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Summary

In a recent article published in Menopause, the effects of NT-814 (a dual NK1/3R antagonist) were studied in menopausal women, In a randomized, double-blind, placebo-controlled study of 2 weeks duration, NT-814 treatment was compared to placebo. NT-814 reduced hot flush frequency by 84% (vs 39% placebo) and waking due to night sweats reduction by 81% (vs 32% placebo) [1]. The drug was well tolerated with no safety concerns. A limitation of this study is that the duration of treatment was only two weeks. However, NT-814 has now been tested in a further randomized, double-blind, placebo-controlled 12-week study in menopausal women. This study showed that NT-814 significantly reduces hot flush frequency, improves sleep, mood and quality of life. There were no safety concerns and, importantly, there was no adverse liver signal [2].

Commentary

Menopause is associated with highly disruptive and intolerable vasomotor symptoms (e.g. hot flushes or flashes or night sweats), which impact around 80% of women and are long-lasting. Consequently, their significant burden on physical and psychosocial health makes them a major problem women desperately seek treatment for. Guidelines currently recommend hormone replacement therapy (HRT) as first-line; however, many women cannot take HRT due to safety and tolerability concerns, including venous thromboembolism, breast and endometrial cancer. Other treatments, including paroxetine, gabapentin, tibolone, cognitive behavioural therapy and herbal remedies, have limited efficacy, which has led to the demand for non-hormonal pharmacological therapies [3,4]. Recent compelling data show that the NKB/NK3R (neurokinin B/ Neurokinin-3-receptor) signalling pathway is implicated in the etiology of menopausal hot flushes. Neurokinin binds to the NK3R to mediate its effects. In postmenopausal women, NKB gene expression is increased, indicating that estrogen deficiency overstimulates this pathway. Furthermore, infusions of NKB agonists have been shown to generate various heat dissipation responses [5-7]. Therefore, NK3R antagonists could act as a novel non-hormonal therapeutic agent in alleviating these troublesome symptoms. To date, three NK3R antagonists have been tested in clinical trials of menopausal patients with hot flushes: pavinetant (MLE4901), fezolinetant (ESN364) and NT-814. Prague et al. conducted the first study showing pavinetant significantly reduced the number and severity of hot flushes by 45% above the effects of placebo [3, 8]. However, concerns regarding its association with rising liver transaminases resulted in its discontinuation. Depypere and colleagues subsequently demonstrated that fezolinetant significantly reduces vasomotor symptom (VMS) episodes by 5 per day [9], which is greater than what Food and Drug Administration (FDA) deems clinically relevant. Furthermore, symptom benefits were achieved following the first dose, indicating rapid action, and were sustained. Although some liver abnormalities were observed, no Hy’s law cases (used by FDA to determine severe drug-induced liver injury) were identified; and importantly, no adverse events occurred [9, 10]. Menopausal hot flushes severely impact the physical and mental wellbeing of millions of women worldwide. Current treatments have poor efficacy and safety profiles. NK3R antagonists are emerging as a superior novel non-hormonal agents as they provide rapid and sustained relief of hot flushes and are well tolerated.
Dr Bijal Patel, Specialist Registrar, Imperial College Healthcare NHS Trust

Professor Waljit S Dhillo, NIHR Research Professor, Imperial College London

Disclosure

Professor Waljit S. Dhillo is consultant for KnDY therapeutics

References

  1. Trower M, Anderson RA, Ballantyne E, Joffe H, Kerr M, Pawsey S. Effects of NT-814, a dual neurokinin 1 and 3 receptor antagonist, on vasomotor symptoms in postmenopausal women: a placebo-controlled, randomized trial. Menopause. 2020;27(5):498-505. https://pubmed.ncbi.nlm.nih.gov/32068688/
  2. Simon J, Anderson -RA, Ballantyne E, Joffe H, Kerr M, Seymore S, Trower M, Pawsey S. OR11-03 NT-814, a Non-Hormonal Dual Neurokinin 1,3 Receptor Antagonist Markedly Improves Vasomotor Symptoms in Post-Menopausal Women; Results of a Randomised, Double-Blind, Placebo-Controlled, Dose-Finding Study (SWITCH-1), Journal of the Endocrine Society, Volume 4, Issue Supplement_1, April-May 2020, OR11–03.
  3. Prague JK, Roberts RE, Comninos AN, et al. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10081):1809-1820.https://pubmed.ncbi.nlm.nih.gov/28385352/
  4. Depypere H, Timmerman D, Donders G, et al. Clinical evaluation of the NK3 receptor antagonist fezolinetant (a.k.a. ESN364) for the treatment of menopausal hot flashes’, Maturitas. Elsevier, 2017; 103, pp. 89–90.
  5. 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. https://pubmed.ncbi.nlm.nih.gov/1708331/
  6. Dacks PA, Krajewski SJ, Rance NE. Activation of neurokinin 3 receptors in the median preoptic nucleus decreases core temperature in the rat. Endocrinology. 2011;152(12):4894-4905.https://pubmed.ncbi.nlm.nih.gov/22028440/
  7. Jayasena CN, Comninos AN, Stefanopoulou E, et al. Neurokinin B administration induces hot flushes in women. Sci Rep. 2015;5:8466. https://pubmed.ncbi.nlm.nih.gov/25683060/
  8. 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. https://pubmed.ncbi.nlm.nih.gov/29533369/
  9. 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. https://pubmed.ncbi.nlm.nih.gov/31415087/
  10. Fraser GL, Lederman S, Waldbaum A, et al. A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause. Menopause. 2020;27(4):382-392. https://pubmed.ncbi.nlm.nih.gov/32102086/
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