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.