Fezolinetant

Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.^[5][6]

In September 2024, the US FDA added a warning to the prescribing label that fezolinetant can cause rare but serious liver injury.^[16]

In May 2017, fezolinetant had completed phase I and phase IIa clinical trials for hot flashes in postmenopausal females.^[14] Phase IIa trials in polycystic ovary syndrome patients are ongoing.^[14]

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.^[17][18]

Fezolinetant shows high affinity for and potent inhibition of the NK₃ receptor in vitro (K_i = 25 nM, IC₅₀Tooltip half-maximal inhibitory concentration = 20 nM).^[13] 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.^[13] 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.^[19] 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.^[20] 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.^[19][20]

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.^[21][22] This would seem to be independent of their actions on the hypothalamic–pituitary–gonadal axis and hence on sex hormone production.^[21][22] 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.^[21][22]

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.^[11] 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.^[11] Each trial ran a total of 52 weeks.^[11] The average age of the trial participants was 54 years old.^[11]

The FDA granted the application for fezolinetant priority review designation.^[11] The approval of Veozah was granted to Astellas Pharma US, Inc.^[11]