THU0067 CR6086, a Selective Antagonist at the EP4 Prostanoid Receptor, Improves or Resolves Disease Features in a Mouse Model of Rheumatoid Arthritis

Background Recent studies highlight the role of the EP4 prostanoid receptor in promoting autoimmune inflammation via T helper cells, Th1 and Th17. Objectives Aim of the present studies was to test CR6086, an EP4 selective antagonist, in a widely recognized animal model for rheumatoid arthritis, i.e. the collagen II-induced arthritis (CIA) model in the Lewis rat. The effect of CR6086 was studied in comparison to the JAK kinase inhibitor DMARD tofacitinib. Methods 60 Lewis male rats were immunized with collagen type II in CFA. Three weeks after the first immunization, the same animals were boosted with the same method. Three days after booster injection, edema was assessed and the animals were then randomized and assigned to the treatment groups (n=12): vehicle; tofacitinib 5 mg/kg b.i.d.; tofacitinib 25 mg/kg b.i.d.; CR6086 15 mg/kg o.a.d. Edema measurement was performed again after 7 and 14 days of treatment, and then hindlimb joints were blindly scored for clinical signs of arthritis (scale 0-4). Hindpaw joints were blindly scored for histological features: edema; synovial hyperplasia; inflammatory cell infiltrate; cartilage damage; bone erosion; periosteal osteogenesis (scale 0-4). Statistical analyses were performed with ANOVA followed by Dunn9s or Holm-Sidak9s tests comparing all treatment groups vs. vehicle. Results After 7 days of treatment, edema was significantly reduced in all treatment groups compared to vehicle (vehicle: 2.16±0.09; CR6086 15 mg/kg o.a.d. 1.77±0.07, p Conclusions In a widely recognized animal model for rheumatoid arthritis, both CR6086 and tofacitinib demonstrated very good efficacy in all parameters examined, including edema, clinical arthritis score, and histological features. The present data suggest that CR6086 may be superior to tofacitinib in terms of potency, in this model. CR6086 is now in clinical phase I. Disclosure of Interest R. Chiusaroli Employee of: Rottapharm Biotech Srl, A. Grotti Employee of: Rottapharm Biotech Srl, M. Lanza Employee of: Rottapharm Biotech Srl, G. Caselli Employee of: Rottapharm Biotech Srl, L. Rovati Shareholder of: Rottapharm Biotech Srl, Employee of: Rottapharm Biotech Srl