Abstract
Introduction: The transcription factor retinoic acid-related orphan receptor gamma (RORγt) has been identified as the master regulator of TH17 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 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 RORγt inverse agonists (until March 2021). Structure proposals for some clinical stage RORγt inverse agonists 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. The 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 RORγt inverse agonists with different chemical structures not interfering with thymocytes maturation and no liver tox inducing properties. With few new frontrunners (e.g. ABBV-157 (cedirogant), BI 730357 or IMU-935) this is still an exciting time for this novel treatment approach.
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