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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

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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 (Tmax) 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 (t1/2) 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.

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Acknowledgements

We thank all patients and their families and acknowledge the contributions of all investigators in this trial. We would also like to acknowledge Tengfei Zhang (PhD, Medical Writer, Jiangsu Hengrui Pharmaceuticals Co., Ltd.) for medical writing support according to Good Publication Practice Guidelines.

Author information

Author notes

  1. Yuan Li and Ying Zheng contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Peking University Third Hospital, 49 Huayuan North Road, Beijing, 100000, China

    Yuan Li, Bing Xu & Hongyan Guo

  2. Department of Gynecologic Oncology, West China Second University Hospital, Sichuan University, Chengdu, China

    Ying Zheng

  3. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China

    Ying Zheng, Linrui Cai & Qin Yu

  4. National Drug Clinical Trial Institute, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, 610000, China

    Linrui Cai & Qin Yu

  5. National Drug Clinical Trial Institution of West China Second Hospital, Chengdu, China

    Linrui Cai & Qin Yu

  6. NMPA Key Laboratory for Technical Resarch on Drug Products In Vitro and In Vivo Correlation, Chengdu, China

    Linrui Cai & Qin Yu

  7. Clinical Research and Development, Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China

    Sheng Feng, Yiming Liu & Zhenyi Zhu

Authors
  1. Yuan Li
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Corresponding authors

Correspondence to Qin Yu or Hongyan Guo.

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Funding

This study was supported by Jiangsu Hengrui Pharmaceuticals Co., Ltd.

Conflict of interest

Sheng Feng, Yiming Liu, and Zhenyi Zhu are employees of Jiangsu Hengrui Pharmaceuticals Co., Ltd. Other co-authors declare no competing interests.

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guideline. Study protocol and all amendments were approved by the independent ethics committee of each participating sites.

Consent to participate

All patients provided written informed consent before enrollment.

Consent for publication

Not applicable.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author contributions

HG, QY, and ZZ were responsible for the conception and design of the study. YL, YZ, BX, LC, ZZ, QY, and HG contributed to the data collection. SF and YL was responsible for the statistical analysis. All authors were responsible for data interpretation and manuscript writing, reviewing, and approving for submission.

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Li, Y., Zheng, Y., Xu, B. et al. 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. Clin Pharmacokinet 62, 1739–1748 (2023). https://doi.org/10.1007/s40262-023-01315-6

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