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Fezolinetant

December 15, 2023

Fezolinetant, sold under the brand name Veozah, is a medication used for the treatment of hot flashes (vasomotor symptoms) due to menopause.[5] 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.[6][7][8]

Fezolinetant
Clinical data
Trade namesVeozah
Other namesESN-364
License data
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding51%[2][unreliable medical source?]
MetabolismCYP1A2, (CYP2C9, CYP2C19 to lesser extent)[1]
MetabolitesES259564[3]
Elimination half-life9.6h[1]
ExcretionUrine 76.9%, feces 14.7%[4][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
  • 1629229-37-3
PubChem CID
  • 117604931
DrugBank
  • DB15669
ChemSpider
  • 58828046
UNII
  • 83VNE45KXX
KEGG
  • D11976
ChEMBL
  • ChEMBL3608680
Chemical and physical data
FormulaC16H15FN6OS
Molar mass358.40 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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

The most common side effects include abdominal pain, diarrhea, insomnia, back pain, hot flush and elevated hepatic transaminases.[5]

Fezolinetant was approved for medical use in the United States in May 2023.[5] 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.[5]

Medical uses edit

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

History edit

In May 2017, fezolinetant had completed phase I and phase IIa clinical trials for hot flashes in postmenopausal females.[8] Phase IIa trials in polycystic ovary syndrome patients are ongoing.[8]

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.[9][10]

Fezolinetant shows high affinity for and potent inhibition of the NK3 receptor in vitro (Ki = 25 nM, IC50 = 20 nM).[7] 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.[7] 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.[11] 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.[12] 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.[11][12]

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.[13][14] This would seem to be independent of their actions on the hypothalamic–pituitary–gonadal axis and hence on sex hormone production.[13][14] 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.[13][14]

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.[5] 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.[5] Each trial ran a total of 52 weeks.[5] The average age of the trial participants was 54 years old.[5]

The FDA granted the application for fezolinetant priority review designation.[5] The approval of Veozah was granted to Astellas Pharma US, Inc.[5]

References edit

  1. ^ a b c "Veozah – fezolinetant tablet, film coated". DailyMed. 19 May 2023. from the original on 25 May 2023. Retrieved 24 May 2023.
  2. ^ "Fezolinetant".
  3. ^ https://classic.clinicaltrials.gov/ct2/show/NCT04793204
  4. ^ "Fezolinetant". DrugBank.com.
  5. ^ a b c d e f g h i j k "FDA Approves Novel Drug to Treat Moderate to Severe Hot Flashes Caused by Menopause". U.S. Food and Drug Administration (FDA) (Press release). 12 May 2023. from the original on 13 May 2023. Retrieved 13 May 2023.   This article incorporates text from this source, which is in the public domain.
  6. ^ "Astellas to Acquire Ogeda SA" (Press release). Astellas Pharma. from the original on 5 November 2021. Retrieved 5 November 2021 – via PR Newswire.
  7. ^ a b c Hoveyda HR, Fraser GL, Dutheuil G, El Bousmaqui M, Korac J, Lenoir F, et al. (July 2015). "Optimization of Novel Antagonists to the Neurokinin‑3 Receptor for the Treatment of Sex-Hormone Disorders (Part II)". ACS Medicinal Chemistry Letters. 6 (7): 736–740. doi:10.1021/acsmedchemlett.5b00117. PMC 4499830. PMID 26191358.
  8. ^ a b c "Fezolinetant – Ogeda". AdisInsight. from the original on 5 November 2021. Retrieved 5 November 2021.
  9. ^ Lederman S, Ottery FD, Cano A, Santoro N, Shapiro M, Stute P, et al. (April 2023). "Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study". The Lancet. 401 (10382): 1091–1102. doi:10.1016/S0140-6736(23)00085-5. PMID 36924778. S2CID 257498379.
  10. ^ "A Study to Find Out if Fezolinetant Helps Reduce Moderate to Severe Hot Flashes in Women Going Through Menopause (Skylight 1)". ClinicalTrials.gov. U.S. National Institutes of Health. 13 July 2022. from the original on 29 March 2023. Retrieved 29 March 2023.
  11. ^ a b Fraser GL, Ramael S, Hoveyda HR, Gheyle L, Combalbert J (2016). "The NK3 Receptor Antagonist ESN364 Suppresses Sex Hormones in Men and Women". J. Clin. Endocrinol. Metab. 101 (2): 417–26. doi:10.1210/jc.2015-3621. PMID 26653113.
  12. ^ a b Fraser GL, Hoveyda HR, Clarke IJ, Ramaswamy S, Plant TM, Rose C, et al. (2015). "The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle". Endocrinology. 156 (11): 4214–25. doi:10.1210/en.2015-1409. PMID 26305889.
  13. ^ a b c "Gone in a Flash: New Drug Class Targets Menopause Symptom". Medscape. from the original on 12 May 2017. Retrieved 29 April 2017.
  14. ^ a b c "Ogeda Announces Positive Data From Phase IIa Trial Of Fezolinetant In The Treatment Of Menopausal Hot Flashes". www.clinicalleader.com. from the original on 6 January 2017. Retrieved 29 April 2017.

December 15, 2023
fezolinetant, sold, under, brand, name, veozah, medication, used, treatment, flashes, vasomotor, symptoms, menopause, small, molecule, orally, active, selective, neurokinin, receptor, antagonist, which, under, development, treatment, hormone, related, disorder. Fezolinetant sold under the brand name Veozah is a medication used for the treatment of hot flashes vasomotor symptoms due to menopause 5 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 6 7 8 FezolinetantClinical dataTrade namesVeozahOther namesESN 364License dataUS DailyMed FezolinetantRoutes ofadministrationBy mouthATC codeG02CX06 WHO Legal statusLegal statusUS only 1 Pharmacokinetic dataProtein binding51 2 unreliable medical source MetabolismCYP1A2 CYP2C9 CYP2C19 to lesser extent 1 MetabolitesES259564 3 Elimination half life9 6h 1 ExcretionUrine 76 9 feces 14 7 4 unreliable medical source IdentifiersIUPAC name 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 methanoneCAS Number1629229 37 3PubChem CID117604931DrugBankDB15669ChemSpider58828046UNII83VNE45KXXKEGGD11976ChEMBLChEMBL3608680Chemical and physical dataFormulaC 16H 15F N 6O SMolar mass358 40 g mol 13D model JSmol Interactive imageSMILES C C H 1C2 NN C N2CCN1C O C3 CC C C C3 F C4 NC NS4 CInChI 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 s1Key PPSNFPASKFYPMN SECBINFHSA NThe most common side effects include abdominal pain diarrhea insomnia back pain hot flush and elevated hepatic transaminases 5 Fezolinetant was approved for medical use in the United States in May 2023 5 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 5 Medical uses editFezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause 5 History editIn May 2017 fezolinetant had completed phase I and phase IIa clinical trials for hot flashes in postmenopausal females 8 Phase IIa trials in polycystic ovary syndrome patients are ongoing 8 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 9 10 Fezolinetant shows high affinity for and potent inhibition of the NK3 receptor in vitro Ki 25 nM IC50 20 nM 7 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 7 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 11 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 12 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 11 12 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 13 14 This would seem to be independent of their actions on the hypothalamic pituitary gonadal axis and hence on sex hormone production 13 14 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 13 14 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 5 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 5 Each trial ran a total of 52 weeks 5 The average age of the trial participants was 54 years old 5 The FDA granted the application for fezolinetant priority review designation 5 The approval of Veozah was granted to Astellas Pharma US Inc 5 References edit a b c Veozah fezolinetant tablet film coated DailyMed 19 May 2023 Archived from the original on 25 May 2023 Retrieved 24 May 2023 Fezolinetant https classic clinicaltrials gov ct2 show NCT04793204 Fezolinetant DrugBank com a b c d e f g h i j k FDA Approves Novel Drug to Treat Moderate to Severe Hot Flashes Caused by Menopause U S Food and Drug Administration FDA Press release 12 May 2023 Archived from the original on 13 May 2023 Retrieved 13 May 2023 nbsp This article incorporates text from this source which is in the public domain Astellas to Acquire Ogeda SA Press release Astellas Pharma Archived from the original on 5 November 2021 Retrieved 5 November 2021 via PR Newswire a b c Hoveyda HR Fraser GL Dutheuil G El Bousmaqui M Korac J Lenoir F et al July 2015 Optimization of Novel Antagonists to the Neurokinin 3 Receptor for the Treatment of Sex Hormone Disorders Part II ACS Medicinal Chemistry Letters 6 7 736 740 doi 10 1021 acsmedchemlett 5b00117 PMC 4499830 PMID 26191358 a b c Fezolinetant Ogeda AdisInsight Archived from the original on 5 November 2021 Retrieved 5 November 2021 Lederman S Ottery FD Cano A Santoro N Shapiro M Stute P et al April 2023 Fezolinetant for treatment of moderate to severe vasomotor symptoms associated with menopause SKYLIGHT 1 a phase 3 randomised controlled study The Lancet 401 10382 1091 1102 doi 10 1016 S0140 6736 23 00085 5 PMID 36924778 S2CID 257498379 A Study to Find Out if Fezolinetant Helps Reduce Moderate to Severe Hot Flashes in Women Going Through Menopause Skylight 1 ClinicalTrials gov U S National Institutes of Health 13 July 2022 Archived from the original on 29 March 2023 Retrieved 29 March 2023 a b Fraser GL Ramael S Hoveyda HR Gheyle L Combalbert J 2016 The NK3 Receptor Antagonist ESN364 Suppresses Sex Hormones in Men and Women J Clin Endocrinol Metab 101 2 417 26 doi 10 1210 jc 2015 3621 PMID 26653113 a b Fraser GL Hoveyda HR Clarke IJ Ramaswamy S Plant TM Rose C et al 2015 The NK3 Receptor Antagonist ESN364 Interrupts Pulsatile LH Secretion and Moderates Levels of Ovarian Hormones Throughout the Menstrual Cycle Endocrinology 156 11 4214 25 doi 10 1210 en 2015 1409 PMID 26305889 a b c Gone in a Flash New Drug Class Targets Menopause Symptom Medscape Archived from the original on 12 May 2017 Retrieved 29 April 2017 a b c Ogeda Announces Positive Data From Phase IIa Trial Of Fezolinetant In The Treatment Of Menopausal Hot Flashes www clinicalleader com Archived from the original on 6 January 2017 Retrieved 29 April 2017 Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Fezolinetant amp oldid 1184111677, wikipedia, wiki, book, books, library,

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