Inhibition of ovulation and pharmacologic mechanism of action of relugolix combination therapy.

Abstract

Objective: To assess the effects of relugolix combination therapy on ovarian function in healthy, ovulatory, premenopausal women.

Design: This was an open-label, single-cohort, pharmacodynamic, safety and tolerability study consisting of five study periods: a Pre-Treatment Period to confirm ovulatory status, three 28-day treatment periods, and a Post-Treatment Period to assess duration of time required to return to ovulation following treatment discontinuation. Ovarian function was assessed by transvaginal ultrasonography and serum hormone concentrations.

Subjects: Healthy, premenopausal female participants, 18-35 years of age.

Intervention/exposure: Relugolix combination therapy (relugolix 40 mg, with estradiol 1 mg and norethindrone acetate 0.5 mg) was taken orally once daily for 84 days.

Main outcome measures: The primary endpoint was the proportion of women in whom ovulation was inhibited during the entire 84-day treatment period. Secondary endpoints included proportion of women in whom ovulation was inhibited within each treatment period, number of women who fulfilled the Landgren criterion; characterization of follicular diameter, hormone concentrations, and endometrial thickness; time to return to ovulation following treatment discontinuation; proportion of women who returned to ovulation within 36 days following treatment discontinuation; safety and tolerability.

Results: Seventy women were enrolled in the study, 67 of whom completed treatment. Treatment with relugolix combination therapy inhibited ovulation in 100% of women who completed treatment (95% confidence interval: 94.6, 100.0). Systemic concentrations of luteinizing hormone and follicle-stimulating hormone were suppressed and maintained at low concentrations during treatment, with an absence of a preovulatory luteinizing hormone surge. Median estradiol concentrations across all women were consistently maintained between 36.8 and 39.1 pg/mL (range: 12.1-121.1 pg/mL) during treatment. All individual progesterone concentrations during treatment remained below 1.57 ng/mL (5 nmol/L). Following treatment discontinuation, all women ovulated or initiated menses. The mean time to return to ovulation was 23.5 days. Treatment was generally well tolerated with no safety or tolerability issues identified.

Conclusion: Relugolix combination therapy inhibits ovulation, which, in the context of this study, was achieved within the first cycle following treatment initiation. The rapid and predictable return of ovarian activity and ovulation following treatment discontinuation is advantageous for patients who wish to conceive thereafter.