Retinoic acid receptor-related orphan receptor gamma-t (RORγt) inhibitors in clinical development for the treatment of autoimmune diseases: a patent review (2016-present)

ABSTRACT

Introduction: RORγt is critical for the differentiation of Th17 cells and the production of IL-17. Inhibition of RORγt is considered as a promising strategy to treat Th17-mediated autoimmune diseases. Quite a number of RORγt inhibitors have been progressed into clinical trials, besides much biological interests in this attractive target.

Areas covered: This article reviews the progress of RORγt inhibitors (antagonists and inverse agonists) that are active in clinical development based on an analysis of the related patents published by the corresponding companies in the period of January 2016 through May 2019.

Expert opinion: The development of RORγt inhibitors has gone through a boom period in the past three years. However, with a little bit frustration, some of the frontrunner clinical compounds were either discontinued or suspended for further development possibly due to some safety concerns or lack of efficacy in humans. There is a need to probe deeply into these concerns in the on-going pre-clinical and clinical studies. Given the effectiveness of a few recently FDA-approved anti-IL-17(R) antibodies on psoriasis, the discovery of RORγt inhibitors continues to be an exciting field for the development of novel treatment approaches.

KEYWORDS:

• RORγt
• Th17
• IL-17
• inhibitors
• autoimmune diseases

Article highlights

• The present patent review comprehensively focuses on the relevant patents applied from January 2016 to May 2019 by the companies that have RORγt inhibitors ongoing in clinical trials.

• Despite VTP-43742, GSK-2981278, JTE-151, JNJ-3534, ABBV-553, TAK-828 and AZD-0284 were either discontinued or suspended for further development, more and more new RORγt inhibitors have been discovered and progressed into clinical trial studies. The development status of these RORγt inhibitors is updated in this review.

• Seven companies, Japan Tobacco, Escalier Biosciences, Aurigene, Bristol Myers Squibb, Reata, Inventiva Pharma/AbbVie, and Lead Pharma/Sanofi, have active clinical RORγt inhibitors. Their patent applications about RORγt inhibitors are reviewed, and potential lead chemical matter is highlighted.

• As a potential target, despite some safety and efficacy concerns raised by a few pre-clinical and clinical observations, RORγt will attract continuous investigation into the discovery of novel high-affinity drug-like inhibitors. Expert opinion is given.

This box summarizes key points contained in the article.

Acknowledgments

The authors gratefully acknowledge Prof. Qiong Xie, Dr. Yafei Huang and Dr. Jinlong Tian for helpful discussions and manuscript proofreadings.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by National Science Foundation of China (grant numbers: 81573276 and 81874287), Shanghai Bio-pharmaceutical Science and Technology Supporting Plan (grant numbers: 17431902100 and 19431900100), National Science and Technology Major Project (grant number: 2018ZX09711002-003-014), Fudan-SIMM Joint Research Fund (grant number: FU-SIMM20174007), and China Postdoctoral Science Foundation (no. 2019M651383).