OP0133 PRECLINICAL EFFICACY OF R835, A NOVEL IRAK1/4 DUAL INHIBITOR, IN RODENT MODELS OF JOINT INFLAMMATION

Abstract

Background:Interleukin receptor associated kinases (IRAK) 1 and 4 are kinases involved in Toll-Like Receptor (TLR) and Interleukin-1 Receptor (IL-1R) signaling pathways, which regulate innate immunity and inflammation. Dysregulation of IRAK1/4 signaling can lead to a variety of inflammatory conditions including rheumatoid and gouty arthritis. As a result, IRAK1/4 are promising therapeutic targets for rheumatic diseases (1). We have identified a potent and selective IRAK1/4 inhibitor, R835, that substantially suppressed the elevation of LPS (TLR4 agonist)-induced serum cytokines in healthy human volunteers in a recently completed phase 1 study.Objectives:The aim of our study was to investigate the effect of IRAK1/4 selective inhibition as a potential therapeutic approach for rheumatological diseases. We evaluated the inhibition by our clinical candidate, R835, on TLR-, IL-1R- and NLRP3 inflammasome-induced cytokine production, as well as in preclinical models of arthritis.Methods:The effect of R835 on TLR- or IL-1R-induced cytokine production was evaluated in vitro using THP-1, human primary endothelial cells and human primary dendritic cells. The activity of R835 on the NLRP3 inflammasome was also tested in vitro using THP-1 cells. The pharmacokinetic-pharmacodynamic relationship of R835 was evaluated in a mouse model of IL-1b-induced cytokine release. Mice were pre-treated orally with vehicle or R835 prior to challenge; serum cytokine and plasma compound levels were determined. The efficacy of IRAK1/4 inhibition by R835 in rodent models of joint inflammation was evaluated in a mouse model monosodium (MSU)-induced peritonitis, in rat model of MSU-induced gouty arthritis and in a rat model of collagen-induced arthritis (CIA).Results:In human cells, R835 blocked proinflammatory cytokine production in response to TLR, IL-1R and NLRP3 inflammasome activation. In mice, R835 dose-dependently decreased serum cytokines in response to administration of IL-1b. Mice pre-treated with R835 demonstrated dose-dependent reductions in MSU crystal-induced serum and peritoneal cytokine levels, as well as neutrophil influx in the peritoneal cavity. Prophylactic and therapeutic treatment with R835 also resulted in significant inhibition of MSU crystal-induced knee edema and pain in a rat model of human gouty arthritis. In the rat model of CIA, R835 blocked both onset and progression of disease, by reducing inflammation, cartilage degeneration and synovial inflammation.Conclusion:R835 is a promising clinical candidate for the treatment of a range of cytokine-driven rheumatological diseases. R835 has proven to have desirable pharmacokinetic properties, was well tolerated and suppressed LPS-induced serum cytokines in healthy volunteers in a recent phase 1 study.