Safety, Pharmacokinetics, and Pharmacodynamics of SHR7280, a Non-peptide GnRH Antagonist in Premenopausal Women with Endometriosis: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

Abstract

Background: Oral gonadotropin-releasing hormone (GnRH) antagonists are promising agents in the treatment of endometriosis-related pain. Here we assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral non-peptide GnRH antagonist in premenopausal women with endometriosis.

Methods: In the Phase 1 part of the randomized, double-blinded, placebo-controlled, dose-ascending, Phase 1/2 trial, premenopausal women with endometriosis were randomized (4:1) to receive SHR7280 or placebo treatment for 21 consecutive days. The treatment dose started from 200 mg QD, and then increased to 300 mg QD and 200 mg BID. Safety, PK, and PD parameters were assessed.

Results: In total, 30 patients received assigned treatment, 24 with SHR7280 and 6 with placebo. SHR7280 was well tolerated. Adverse events (AEs) were reported in 19 (79.2%, 19/24) patients in the SHR7280 group and 5 (83.3%, 5/6) patients in the placebo group. Most AEs were mild and no severe AEs occurred. SHR7280 showed a rapid absorption, with a time to maximum plasma concentration (T_max) of 1.0 h, 1.0 h, and 0.8 h for the 200 mg QD, 300 mg QD, and 200 mg BID regimens, respectively. Plasma concentration of SHR7280 was dose dependent. The mean half-life (t_1/2) at steady state was 6.9 h, 7.4 h, and 2.8 h, respectively, and little or no accumulation was observed. Pharmacodynamic analysis showed that SHR7280 could effectively suppress estradiol and luteinizing hormone concentrations and prevent progesterone increase in a dose-dependent manner. SHR7280 at doses of 300 mg QD and 200 mg BID could suppress estradiol levels within the desired therapeutic window of 20-50 pg/mL throughout the treatment period.

Conclusions: SHR7280 showed favorable safety, PK, and PD profiles in the doses of 200 mg QD, 300 mg QD, and 200 mg BID. The results of this study provide evidence to support the further development of SHR7280 as a GnRH antagonist for the treatment of endometriosis-related pain in the subsequent Phase 2 trial.

Trial registry: Trial registration number: Clinicaltrials.gov, identifier: NCT04417972. Trial registration date: 5 June 2020.