CONTEXT: 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.
DESIGN AND SETTING: This was a first-in-human, double-blind, placebo-controlled, 
combined single and multiple ascending dose trial.
PARTICIPANTS: Forty-one men and 24 regularly cycling women participated in the 
study.
INTERVENTION(S): 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.
MAIN OUTCOME MEASURE(S): 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.