A phase 2a, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral gonadotropin-releasing hormone antagonist, ASP1707, in postmenopausal female patients with rheumatoid arthritis taking methotrexate

Abstract

Objectives

Many patients with rheumatoid arthritis (RA) are not able to achieve long-term disease remission. This phase 2a study (NCT02884635) evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of the novel, oral, gonadotropin-releasing hormone antagonist, ASP1707, in combination with methotrexate (MTX) for treatment of RA.

Methods

Postmenopausal women with RA who had been receiving MTX for ≥90 days were randomized to ASP1707 30 mg twice daily or placebo for 12 weeks. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Secondary endpoints included: ACR20, ACR50, and ACR70 response rates; disease activity score (DAS)28-CRP; DAS28-ESR; Tender or Swollen Joint Counts; and remission rates.

Results

Of 105 patients screened, 72 were randomized to ASP1707 30 mg twice daily (n = 37) or placebo (n = 35). ASP1707 did not improve ACR20, ACR50, or ACR70 response rates at any time point and did not improve any secondary efficacy endpoint. Plasma luteinizing hormone (LH) concentration decreased >90% in >90% of patients receiving ASP1707, with a rapid decrease to <1 IU/L at week 1 that remained stable throughout the treatment.

Conclusion

In the current study, ASP1707 did not demonstrate a clinical benefit.

Keywords:

• Arthritis
• DAS28
• methotrexate
• gonadotropin-releasing hormone (GnRH) antagonist
• rheumatoid arthritis
• treatment

Acknowledgements

The authors thank the investigators and staff at all study sites. All authors had access to study results, and the lead author vouches for the accuracy and completeness of the data reported. Medical writing and editorial support was provided by Mike Zbreski, PhD, Elizabeth Hermans, PhD, and Patrick Tucker, PhD of OPEN Health Medical Communications (Chicago, IL) and funded by the study sponsor.

Ethical approval

An Institutional Review Board at each study site reviewed and approved the study protocol and have therefore been performed in accordance with the ethical standards laid down in the WMA Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subject.

Data sharing

Researchers may request access to anonymized participant level data, trial level data and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com.

For the Astellas criteria on data sharing see: https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx

Conflict of interest

CH, MI, KK, RA, CL: Employees of Astellas Pharma, Inc.

TT: Grants from Astellas Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie GK, Asahikasei Pharma Corp., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Eisai Co., Ltd., AYUMI Pharmaceutical Corporation, Nipponkayaku Co., Ltd., Novartis Pharma K.K. Speaking fees from AbbVie GK., Bristol–Myers K.K., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Astellas Pharma, Inc., Diaichi Sankyo Co., Ltd., Eisai Co., Ltd., Sanofi K.K., Teijin Pharma Ltd., Takeda Pharmaceutical Co., Ltd., Novartis Pharma K.K. Consulting fees from Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Co., Abbivie GK, Nipponkayaku Co., Ltd., Janssen Pharmaceutical K.K., Astellas Pharma, Inc., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., UCB Japan Co., Ltd.

YT: Speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Eli Lilly, Chugai, Sanofi, Abbvie, YL Biologics, Bristol-Myers, Glaxo-Smithkline, UCB, Mitsubishi-Tanabe, Novartis, Eisai, Takeda, Janssen, Asahi-kasei. Grants from Mitsubishi-Tanabe, Bristol-Myers, Eisai, Chugai, Takeda, Abbvie, Astellas, Daiichi-Sankyo, Ono, MSD, Taisho-Toyama.

Additional information

Funding

This study was funded by Astellas Pharma, Inc.