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

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. References: [1]Signals via the Adaptor MyD88 in B cells and DCs Make Distinct and Synergistic Contributions to Immune Activation and Tissue Damage in Lupus. Lino L. Teichmann, Dominik Schenten, Ruslan Medzhitov, Michael Kashgarian, and Mark J. Shlomchik. Immunity. 2013 March 21; 38(3): 528–540. [2]Suppression of IRAK1 or IRAK4 Catalytic Activity, but Not Type 1 IFN Signaling, Prevents Lupus Nephritis in Mice Expressing a Ubiquitin Binding-Defective Mutant of ABIN1. Nanda SK, Lopez-Pelaez M, Arthur JS, Marchesi F, Cohen P. J Immunol. 2016 Dec 1;197(11):4266-4273. Disclosure of Interests: Chrystelle Lamagna Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Meagan Chan Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Art Bagos Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Ernest Tai Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Chi Young Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Yan Chen Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Lu Chou Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Gary Park Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Esteban Masuda Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals, Vanessa Taylor Shareholder of: Rigel Pharmaceuticals, Employee of: Rigel Pharmaceuticals