Fezolinetant

Fezolinetant
Names
Trade namesVeozah
Other namesESN-364
IUPAC 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]methanone
Clinical data
Drug classNK3 receptor blocker.[1]
Main usesHot flashes due to menopause[2]
Side effectsAbdominal pain, diarrhea, trouble sleeping, back pain, liver problems[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
Typical dose45 mg OD[1]
Legal
License data
Legal status
Chemical and physical data
FormulaC16H15FN6OS
Molar mass358.40 g·mol−1
3D model (JSmol)
SMILES
  • C[C@@H]1C2=NN=C(N2CCN1C(=O)C3=CC=C(C=C3)F)C4=NC(=NS4)C
InChI
  • 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, is a medication used to treat hot flashes due to menopause.[2] Specifically it is used for moderate or severe symptoms.[1] It is taken by mouth.[1]

Common side effects include abdominal pain, diarrhea, trouble sleeping, back pain, and liver problems.[1] Use is not recommended in those with significant kidney or liver problems.[1] It is a neurokinin-3 (NK3) receptor blocker.[1]

Fezolinetant was approved for medical use in the United States in 2023.[1] In the United States it costs about 560 USD per month as of 2023.[3] The manufacturer applied for approval in Europe in 2022.[4]

Medical uses

Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.[2]

Dosage

It is taken at a dose of 45 mg once per day.[1]

History

It is developed by Astellas Pharma which acquired it from Ogeda (formerly Euroscreen) in April 2017.[5][6][7] 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.[2]

As of May 2017, it has completed phase I and phase IIa clinical trials for hot flashes in postmenopausal women.[7] Phase IIa trials in polycystic ovary syndrome patients are ongoing.[7]

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.[8][9]

Fezolinetant shows high affinity for and potent inhibition of the NK3 receptor in vitro (Ki = 25 nM, IC50 = 20 nM).[6] 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.[6] 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 women and testosterone levels in men.[10] 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.[11] 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.[10][11]

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 women.[12][13] This would seem to be independent of their actions on the hypothalamic–pituitary–gonadal axis and hence on sex hormone production.[12][13] 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.[12][13]

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.[2] In both trials, after the first 12 weeks, the women on placebo were then re-randomized to Veozah for a 40-week extension study to evaluate safety.[2] Each trial ran a total of 52 weeks.[2] The average age of the trial participants was 54 years old.[2]

The FDA granted the application for fezolinetant priority review designation.[2] The approval of Veozah was granted to Astellas Pharma US, Inc.[2]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 "Veozah- fezolinetant tablet, film coated". DailyMed. 19 May 2023. Archived from the original on 25 May 2023. Retrieved 24 May 2023.
  2. 1 2 3 4 5 6 7 8 9 10 "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. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ↑ "Fezolinetant". GoodRx. Retrieved 13 August 2023.
  4. ↑ Inc, Astellas Pharma. "European Medicines Agency Accepts Astellas' Marketing Authorization Application for Fezolinetant". www.prnewswire.com. Archived from the original on 16 October 2022. Retrieved 13 August 2023.
  5. ↑ "Astellas to Acquire Ogeda SA" (Press release). Astellas Pharma. Archived from the original on 5 November 2021. Retrieved 5 November 2021 – via PR Newswire.
  6. 1 2 3 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.
  7. 1 2 3 "Fezolinetant - Ogeda". AdisInsight. Archived from the original on 5 November 2021. Retrieved 5 November 2021.
  8. ↑ 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.
  9. ↑ "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.
  10. 1 2 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.
  11. 1 2 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.
  12. 1 2 3 "Gone in a Flash: New Drug Class Targets Menopause Symptom". Medscape. Archived from the original on 12 May 2017. Retrieved 29 April 2017.
  13. 1 2 3 "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.
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