OP0046 TARGETING IRAK1 AND 4 SIGNALING WITH R835, A NOVEL ORAL SMALL MOLECULE INHIBITOR: A POTENTIAL NEW TREATMENT FOR SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract

Background:Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by loss of immunological tolerance, hyperactivation of immune cells, proinflammatory cytokine production and, ultimately, end organ damage due to immune complex deposition. Toll-like receptors (TLRs), which are essential to the innate immune response to microbes and other danger signals, play a key role in the pathogenesis of SLE by recognition of self-molecules (1). Interleukin receptor associated kinases (IRAK)1 and 4 are responsible for initiating MyD88-dependent signaling from most TLRs and Interleukin-1 Receptors (IL-1R) and represent attractive targets for the therapeutic treatment of SLE (2). 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 potential therapeutic approach for SLE. We evaluated the effect of our clinical candidate R835 on TLR7 signaling and in a mouse model of lupus-like disease.Methods:Human primary dendritic cells and whole blood were stimulated with gardiquimod (TLR7 agonist) to evaluate the effect of R835 on Interferon-alpha (IFN-α) production. R835 was further evaluated for its efficacy on survival and disease progression in lupus-prone NZB/W F1 mice with early or active signs of disease.Results:R835 inhibited TLR7-induced cytokine production in human dendritic cells and whole blood. Given orally to mice, R835 dose-dependently decreased serum IFN-α in response to administration of a TLR7 agonist. Furthermore, treatment of NZB/W F1 lupus-prone mice with R835 reversed the progression of lupus-like disease and the establishment of a pro-inflammatory environment, as demonstrated by decreased levels of proteinuria, blood urea nitrogen and autoantibodies, and reversal of renal pathology.Conclusion:To our knowledge, R835 is the first dual IRAK1/4 inhibitor to enter clinical development and provides an attractive approach to treat a range of autoimmune and rheumatic diseases, including lupus.