Retinoic acid-related orphan receptor gamma t (RORγt) inverse agonists/antagonists for the treatment of inflammatory diseases – where are we presently?

ABSTRACT

Introduction: The transcription factor retinoic acid-related orphan receptor gamma t (RORγt) has been identified as the master regulator of T_H17 cell differentiation and IL-17/22 production and is therefore an attractive target for the treatment of inflammatory diseases. Several orally or topically administered small molecule RORγt inverse agonists (RIAs) have progressed up to the end of clinical Phase 2.

Areas covered: Based on publications and patent evaluations this review summarizes the evolution of the chemical matter for all 16 pharmaceutical companies, who develop(ed) a clinical-stage RIAs (until March 2021). Structure proposals for some clinical stage RIAs are presented and the outcome of the clinical trials is discussed.

Expert opinion: So far, the clinical trials have been plagued with a high attrition rate. Main reasons were lack of efficacy (topical) or safety signals (oral) as well as, amongst other things, thymic lymphomas as seen with BMS-986251 in a preclinical study and liver enzyme elevations in humans with VTP-43742. Possibilities to mitigate these risks could be the use of RIAs with different chemical structures not interfering with thymocytes maturation and no livertox-inducing properties. With new frontrunners (e.g., ABBV-157 (cedirogant), BI 730357 or IMU-935) this is still an exciting time for this treatment approach.

KEYWORDS:

• Allosteric
• autoimmune disease
• clinical trial
• drug discovery
• rational drug design
• RORc
• RORγt
• structure disclosure
• thymus

Article highlights

• Analysis of key chemical structures for all 16 pharmaceutical companies with a former or present RORγt inverse agonist in the clinic based on publications and patents.

• New structure proposal for some clinical stage RORγt inverse agonists based on comprehensive evaluation of filed patent applications and their prosecution.

• Most current failures or terminations in the clinic were due to safety concerns for some of the oral drugs and not sufficient efficacy with topical drugs.

• Significant challenges remain in overcoming safety concerns regarding thymic lymphomas seen in rodent tox species.

• Possible solutions could be the expansion to non-chronic diseases, the use of partial inverse agonists or application of polypharmacology/combination therapies.

Acknowledgments

The statements in this review do not necessarily reflect the views of his employer.

Declaration of interest

C Gege is an employee of Immunic AG, Germany. Furthermore, C Gege works in the field of RORγt inverse agonists and has several granted patents covering this topic. He has 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.

Reviewer disclosures

One reviewer is a stockholder in Escalier Biosciences - one of the companies that has RORγt inverse agonists in development. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript has not been funded.