Fezolinetant

Identification

Summary

Fezolinetant is a non-hormonal drug used to treat moderate to severe vasomotor symptoms due to menopause.

Brand Names
Veozah
Generic Name
Fezolinetant
DrugBank Accession Number
DB15669
Background

Vasomotor symptoms (VMS), more colloquially known as hot flashes or night sweats, are some of the most common symptoms in menopause. With a median duration of 7.4 years, vasomotor symptoms are also the most common reasons why women seek treatments for menopausal issues.1,2 Although mostly considered a nuisance, vasomotor symptoms can significantly affect quality of life, as women with 7 or more moderate to severe VMS daily have reported a decline in sleep quality, concentration, sexual activity, energy, and concentration.3

Although the pathophysiology of VMS is not fully understood, unpredictable fluctuation in estrogen levels is thought to be the main cause of VMS, as estrogen therapy has been one of the most effective treatments for VMS by relieving symptoms in as many as 95% of menopausal women. Women undergoing abrupt menopause due to oophorectomy also experienced more severe symptoms than those going through a gradual transition.4,3 Additionally, thermoregulatory dysfunction has been proposed as one of the three possible mechanisms for VMS in menopause.4 Estrogen is a potent neuromodulator, particularly in the hypothalamus, and has been shown to be involved as a negative regulator in generating Gonadotropin-releasing hormone (GnRH) pulse through the kisspeptin, neurokinin B, and dynorphin (KNDy) neurons.1,5 NK3, one of the receptors expressed in KNDy neurons, is activated by neurokinin B and can thus induce the release of GnRH.1,5 Lower estrogen levels during menopause will decrease the estrogen-mediated feedback loop and increase neurokinin B signalling, increasing the activity of KNDy neurons and therefore the activity of the temperature control center.1,5 By antagonizing NK3 receptors, neuronal signalling can be dampened to reduce VMS.1,5

Although hormone therapy is available for menopausal women, safety and tolerability concerns, such as an increased risk of stroke and venous thromboembolism or hormone-dependent cancer like breast cancer, can prevent some women from receiving this treatment.5 Fezolinetant, an NK3 receptor antagonist, was developed in response to this issue as well as more understanding of the role of NK3R in the hypothalamic-pituitary-gonadal (HPG) axis.5 Although previous NK3 receptor antagonists exist, such as osanetant and talnetant, only fezolinetant showed tangible effects on the HPC axis, potentially due to its favorable pharmacokinetics profile to cross the blood-brain barrier.5

Fezolinetant was approved by the FDA in May 2023 under the brand name Veozah.6 It was subsequently approved by the EMA in December 2023 for the same indication.8

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 358.4
Monoisotopic: 358.101208464
Chemical Formula
C16H15FN6OS
Synonyms
  • Fezolinetant
External IDs
  • ESN 364
  • ESN-364

Pharmacology

Indication

Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.6,7

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofModerate to severe vasomotor symptoms•••••••••••••••••• •••••••••••••
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Pharmacodynamics

Fezolinetant has a high affinity for the NK3 receptor (Ki value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than the binding affinity for NK1 or NK2 receptors.6

Treatment with fezolinetant did not show any clear trends in sex hormones measured (follicle-stimulating hormone, testosterone, estrogen, and dehydroepiandrosterone sulfate) in menopausal women. A transient decrease of luteinizing hormone (LH) levels was observed at peak concentrations of fezolinetant. At a dose 20 times the maximum approved recommended dose, fezolinetant does not prolong the QT interval to any clinically relevant extent.6

In a phase 2a clinical trial, fezolinetant 90 mg BID significantly reduce the frequency and severity of vasomotor symptoms in postmenopausal women by more than 50%. The improvement was observed as early as in the first week of treatment and was maintained throughout the 12 weeks of treatment.1

Mechanism of action

Fezolinetant is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center.6

TargetActionsOrganism
ANeuromedin-K receptor
antagonist
Humans
Absorption

In healthy women, fezolinetant Cmax and AUC increased proportionally over a dosage range from 20 to 60 mg once daily (0.44 to 1.33 times the approved recommended dosage). Steady-state plasma concentrations of fezolinetant were reached after two once-daily doses, with minimal fezolinetant accumulation. The median (range) time to reach fezolinetant Cmax is 1.5 (1 to 4) hours in healthy women.6

Volume of distribution

The mean apparent volume of distribution (Vz/F) of fezolinetant is 189 L.6

Protein binding

The plasma protein binding of fezolinetant is 51%. The blood-to-plasma ratio is 0.9.6

Metabolism

Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19. A major metabolite of fezolinetant, ES259564, was identified in plasma. ES259564 is approximately 20-fold less potent than the parent. The metabolite-to-parent ratio ranges from 0.7 to 1.8.6

Route of elimination

Following oral administration of fezolinetant, 76.9% of the dose was excreted in urine (1.1% unchanged) and 14.7% in feces (0.1% unchanged).6

Half-life

The effective half-life (t1/2) of fezolinetant is 9.6 hours in women with vasomotor symptoms.6

Clearance

The apparent clearance at steady state of fezolinetant is 10.8 L/h.6

Adverse Effects
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Toxicity

In embryo-fetal development toxicity studies in rats and rabbits, embryo-lethality was noted at the highest doses (128- and 174-fold the human AUC24 at the human therapeutic dose for rats and rabbits, respectively). The no observed adverse effect level (NOAEL) for embryo-fetal development was 50 mg/kg/day in rats and 45 mg/kg/day in rabbits (62- and 16-fold the human AUC24 at the human therapeutic dose for rats and rabbits, respectively). Fezolinetant showed no effects on fertility and early embryonic development in rats.6

In the pre-and post-natal development study in rats, the NOAEL for maternal and fetal toxicity was 30 mg/kg/day (36-fold the human AUC24 at the human therapeutic dose) based on delayed parturition and embryo-lethality at 100 mg/kg/day. The NOAEL for F1 generation development was determined to be 100 mg/kg/day for females (204-fold the human AUC24 at the human therapeutic dose) and 10 mg/kg/day for males (11-fold the human AUC24 at the human therapeutic dose).6

In the pre-and post-natal development study in rats, the F1 male showed incomplete balanopreputial separation at doses greater than or equal to 30 mg/kg/day (36-fold the human AUC24 at the human therapeutic dose), which delayed male reproductive maturation and affected fertility. These effects were not observed following dosing at 10 mg/kg/day (11-fold the human AUC24 at the human therapeutic dose).6

Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys. In female rats, daily administration of fezolinetant for 26 weeks at doses equal to or greater than 30 mg/kg/day (56-fold the human AUC24 at the human therapeutic dose) showed uterine atrophy and epithelial mucification of the vagina and cervix. In female cynomolgus monkeys, daily administration for 39 weeks at doses equal to or greater than 10 mg/kg/day (19-fold the human AUC24 at the human therapeutic dose) showed reduced ovarian activity.6

Fezolinetant is contraindicated in individuals with severe (eGFR 15 to less than 30 mL/min/1.73 m2) renal impairment or end-stage renal disease (eGFR less than 15 mL/min/1.73 m2). No dose adjustment of fezolinetant is recommended for individuals with mild (eGFR 60 to less than 90 mL/min/1.73 m2) or moderate (eGFR 30 to less than 60 mL/min/1.73 m2) renal impairment.6

Child-Pugh Class A or B hepatic impairment increased the exposure to fezolinetant. Fezolinetant has not been studied in individuals with Child-Pugh Class C hepatic impairment.6

In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC24 at the human therapeutic dose of 45 mg, respectively.6

Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test.6

Treatment of overdose consists of discontinuation of fezolinetant therapy with the institution of appropriate symptomatic care.6

Pathways
Not Available
Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Fezolinetant can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Fezolinetant can be increased when combined with Abatacept.
AbirateroneThe serum concentration of Fezolinetant can be increased when it is combined with Abiraterone.
AcenocoumarolThe metabolism of Fezolinetant can be decreased when combined with Acenocoumarol.
AcetaminophenThe metabolism of Fezolinetant can be decreased when combined with Acetaminophen.
Food Interactions
Not Available

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VeozahTablet, film coated45 mg/1OralAstellas Pharma US, Inc.2023-05-12Not applicableUS flag
VeozahTablet, film coated45 mg/1OralAstellas Pharma US, Inc.2023-05-16Not applicableUS flag
VeozahTablet, film coated45 mg/1OralAstellas Pharma US, Inc.2023-05-12Not applicableUS flag

Categories

ATC Codes
G02CX06 — Fezolinetant
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as 4-halobenzoic acids and derivatives. These are benzoic acids or derivatives carrying a halogen atom at the 4-position of the benzene ring.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
4-halobenzoic acids and derivatives
Alternative Parents
Triazolopyrazines / Benzamides / Benzoyl derivatives / Fluorobenzenes / Aryl fluorides / Pyrazines / Heteroaromatic compounds / Tertiary carboxylic acid amides / Thiadiazoles / Triazoles
show 7 more
Substituents
1,2,4-triazole / 4-halobenzoic acid or derivatives / Aromatic heteropolycyclic compound / Aryl fluoride / Aryl halide / Azacycle / Azole / Benzamide / Benzoyl / Carboxamide group
show 19 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
83VNE45KXX
CAS number
1629229-37-3
InChI Key
PPSNFPASKFYPMN-SECBINFHSA-N
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
IUPAC Name
5-[(8R)-7-(4-fluorobenzoyl)-8-methyl-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-3-methyl-1,2,4-thiadiazole
SMILES
C[C@H]1N(CCN2C1=NN=C2C1=NC(C)=NS1)C(=O)C1=CC=C(F)C=C1

References

General References
  1. Santoro N, Waldbaum A, Lederman S, Kroll R, Fraser GL, Lademacher C, Skillern L, Young J, Ramael S: Effect of the neurokinin 3 receptor antagonist fezolinetant on patient-reported outcomes in postmenopausal women with vasomotor symptoms: results of a randomized, placebo-controlled, double-blind, dose-ranging study (VESTA). Menopause. 2020 Dec;27(12):1350-1356. doi: 10.1097/GME.0000000000001621. [Article]
  2. Thurston RC, Joffe H: Vasomotor symptoms and menopause: findings from the Study of Women's Health across the Nation. Obstet Gynecol Clin North Am. 2011 Sep;38(3):489-501. doi: 10.1016/j.ogc.2011.05.006. [Article]
  3. Pinkerton JV, Redick DL, Homewood LN, Kaunitz AM: Neurokinin receptor antagonist, fezolinetant, for treatment of menopausal vasomotor symptoms. J Clin Endocrinol Metab. 2023 Apr 25:dgad209. doi: 10.1210/clinem/dgad209. [Article]
  4. Deecher DC, Dorries K: Understanding the pathophysiology of vasomotor symptoms (hot flushes and night sweats) that occur in perimenopause, menopause, and postmenopause life stages. Arch Womens Ment Health. 2007;10(6):247-57. doi: 10.1007/s00737-007-0209-5. Epub 2007 Dec 12. [Article]
  5. Depypere H, Lademacher C, Siddiqui E, Fraser GL: Fezolinetant in the treatment of vasomotor symptoms associated with menopause. Expert Opin Investig Drugs. 2021 Jul;30(7):681-694. doi: 10.1080/13543784.2021.1893305. Epub 2021 Jul 12. [Article]
  6. FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]
  7. EMA Summary of Product Characteristics: Veoza (fezolinetant) film-coated tablets for oral administration [Link]
  8. Astellas Newsroom: Astellas' VEOZA™ (fezolinetant) Approved by European Commission for Treatment of Vasomotor Symptoms Associated with Menopause [Link]
ChemSpider
58828046
BindingDB
50112244
RxNav
2637134
ChEMBL
CHEMBL3608680
ZINC
ZINC000218861630
Wikipedia
Fezolinetant

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3CompletedTreatmentCoronavirus Disease 2019 (COVID‑19) / Hot Flashes3
3CompletedTreatmentHot Flashes2
3CompletedTreatmentVasomotor Symptoms Associated With Menopause1
3Not Yet RecruitingTreatmentHot Flashes2
2CompletedTreatmentHot Flashes2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral45 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US10836768No2020-11-172034-03-28US flag
US9987274No2018-06-052034-03-28US flag
US9422299No2016-08-232034-03-28US flag
US8871761No2014-10-282031-04-04US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility0.29 mg/mLL46422
Predicted Properties
PropertyValueSource
Water Solubility0.306 mg/mLALOGPS
logP1.57ALOGPS
logP1.78Chemaxon
logS-3.1ALOGPS
pKa (Strongest Basic)0.87Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count5Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area76.8 Å2Chemaxon
Rotatable Bond Count2Chemaxon
Refractivity114.39 m3·mol-1Chemaxon
Polarizability36.15 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0009000000-5ddc1afa68de18b79a1f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0039000000-e088bef970ae9d8bbd36
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a4i-0029000000-19755870463f43ed8157
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a73-0449000000-8d98c8ac9963500a383d
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0596-0903000000-8ddbf0e86d1d310966a1
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0596-5944000000-9bf98d6bdd5a2e369bef
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Tachykinin receptor activity
Specific Function
This is a receptor for the tachykinin neuropeptide neuromedin-K (neurokinin B). It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order...
Gene Name
TACR3
Uniprot ID
P29371
Uniprot Name
Neuromedin-K receptor
Molecular Weight
52201.35 Da
References
  1. Depypere H, Lademacher C, Siddiqui E, Fraser GL: Fezolinetant in the treatment of vasomotor symptoms associated with menopause. Expert Opin Investig Drugs. 2021 Jul;30(7):681-694. doi: 10.1080/13543784.2021.1893305. Epub 2021 Jul 12. [Article]
  2. FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. FDA Approved Drug Products: VEOZAHTM (fezolinetant) tablets, for oral use [Link]

Drug created at April 20, 2020 15:29 / Updated at February 15, 2024 07:14