Fezolinetant

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Fezolinetant
Above: molecular structure of fezolinetant Below: 3D representation of a fezolinetant molecule
Clinical data
Trade namesVeozah, Veoza
Other namesESN-364
AHFS/Drugs.comMonograph
MedlinePlusa623051
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding51%[8][unreliable medical source?]
MetabolismCYP1A2, (CYP2C9, CYP2C19 to lesser extent)[5]
MetabolitesES259564[9]
Elimination half-life9.6h[5]
ExcretionUrine 76.9%, feces 14.7%[10][unreliable medical source?]
Identifiers
  • (4-fluorophenyl)-[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]methanone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
CompTox Dashboard (EPA)
  • {{#property:P3117}}Lua error in Module:EditAtWikidata at line 29: attempt to index field 'wikibase' (a nil value).
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Chemical and physical data
FormulaC16H15FN6OS
Molar mass358.40 g·mol−1
3D model (JSmol)
  • C[C@@H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C
  • InChI=1S/C16H15FN6OS/c1-9-13-19-20-14(15-18-10(2)21-25-15)23(13)8-7-22(9)16(24)11-3-5-12(17)6-4-11/h3-6,9H,7-8H2,1-2H3/t9-/m1/s1
  • Key:PPSNFPASKFYPMN-SECBINFHSA-N

Fezolinetant, sold under the brand name Veozah, among others, is a medication used for the treatment of hot flashes (vasomotor symptoms) due to menopause.[5][11] It is a small-molecule, selective neurokinin-3 (NK3) receptor antagonist taken by mouth.[5] It was developed by Astellas Pharma, which acquired it from Ogeda (formerly Euroscreen) in April 2017.[12][13][14]

The most common side effects of fezolinetant include abdominal pain, diarrhea, insomnia, back pain, hot flush, and elevated hepatic transaminases.[11]

Fezolinetant was approved for medical use in the United States in May 2023,[11] and it was approved in the European Union in December 2023.[6][7] Fezolinetant is the first NK3 receptor antagonist approved by the US Food and Drug Administration (FDA) to treat moderate to severe hot flashes from menopause.[11] The FDA considers it to be a first-in-class medication.[15]

Medical uses

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

Adverse effects

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

History

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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 (Ki = 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]

Society and culture

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In October 2023, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Veoza, intended for the treatment of hot flushes (vasomotor symptoms) associated with menopause.[6] The applicant for this medicinal product is Astellas Pharma Europe B.V.[6]

Fezolinetant was approved for medical use in the United States in May 2023,[11] and in the European Union in December 2023.[6][7]

Brand names

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Fezolinetant is the international nonproprietary name.[23]

Fezolinetant is sold under the brand names Veozah and Veoza.[5][6]

References

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