RORγ antagonists and inverse agonists: a patent review

ABSTRACT

Introduction: The transcription factor RORγ plays a critical role in the expression of pro-inflammatory cytokine interleukin IL-17 and is therefore an attractive target for the treatment of inflammatory diseases. Interest in this molecular target has been heightened by the advancement of orally and topically administered RORγ modulators into clinical trials.

Areas covered: The present review seeks to summarize published patent applications from assignee companies that have disclosed Investigational New Drug (IND) filings for small molecule RORγ/RORγt antagonists and inverse agonists.

Expert opinion: The field of RORγ research is extremely competitive, with the majority of companies targeting psoriasis as the primary disease indication. Vitae Pharmaceuticals is currently the most advanced, with a potential first-in-class oral RORγ-modulator for the treatment of psoriasis. Future efforts will likely expand into potential applications of RORγ-modulators in the lesser explored immune-related areas of rheumatoid arthritis, type 1 diabetes, lupus, and irritable bowel disorder, as well as cancer immunotherapy and castration-resistant prostate cancer.

KEYWORDS:

• RORγ
• nuclear receptor
• IL-17
• psoriasis
• RORc

Article highlights

• Comprehensive review of published patent applications reporting RORγ/RORγt small molecule antagonists and inverse agonists from assignee companies that have filed Investigational New Drug (IND) applications.

• Vitae Pharmaceuticals has the most advanced oral RORγ-modulator program with reported data from the Phase 2a clinical trial of VTP-43742. Three published patent applications from Vitae are reviewed, and potential lead chemical matter is highlighted.

• Published patent applications from GlaxoSmithKline (GSK), which recently concluded the Phase 1 clinical trial of RORγ inverse agonist GSK2981278, are reviewed. Advanced chemical matter, based on potency and a published process route patent application, is reviewed.

• Published patent applications from Japan Tobacco as well as Arrien Pharmaceuticals, which both have RORγ modulators in Phase 1 clinical trials, are also discussed.

This box summarizes key points contained in the article.

Acknowledgments

We gratefully acknowledge Celine Eidenschenk, Nico Ghilardi, Leonard Dragone, Mike Siu, and Patrick Cyr for helpful discussions and edits.

Declaration of interest

The authors are employees of Genentech, Inc. The authors have no other 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 apart from those disclosed.

Additional information

Funding

This paper was funded by Genentech.