The potent, selective RORγt blocker, VTP-43742, suppresses Th17 production in vivo and provides greater benefit than IL-17 blockade in the EAE model of autoimmunity (THER3P.968)

Antibodies targeting IL-23 or IL-17 are highly effective in the treatment of psoriasis and psoriatic arthritis, validating the RORγt /Th17 pathway in human disease. VTP-43742 is a potent, selective and orally active inhibitor of RORgt that is being pursued as a treatment of autoimmune disorders. Herein, we present data showing the effects of VTP-43742 in two separate mouse studies using the MOG35-55/CFA immunized EAE model. In a subchronic study, prophylactic dosing of VTP-43742 for 11 days gave a dose-dependent suppression of both CD4 + IL-17 + IFNγ - and CD4 + IL-17 + IFNγ + T cells in spleen and in draining lymph nodes. Splenocytes from these mice restimulated in vitro with the MOG35-55 peptide showed specific suppression of Th17 derived cytokines. In a chronic disease study, the maximal pharmacological effect of VTP-43742 was compared to maximal IL-17 blockade by mouse monoclonal antibody MM17F3 (eBioscience) in a prophylactic setting. High dose VTP-43742 completely suppressed the EAE clinical score, significantly beyond the reduction seen with MM17F3 (p