AZD6793, A Novel IRAK4 Inhibitor, Targets Multiple Disease-relevant Pathways in Pre-clinical Models of Chronic Obstructive Pulmonary Disease

Abstract RATIONALE Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide and approved treatment options today are insufficient to adequately prevent exacerbations or to alter the progression of the disease. COPD is a biologically complex disease with multiple disease drivers leading to chronic inflammation, emphysema development and small airway remodeling. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a key regulator of signaling downstream of toll-like receptors (TLRs) and receptors of the interleukin 1(IL-1) family, including the receptors for IL-33, IL-1α, IL-1β and IL-36. TLR/IL-1R signaling, triggered by viral and bacterial infections as well as cigarette smoke, can drive COPD disease pathology, and therapeutic strategies targeting e.g. IL-33 are now in clinical development for COPD. Therefore, the aim of this study was to evaluate the pre-clinical effect of AZD6793, a novel oral IRAK4 inhibitor currently undergoing clinical investigation, in disease relevant models of COPD. METHODS Primary human cells, lung tissue, and mouse in vivo models were used to study the effect of AZD6793 on airway inflammation triggered by lipopolysaccharide (LPS), cigarette smoke, IL-33, IL-1β and IL-36. RESULTSIn vitro, IRAK4 inhibition with AZD6793 resulted in potent and substantial suppression of inflammatory cytokine release downstream of IL-1 family cytokines and TLR ligands in human peripheral blood mononuclear cells, as well as in small airway epithelial cells and alveolar macrophages from COPD patients. We showed that AZD6793 efficiently blocked IL-33 induced IL-5 release in fresh human lung tissue as well as in an in vivo model of intranasal IL-33 administration. Moreover, AZD6793 was shown to have a robust effect on blocking neutrophilic airway inflammation induced by LPS or IL-36 in vivo in mice. AZD6793 also reduced the release of proteases (matrix metalloproteinase 12 and 8 and neutrophil elastase) in the airways and suppressed the expression of the mucus gene Muc5ac in mice exposed to cigarette smoke. Importantly, AZD6793 efficiently blocked inflammation that could not be suppressed by steroids in models of IL-1β and IL-36γ-induced inflammation. CONCLUSION Overall, our data indicate that IRAK4 is a central regulator of multiple inflammatory processes in the airways and support the development of AZD6793 as a novel therapeutic approach in COPD.