About 80% of women experience vasomotor symptoms (VMS) – hot flashes and night sweats — as they transition into the menopause.  For most, the symptoms are manageable, but for a about 1 out of 3 perimenopausal women, vasomotor symptoms are severe and can negatively affect sleep, mood, and quality of life.  While clinical guidelines suggest that menopausal vasomotor symptoms (VMS) typically last from 6 months to 2 years, new research suggests that for many women, the duration of symptoms is much longer, with many women experiencing vasomotor symptoms over a period of 5 or more years.  Given the number of perimenopausal women experiencing significant, troublesome, and sometimes disabling symptoms, there is   a clear need for interventions that are both safe and well-tolerated over long-term use. 

It is postulated that the variable and ultimately falling levels of estrogen that a woman experiences as she transitions into the menopause are responsible for vasomotor symptoms.  However, exactly how changes in estrogen levels lead to these symptoms is not fully understood. Most recently, the neurokinin signaling pathway, which is involved in thermoregulation, has been implicated in the development of vasomotor symptoms, and researchers are now exploring the potential of pharmacologic agents which modulate NKB activity to ameliorate menopausal symptoms.  

Neurokinin 3 receptor (NK3R) antagonists belong to a new class of medications being developed for the treatment of vasomotor symptoms.  NK3 receptor antagonists bind to and block NK3 receptors in the hypothalamus.  In May 2023, the U.S. Food and Drug Administration approved the first NK3 receptor antagonist, fezolinetant (marketed as Veozah), for the treatment of moderate to severe vasomotor symptoms in peri- and post-menopausal women.

Last week Bayer submitted a New Drug Application for elinzanetant (BAY-3427080; Bayer), another NK3 receptor antagonist for the treatment of moderate-to-severe vasomotor symptoms in menopausal women.  This submission follows on the heels of positive safety and efficacy results from the Phase 1, Phase 2, and Phase 3 OASIS studies (presented at the 2024 American College of Obstetricians and Gynecologists Annual Clinical & Scientific Meeting in May).  Data from the OASIS studies have not yet been published in a peer-reviewed publication.  

Elinzanetant is the first dual neurokinin-1 and 3 receptor antagonist.This differs from other treatment options such as fezolinetant which is only a neurokinin-3 receptor antagonist. Neurokinin-1 (NK-1) receptor antagonists are currently used for the treatment of nausea and vomiting associated with chemotherapy, however, NK-1 receptor antagonists have distinct anxiolytic and antidepressant properties.  In another study (NIRVANA), the efficacy of elinzanetant for sleep disturbances associated with menopause is being evaluated.

Because the NK3R antagonists are a new type of drug, further studies are required to establish the long-term safety of this class of medication.  Phase 2 studies with MLE4901 (another NK-3 receptor antagonist were discontinued because some women experienced transient elevations of liver transaminase enzymes. Other, structurally dissimilar, NK3R antagonists have not demonstrated any liver toxicity, and it is believed that the elevation in transaminases reported with MLE4901 may be an idiosyncratic effect related to its chemical structure rather than a class effect of NK3R antagonists as a whole. One of the OASIS studies has followed women for 52 weeks to establish long-term safety.

Further studies will help to further clarify the effectiveness and safety profile of the NK3R antagonists in peri- and postmenopausal women.

Ruta Nonacs, MD PhD

References:

Bayer submits New Drug Application to U.S. FDA for elinzanetant for the treatment of moderate to severe vasomotor symptoms associated with menopause. Bayer. August 1, 2024. 

Krewson C. New data shows elinzanetant’s efficacy in treating menopausal symptoms. May 18, 2024.

Modi M, Dhillo WS.  Neurokinin 3 Receptor Antagonism: A Novel Treatment for Menopausal Hot Flushes.  Neuroendocrinology. 2019; 109(3):242-248. 

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 May 6;389(10081):1809-1820. Free Article

Simpson P, Currie H, Morris E.  Neurokinin 3 receptor antagonism – Is this the end of HRT?  Post Reprod Health. 2018 Jun;24(2):61-62.