showed a low risk of bias, while 1 study showed some concerns of bias based on lack of information regarding the randomization process. Fezolinetant, compared to placebo, significantly decreased VMS frequency at 4 weeks (mean difference [MD], -0.56; 95% confidence interval [CI], -0.79 to – 0.34; P <0.001) and at 12 weeks (MD, -0.54; 95% CI, -0.74 to -0.33; P < 0.001). Vasomotor symptom severity was also decreased with fezolinetant versus placebo at 4 weeks (MD, -0.54; 95% CI, -0.75 to -0.33; P < 0.001) and 12 weeks (MD, -0.34; 95% CI, -0.48 to -0.21; P < 0.001). The most common dosage used was 30 mg across all studies. The MENQol scoring was also significantly reduced with fezolinetant at doses of 30 and 45 mg (MD, -0.15; P = 0.04 and -0.3, P < 0.001, respectively), while other doses studied did not provide statistically significant differences.

Elinzanetant
The key clinical trials leading to the FDA-approval for elinzanetant included the OASIS 1 and OASIS 2 trials, which demonstrated a statistically and clinically significant decrease in moderate to severe VMS due to menopause compared to placebo after treatment for 4 and 12 weeks.⁶ Sobral et al (2025) published a systematic review and meta-analysis of 3 RCTs, including OASIS 1 and 2, evaluating the efficacy and safety of elinzanetant for VMS associated with menopause.⁸ Eligible studies compared elizanetant with placebo and reported at least 1 of the following primary endpoints: the change in frequency and/or severity of VMS, MENQol score, and/or Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form (PROMIS SD SF) score.

Across these studies, 995 participants were randomized to elinzanetant (40 to 120 mg daily) or placebo.⁸ The mean age of participants was 55 years. Included studies were assessed to have a low risk of bias. Elinzanetant, compared to placebo, significantly reduced the frequency (MD, – 3.09; 95 % CI, -4.18 to -2.01; P < 0.01) and severity (MD, -0.32; 95 % CI, -0.43 to -0.21; P < 0.01) of VMS by week 12 in all 3 trials. Elizanetant also demonstrated a better quality of life compared to placebo, using the MENQOL questionnaire score (MD, -0.46; 95 % CI, -0.62 to – 0.30; P < 0.01) and PROMIS SD SF score (MD, -5.40; 95 % CI, -6.48 to -4.32; P < 0.01).

Panay et al (2025) published results from OASIS-3, a 52-week extension trial on the OASIS-1 and OASIS-2 phase 3 clinical trials investigating elizanetent for treatment of menopausal VMS.⁹ The aim of OASIS-3 was to evaluate the efficacy of elinzanetant for the frequency of daily moderate to severe VMS in postmenopausal women at 50 weeks and other exploratory endpoints up to 52 weeks. The median age of participants was 55 years. Six-hundred and twenty-eight women were randomized to receive either elinzanetant 120 mg (n=313) or placebo (n=315) once daily. At their baseline, women reported a mean of 6.7 to 6.8 moderate to severe VMS events per day. By week 50, the mean VMS events per day was 1.4 (95% CI, 1.1 to 1.7) and 3.5 (95% CI, 2.8 to 4.2) in the elinzanetant group and placebo group, respectively. Significant quality of life scores with elinzanetant were maintained at 52 weeks.

Meta-analyses including both medications
De Oliveira et al (2025) published a systematic review and meta-analysis of efficacy and safety of fezolinteant and elinzanetant for VMS.¹⁰ Included studies were RCTs that compared either medication with placebo in women with moderate to severe VMS. Overall, 10 studies were included, comprising 4663 participants. Of the 10 studies, 3 were assessed to have some concerns with bias related to deviations from intended interventions and/or missing outcome data. Data analyses revealed elinzanetant (≥100 mg) and fezolinetant (≤45 mg) reduced VMS frequency at 12 weeks (MD, -2.83, 95% CI, -3.89 to -1.76, P <0.01; MD, -1.54, 95% CI, -2.94 to -0.14, P= 0.03, respectively). Severity of VMS was also reduced for elinzanetant (≥100 mg) and fezolinetant (≤45 mg) at 12 weeks (MD, – 0.34, 95% CI, -0.43 to -0.25, P <0.01; MD, -0.22, 95% CI, -0.31 to -0.14, P <0.01, respectively). Quality of life was improved with elinzanetant (≥100 mg) using MENQol scoring (MD, -0.42; P = 0.05). Higher doses of both drugs were associated with increased adverse effects, with elinzanetant demonstrating a significantly increased risk of treatment-related adverse effects compared to placebo.

There is a lack of comparative evidence with NK-3 receptor antagonists, HT, and other nonhormonal treatment options for VMS in menopause. This was addressed by Oliveira Amador et al (2025) who published a systematic review and Bayesian network meta-analysis of efficacy and safety of pharmacological treatments for VMS in menopause.¹¹ Eligible studies were phase 2 or 3 RCTs evaluating safety or efficacy with a follow-up period of at least 12 weeks and including women experiencing moderate to severe VMS. The primary outcome was the mean change from baseline to week 12 in the average daily frequency and severity of VMS.

Of 2632 articles reviewed for inclusion and exclusion criteria, 186 were included, totaling 14453 participants, with a mean age of 53 years.¹¹ Treatments in meta-analyses included HT and nonhormone therapies such as desvenlafaxine, gabapentin, paroxetine, and the NK-3 receptor antagonists (4 trials with fezolinetant, 2 trials with elinzanetant). Twenty-two studies had a low risk of bias, while 19 had some concerns for bias. Elinzanetant 120 mg was the nonhormonal treatment option with the highest probability of reducing VMS frequency based on Surface Under the Cumulative Ranking Curve (SUCRA) efficacy rankings (SUCRA=0.512), followed by fezolinetant (SUCRA=0.346; moderate efficacy). Fezolinetant 45 mg (SUCRA=0.432) and elinzanetant 120 mg (SUCRA=0.345) demonstrated moderate efficacy for reduction of VMS severity, ranking below desvenlafaxine 200 mg (SUCRA=0.483). Compared to HT, neither medication demonstrated superior efficacy in reduction of VMS frequency or severity.

Compared with placebo, elinzanetant 120 mg, fezolinetant 45 mg, and fezolinetant 30 mg all significantly reduced the frequency of VMS symptoms.¹¹ However, elinzanetant (MD, -0.20; 95% CI, -0.39 to 0.00) and fezolinetant 30 mg (MD, 0.17; 95% CI, -0.34 to 0.00) did not significantly reduce the severity of VMS compared to placebo; fezolinetant 45 mg did significantly reduce the severity (MD, -0.25; 95% CI, -0.42 to -0.07).

Conclusion
Neurokinin-3 receptor antagonists represent an important and expanding advancement in nonhormonal treatments for menopausal VMS. Fezolinetant and elinzanetant have demonstrated clinically meaningful reductions in both VMS frequency and severity, with the added benefit of improving quality of life in key clinical trials. Comparative effectiveness against other nonhormonal treatment options is limited to a single meta-analysis, which demonstrated that NK-3 receptor antagonists were the most effective nonhormonal treatment options for decreasing VMS severity and frequency.

References

1. ACOG practice bulletin no. 141: management of menopausal symptoms. Obstet Gynecol. 2014;123(1):22-216. doi: 10.1097/01.AOG.0000441353.20693.78
2. Dang DK, Chen JT. Menopause. In: Haines ST, Nolin TD, Ellingrod VL, Posey L, et al, eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 13th Edition. McGraw Hill; 2026. Accessed November 20, 2025. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3386§ionid=293563412
3. The 2023 nonhormone therapy position statement of the North American Menopause Society. Menopause. 2023;30(6):573-590. doi: 10.1097/GME.0000000000002200
4. Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky A, Krajewski-Hall S. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol. 2013;34(3):211-227. doi:10.1016/j.yfrne.2013.07.003
5. Veozah. Package Insert. Astellas Pharma US, Inc.; 2024.
6. Lynkuet. Package Insert. Bayer HealthCare Pharmaceuticals Inc.; 2025.
7. AlBarakat MM, Feras AlSamhori J, Abdelaziz A, et al. Efficacy and safety of fezolinetant for vasomotor symptoms in postmenopausal women: a comprehensive systematic review and meta-analysis of randomized controlled trials. Proc (Bayl Univ Med Cent). 2025;38(4):535-546. doi: 10.1080/08998280.2025.2491894
8. Sobral MVS, Rocha P, Rodrigues LK, et al. Efficacy and safety of elinzanetant in vasomotor symptoms associated with menopause: a meta-analysis of randomized controlled trials. Eur J Obstet Gynecol Reprod Biol. 2025;307:142-147. doi: 10.1016/j.ejogrb.2025.01.050
9. Panay N, Joffe H, Maki PM, et al. Elinzanetant for the treatment of vasomotor symptoms associated with menopause: A phase 3 randomized clinical trial. JAMA Intern Med. 2025;185(11):1319-1327. doi: 10.1001/jamainternmed.2025.4421
10. de Oliveira HM, Diaz CAV, Barbosa LM, Flávio-Reis VHP, Zamora FV, Gonçalves Barbosa Júnior O. Efficacy and safety of fezolinetant and elinzanetant for vasomotor symptoms in postmenopausal women: a systematic review and meta-analysis. Maturitas. 2025;195:108220. doi: 10.1016/j.maturitas.2025.108220
11. Oliveira Amador WF, Saraiva CA, Ruelas MG, et al. Pharmacological treatments for menopausal vasomotor symptoms: a systematic review and Bayesian network meta-analysis of efficacy and safety. Eur J Obstet Gynecol Reprod Biol. 2025;312:114552. doi: 10.1016/j.ejogrb.2025.114552

Prepared by:
Piper Spengel
PharmD Candidate Class of 2026
University of Illinois Chicago Retzky College of Pharmacy

January 2026

The information presented is current as of November 12, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.