Suppressive Effects of JTE-151, a Novel Orally Available RORγ Antagonist, in Experimental Models of Rheumatoid...

Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic joint inflammation and cartilage damage. The main treatment goal of RA is clinical remission using various kinds of disease-modifying antirheumatic drugs (DMARDs), but there remain unmet medical needs such as the need for sufficient therapeutic efficacy, long-term safety, and affordable treatment. Many preclinical studies suggest that T helper type-17 (Th17) cells have critical roles in the development of RA. Previously, we developed a novel orally available retinoid-related orphan receptor-γ (RORγ) antagonist, JTE-151, which specifically inhibited the transcriptional activity of RORγ and suppressed the differentiation and activation of Th17 cells in vitro and in vivo. In this study, we investigated the effect of JTE-151 in the two established arthritis models, collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA), which are also widely accepted experimental models for RA. Both prophylactic and therapeutic treatment with JTE-151 ameliorated hindpaw swelling, bone destruction, and inhibited mRNA expression of Th17-related genes in knee synovial tissue in CIA rats. Additionally, these inhibitory effects of JTE-151 were similarly observed in AIA rats. Furthermore, co-administration of JTE-151 and anti-tumor necrosis factor α (TNFα) antibody, compared with each administered individually, resulted in a stronger effect on the arthritis symptoms in CIA mice. These results suggest that JTE-151 has the potential to become a new treatment option for patients with RA.