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

Introduction: The transcription factor retinoic acid-related orphan receptor gamma t (ROR gamma t) has been identified as the master regulator of T(H)17 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 ROR gamma t 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.

Automated summary

The transcription factor ROR gamma t is a promising target for treating inflammatory diseases. Clinical trials of small molecule ROR gamma t inverse agonists have faced challenges, such as lack of efficacy and safety concerns. However, new potential treatments with different chemical structures offer hope for the future.