Fezolinetant

Fezolinetant, sold under the brand name Veozah, is a medication used for the treatment of hot flashes (vasomotor symptoms) due to menopause. It is a small-molecule, orally active, selective neurokinin-3 (NK3) receptor antagonist which is under development by for the treatment of sex hormone-related disorders. It is developed by Astellas Pharma which acquired it from Ogeda (formerly Euroscreen) in April 2017.
The most common side effects include abdominal pain, diarrhea, insomnia, back pain, hot flush and elevated hepatic transaminases.
Fezolinetant was approved for medical use in the United States in May 2023. Fezolinetant is the first neurokinin 3 (NK3) receptor antagonist approved by the US Food and Drug Administration (FDA) to treat moderate to severe hot flashes from menopause.
Medical uses
Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.
History
In May 2017, fezolinetant had completed phase I and phase IIa clinical trials for hot flashes in postmenopausal females. Phase IIa trials in polycystic ovary syndrome patients are ongoing.
In March 2023, results from SKYLIGHT 1, a Phase III clinical study of the treatment of moderate to severe hot flashes due to menopause, were published in The Lancet.
Fezolinetant shows high affinity for and potent inhibition of the NK3 receptor in vitro (Ki = 25 nM, = 20 nM). Loss-of-function mutations in TACR and TACR3, the genes respectively encoding neurokinin B and its receptor, the NK3 receptor, have been found in patients with idiopathic hypogonadotropic hypogonadism. In accordance, NK3 receptor antagonists like fezolinetant have been found to dose-dependently suppress luteinizing hormone (LH) secretion, though not that of follicle-stimulating hormone (FSH), and consequently to dose-dependently decrease estradiol and progesterone levels in females and testosterone levels in males. As such, they are similar to GnRH modulators, and present as a potential clinical alternative to them for use in the same kinds of indications. However, the inhibition of sex hormone production by NK3 receptor inactivation tends to be less complete and "non-castrating" relative to that of GnRH modulators, and so they may have a reduced incidence of menopausal-like side effects such as loss of bone mineral density.
Unlike GnRH modulators, but similarly to estrogens, NK3 receptor antagonists including fezolinetant and MLE-4901 (also known as AZD-4901, formerly AZD-2624) have been found to alleviate hot flashes in menopausal females. This would seem to be independent of their actions on the hypothalamic–pituitary–gonadal axis and hence on sex hormone production. NK3 receptor antagonists are anticipated as a useful clinical alternative to estrogens for management of hot flashes, but with potentially reduced risks and side effects.
The effectiveness of Veozah to treat moderate to severe hot flashes was demonstrated in each of the first 12-week, randomized, placebo-controlled, double-blind portions of two phase III clinical trials. In both trials, after the first 12 weeks, the females on placebo were then re-randomized to Veozah for a 40-week extension study to evaluate safety. Each trial ran a total of 52 weeks. The average age of the trial participants was 54 years old.
The FDA granted the application for fezolinetant priority review designation. The approval of Veozah was granted to Astellas Pharma US, Inc.
References
Antigonadotropins
Fluoroarenes
NK3 receptor antagonists
Thiadiazoles
Triazolopyrazines
N-benzoylpiperazines