title: The NK3 Receptor Antagonist ESN364 Suppresses Sex Hormones in Men and Women.
abstract: BACKGROUND
  Women's health disorders are commonly treated by agents that suppress the hypothalamic-pituitary-gonadal axis. NK3 receptor antagonism modulates this axis with distinct pharmacology compared to existing therapies.
  
  
  OBJECTIVE
  The study aim was to evaluate safety, pharmacokinetics, and pharmacodynamics on gonadotropins and sex hormones after single- and multiple-dose administration of an NK3R antagonist to healthy men and women.
  
  
  METHODS
  This was a first-in-human, double-blind, placebo-controlled, combined single and multiple ascending dose trial.
  
  
  METHODS
  Forty-one men and 24 regularly cycling women participated in the study.
  
  
  METHODS
  In part 1 of the study, men received single oral doses of 3-180 mg or placebo. In part 2, men received placebo or 20, 60, or 180 mg each day for 10 days. In part 3, women received placebo or 20, 60, or 180 mg each day for 21 days, where dosing was initiated on day 3 ± 2 after menses.
  
  
  METHODS
  Safety, tolerability, pharmacokinetics, and pharmacodynamics on circulating levels of LH, FSH, testosterone, estradiol, and progesterone, in addition to physiological biomarkers of endometrial thickening, follicle growth, and the duration of the menstrual cycle were evaluated.
  
  
  RESULTS
  ESN364 was well-tolerated and rapidly bioavailable with linear pharmacokinetics and no drug accumulation with repeated, daily oral administration. Drug treatment dose-dependently decreased basal LH, but not FSH, and consequently decreased estradiol and progesterone (in women) as well as testosterone (in men). The hormonal changes in women corresponded to delayed ovulation, decreased endometrial thickening, impeded follicular maturation, and prolongation of the menstrual cycle. Drug effects were rapidly reversible.
  
  
  CONCLUSIONS
  Oral administration of the NK3R antagonist, ESN364, suppressed the hypothalamic-pituitary-gonadal axis in healthy volunteers by selective modulation of gonadotropin secretion, leading to a restrained decrease in ovarian hormone levels in women. These results suggest that ESN364 may offer therapeutic benefit in the treatment of women's health disorders with a mitigated risk of menopausal-like adverse events.
authors.affiliation: Euroscreen S.A. (G.L.F., S.R., H.R.H., J.C.), Gosselies, Belgium; SGS Life Science Services (L.G.), Clinical Pharmacology Unit, Antwerp, Belgium.
authors.forename: Graeme L
authors.initials: GL
authors.lastname: Fraser
authors.affiliation: Euroscreen S.A. (G.L.F., S.R., H.R.H., J.C.), Gosselies, Belgium; SGS Life Science Services (L.G.), Clinical Pharmacology Unit, Antwerp, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ramael
authors.affiliation: Euroscreen S.A. (G.L.F., S.R., H.R.H., J.C.), Gosselies, Belgium; SGS Life Science Services (L.G.), Clinical Pharmacology Unit, Antwerp, Belgium.
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Hoveyda
authors.affiliation: Euroscreen S.A. (G.L.F., S.R., H.R.H., J.C.), Gosselies, Belgium; SGS Life Science Services (L.G.), Clinical Pharmacology Unit, Antwerp, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Gheyle
authors.affiliation: Euroscreen S.A. (G.L.F., S.R., H.R.H., J.C.), Gosselies, Belgium; SGS Life Science Services (L.G.), Clinical Pharmacology Unit, Antwerp, Belgium.
authors.forename: Jean
authors.initials: J
authors.lastname: Combalbert
mesh_terms: D000293:Adolescent; D000328:Adult; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004717:Endometrium / Q000187:drug effects; D005260:Female; D012739:Gonadal Steroid Hormones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006062:Gonadotropins / Q000097:blood; D006066:Gonads / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008297:Male; D008597:Menstrual Cycle / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000254:growth & development; D010060:Ovulation / Q000187:drug effects; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D013830:Thiadiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D012739:Gonadal Steroid Hormones; D006062:Gonadotropins; D006574:Heterocyclic Compounds, 2-Ring; D006727:Hormone Antagonists; D018042:Receptors, Neurokinin-3; D013830:Thiadiazoles; C000608808:fezolinetant