Fezolinetant

Vasomotor symptoms (VMS), more colloquially known as hot flashes or night sweats, are the most common symptoms, if not the cardinal symptoms, in women. With a median duration of 7.4 years, vasomotor symptoms are also the most common reasons why women seek treatments for menopausal issues. Although mostly considered a nuisance, vasomotor symptoms could potentially affect the quality of life, as women with 7 or more daily moderate to severe VMS reported a decline in sleep quality, concentration, sexual activity, energy, and concentration.

Although the pathophysiology of VMS is not fully understood, unpredictable fluctuation of estrogen level is thought to be the main cause of VMS, as estrogen therapy has been one of the most effective treatments for VMS by relieving symptoms in as many as 95% of menopausal women. Women undergoing abrupt menopause due to oophorectomy also experienced more severe symptoms than those going through a gradual transition. Additionally, thermoregulatory dysfunction has been proposed as one of the three possible mechanisms for VMS in menopause. Estrogen is a potent neuromodulator, particularly in the hypothalamus, and has been shown to be involved as a negative regulator in generating Gonadotropin-releasing hormone (GnRH) pulse through the kisspeptin, neurokinin B, and dynorphin (KNDy) neurons. NK3, one of the receptors expressed in KNDy neurons, is activated by neurokinin B and can thus induce the release of GnRH. Lower estrogen levels during menopause will decrease the estrogen-mediated feedback loop and increase neurokinin B signalling, increasing the activity of KNDy neurons and therefore the activity of the temperature control center. By antagonizing NK3 receptors, neuronal signalling can be dampened to reduce VMS.

Although hormone therapy is available for menopausal women, safety and tolerability concerns, such as an increased risk of stroke and venous thromboembolism or hormone-dependent cancer like breast cancer, can prevent some women from receiving this treatment. Fezolinetant, an NK3 receptor antagonist, was developed in response to this issue as well as more understanding of the role of NK3R in the hypothalamic-pituitary-gonadal (HPG) axis. Although previous NK3 receptor antagonists exist, such as osanetant and talnetant, only fezolinetant showed tangible effects on the HPC axis, potentially due to its favorable pharmacokinetics profile to cross the blood-brain barrier.

Fezolinetant is approved by the FDA in May 2023 under the brand name VEOZAH.