Safety, pharmacokinetics, and sex hormone suppression of LY01021 versus relugolix: A single- and multiple-dose escalation study

BACKGROUND: LY01021 is a novel oral small-molecule gonadotropin-releasing hormone (GnRH) receptor antagonist intended for the treatment of various sex hormone-dependent disorders. This study aimed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of LY01021, compared with the approved GnRH receptor antagonist relugolix. METHODS: This randomized, double-blind, placebo- and relugolix-controlled study enrolled healthy volunteers. Part1 (single-dose escalation) included 59 premenopausal women (Part1A: placebo, LY01021 5-80 mg, or relugolix 40 mg) and 70 men (Part1B: placebo, LY01021 40-540 mg, or relugolix 120 mg). Part2 (multiple-dose escalation) included 40 premenopausal women receiving daily oral placebo or LY01021 10-60 mg for 14 days. Key endpoints were adverse events (AEs) and concentrations of LY01021, relugolix, luteinizing hormone (LH), estradiol, and testosterone. RESULTS: LY01021 demonstrated good safety and tolerability, that all AEs were classified as CTCAE grade 1 or 2. LY01021 was rapidly absorbed, exhibiting nonlinear PK likely due to P-glycoprotein saturation. Daily doses of ≥20 mg effectively suppressed LH surges. Daily doses of ≥40 mg achieved sustained suppression of estradiol to <0.05 ng/mL, the therapeutic threshold for endometriosis or uterine fibroids. Doses of ≥120 mg suppressed testosterone to castration levels (<0.5 ng/mL). The safety and hormone-suppressing effects of LY01021 were comparable to those of relugolix. CONCLUSION: LY01021 was well tolerated and effectively suppressed hormone secretion in healthy volunteers, supporting its further clinical development.