The NK3 Receptor Antagonist ESN364 Suppresses Sex Hormones in Men and Women

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.