Background: Interleukin-1 receptor-associated kinase 4 (IRAK-4) is involved in Toll-Like Receptor (TLR) and Interleukin-1 Receptor (IL-1R) signaling pathways regulating innate immunity. Inhibition of IRAK4 could block the expression of cytokines involved in autoimmune disorders such as rheumatoid arthritis. CA-4948 is a member of the oxazolopyridine class of IRAK4 inhibitors and has been shown to suppress TLR agonist-induced NF-kappaB activation, TNF-alpha and IL-1beta expression in the THP-1 monocytic cell line.

Objectives: Determine whether a highly specific oxazolopyridine IRAK4 inhibitor demonstrates efficacy in mouse models of arthritis and systemic inflammation; compared to an isoquinoline inhibitor PF-06650833.

Methods: We used the mouse model of collagen induced arthritis (CIA) and lipopolysaccharide (LPS)-induced cytokine release mouse model of systemic inflammation. Mice were treated with CA-4948 or PF-06650833. In the CIA mouse model, disease activity was determined by measuring inflammation swelling in the affected joints (paw volume) and clinical score over time. Histopathological evaluation of the sum of hindpaws was performed for CIA study. A single oral dose of IRAK4 inhibitor was administered to CD-1 mice followed by intraperitoneal administration of LPS at 3 hours. ELISA kits were used to evaluate cytokine levels in mouse serum samples at 1 and 3 hours after LPS challenge.

Results: Treatment with CA-4948 or PF-06650833 resulted in inhibition of arthritis severity in the CIA mouse model and a decreased expression of proinflammatory cytokines as measured in mouse blood after LPS challenge. Consistent with CIA in-life data, treatment with CA-4948 decreased the score of all histopathological parameters (inflammation, cartilage erosion, synovial hyperplasia and pannus, bone degeneration/resorption, periosteal/exostotic changes, and composite scores) when compared to vehicle control and the differences attained statistical significance for all histopathological parameters. Treatment with CA-4948 resulted in a significant reduction of cytokine levels by 72% for TNF-alpha and 35% for IL-6 in LPS-induced cytokine release mouse model.

Conclusion: A highly specific oxazolopyridine IRAK4 inhibitor, CA-4948, demonstrated potent therapeutic efficacy in mouse models of arthritis and systemic inflammation.

Disclosure of Interests: Andrey Ugolkov Employee of: I am employed by Curis., Reinhard von Roemeling Employee of: I am employed by Curis, Robert Martell Employee of: I am employed by Curis.