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Vasomotor symptoms (VMS) are common, bothersome, and can persist for years before and after menopause. Recently, Johnson et al. [1] published the results of SKYLIGHT 2, a phase 3 double-blind placebo controlled RCT aimed at assessing the efficacy and safety of fezolinetant for the treatment of moderate-to-severe menopause related VMS. Women, age 40-65 years with a minimum mean of 7 moderate-to-severe VMS per day, were randomized to receive 12 weeks once-daily fezolinetant 30 mg, fezolinetant 45 mg or placebo. Those who completed 12 weeks were re-randomized to fezolinetant 30mg or 45 mg for 40 additional weeks. Primary endpoints were mean daily change of frequency and severity of VMS from baseline to W4 and W12. The study reported that both fezolinetant doses significantly reduced moderate-to-severe VMS frequency and severity at W4 and W12 in comparison to placebo. For VMS frequency, W4 least squares mean (SE) reduction vs placebo was: fezolinetant 30 mg, -1.82 (0.46; p < 0.001); 45 mg, -2.55 (0.46; p < 0.001); W12: 30 mg, -1.86 (0.55; p < 0.001); 45 mg, -2.53 (0.55; p < 0.001). For VMS severity (scale 0-3) results were: W4: 30 mg, -0.15 (0.06; p< 0.05); 45 mg, -0.29 (0.06; p < 0.001); W12: 30 mg, -0.16 (0.08; p <0.05); 45 mg, -0.29 (0.08; p < 0.001). Significant improvement in VMS frequency (30 and 45 mg) and severity (45 mg) was observed by W1 and was maintained through W12. Serious treatment-emergent adverse events were infrequent: 2%, 1%, and 0% of those receiving fezolinetant 30 mg, fezolinetant 45 mg, and placebo, respectively; liver function abnormalities were rare and transient. The authors concluded that daily fezolinetant 30 mg and 45 mg were efficacious and well-tolerated for the treatment of moderate-to-severe menopause related VMS.


Following the cessation of drug development of the NKB antagonist, pavinetant, due to safety concerns, the race was on. Pavinetant came out of the gate with promising findings regarding efficacy of a new nonhormonal therapy for menopausal symptoms in a small phase 2 crossover trial [2]. Pharmaceutical agents acting at the hypothalamic Kisspeptin, Neurokinin B, Dynorphin (KNDy) neuron complex were first recognized as potential therapies for menopausal VMS when it was discovered that postmenopausal hypertrophied KNDy neurons cross-talk with the adjacent hypothalamic thermoregulatory center [3,4]. The observation that KNDy neurons control the GnRH pulse generator [5] further elucidated the mechanism by which NKB antagonists decrease VMS, acting upstream from the GnRH pulse generator. It now appears the search for an effective NKB antagonist, that did not alter hepatic function, is nearing the finish line with fezolinetant.

The SKYLIGHT 2 report by Johnson et al. (n=500) [1] was quickly followed by the report of SKYLIGHT 1 (n=522) [6]. The combined evidence from these phase 3 RCTs is compelling and at the writing of this commentary, fezolinetant sits before the Food and Drug Administration (FDA) awaiting approval. With findings of a decrease of only 2.5 VMS per day above placebo reported in SKYLIGHT 2 [1], and a decrease of 3 VMS per day above placebo reported in SKYLIGHT 1 [6], efficacy of fezolinetant appears somewhat disappointing at first blush. Phase 2 RCT findings showed that fezolinetant decreased up to 5 VMS per day above placebo [7]. Why the inconsistent findings? First, Phase 3 trials often have less dramatic findings than their phase 2 counterparts, as doses may be lowered in phase 3 trials to diminish the risk of side effects. Second, SKYLIGHT 2 had a relatively high placebo effect (44%) as compared with a more modest placebo effect (33%) often observed in other VMS RCTs [8]. Finally, it should be pointed out that SKYLIGHT 2 participants had 11-12 moderate-to-severe hot flashes per day at baseline, a frequency and severity much greater than that experienced by the general population. SKYLIGHT 2 findings are representative of a subpopulation of individuals with the most extreme symptoms.

Regardless of the challenges in interpreting the findings of SKYIGHT 2, I hope that the FDA shares my enthusiasm for approval of fezolinetant. If so, post-marketing surveillance will be important, providing additional data on safety and efficacy for the general population. Opportunity will be ripe for a head-to-head trial comparing fezolinetant with the gold standard treatment, hormone therapy (HT). Postmenopausal estrogen therapy was FDA approved in 1942 [9], a time when FDA approvals for menopausal VMS interventions were less stringent. A Cochrane review, perhaps our best evidence-based summary of HT efficacy, demonstrated a decrease of only 2.6 mild, moderate, or severe VMS per day over placebo with a high placebo response rate (48%) [10]. Moving forward, investigations for VMS interventions will require head to head comparisons of HT and NKB antagonists in real world populations, bringing with them the possibility of crowning a new gold standard.

Susan D. Reed, MD, MPH
Professor Emeritus
Department of Obstetrics and Gynecology, Adjunct Epidemiology
University of Washington School of Medicine
Seattle, WA USA


  1. 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 Feb 3:dgad058.
  2. Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism rapidly improves vasomotor symptoms with sustained duration of action. Menopause. 2018;25(8):862-869.
  3. Rance NE, Young WS 3rd. Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology. 1991;128(5):2239-2247.
  4. Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. 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.
  5. Guerriero KA, Keen KL, Millar RP, Terasawa E. Developmental changes in GnRH release in response to kisspeptin agonist and antagonist in female rhesus monkeys (Macaca mulatta): implication for the mechanism of puberty. Endocrinology. 2012;153(2):825-836.
  6. Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet. 2023;401(10382):1091-1102.
  7. Depypere H, Timmerman D, Donders G, et al. Treatment of Menopausal Vasomotor Symptoms With Fezolinetant, a Neurokinin 3 Receptor Antagonist: A Phase 2a Trial. J Clin Endocrinol Metab. 2019;104(12):5893-5905.
  8. Reed SD, LaCroix AZ, Anderson GL, et al. Lights on MsFLASH: a review of contributions. Menopause. 2020;27(4):473-484.
  9. Center for Drug Evaluation and Research (CDER), Federal Drug Administration, Federal Register Volume 62, Number 152 (Thursday, August 7, 1997, Pages 42562-42575).
  10. Maclennan AH, Broadbent JL, Lester S, Moore V. Oral oestrogen and combined oestrogen/progestogen therapy versus placebo for hot flushes. Cochrane Database Syst Rev. 2004;2004(4):CD002978.

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