Background/Purpose: Rheumatoid arthritis (RA) is characterized by leukocyte infiltration, synoviocyte hyperplasia and osteoclastogenesis, and tyrosine kinases have key roles in the signaling pathways that regulate these processes. Bruton’s tyrosine kinase (Btk) is a key regulator of B-cell receptor (BCR) function. B-cell receptors play a central role in signal transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. Furthermore, Btk mutations in humans cause X-linked agammaglobulinaemia, an inherited disorder characterized by severe B-cell specific defects, including the complete absence of B-cells in the periphery. The effectiveness of B-cell targeted therapy in the treatment of RA (e.g., Rituximab), further supports the role of B-cells in RA. ONO-4059 is a highly potent and selective Btk inhibitor with an IC₅₀in the sub-nmol/L range. The activity of ONO-4059 was evaluated in a mouse collagen induced arthritis (CIA) model.

Methods: Male DBA/1J mice were immunized on days 0 and 21 with Freund’s Complete Adjuvant containing bovine type II collagen. Mice were randomized to three treatment groups starting from day 22 to 36 and received oral ONO-4059, once daily at doses of 1 mg/kg, 3 mg/kg and 10 mg/kg respectively. The mice were weighed weekly and scored daily for signs of arthritis. Each paw was scored and the sum of all four scores was recorded using the Arthritic Index (AI). The maximum possible AI score was 16. Joint histology on day 36 was evaluated for cartilage damage, bone damage, extra-articular inflammation and pannus. To further characterize the effect of ONO-4059 in the CIA model, human monocytes were stimulated with immobilized hIgG or TLR-9 ligand (CpG-B) for 18 hr. TNFα and IL-6 production was determined by Luminex.

Results: Treatment with ONO-4059 resulted in a dose-dependent inhibition of arthritis severity and bone damage in the CIA model. The mean disease score of the ONO-4059-treated animals was 10.9, 5.3 and 2.3 for the 1, 3 and 10 mg/kg dose groups respectively. In comparison, the mean score in the vehicle-treated animals was 13. In a cell-based assay, ONO-4059 prevented FcγR-induced TNFα and IL-6 production in monocytes with IC₅₀ values of 5.66 nM and 22.4 nM, respectively. ONO-4059 also suppressed TLR9-induced TNFα and IL-6 production in monocytes with IC₅₀values of 4.45 nM and 12.4 nM, respectively. Furthermore, ONO-4059 prevented B-cell activation in the 10 nM range but it had no effects on T-cell activation.

Conclusion: ONO-4059 is a highly potent and selective oral Btk inhibitor. We have demonstrated that ONO-4059 potently and dose-dependently reversed clinical arthritis and prevented bone damage in the CIA model.. The cellular and molecular mechanisms by which Btk mediates inflammation are not fully understood. This data supports that ONO-4059 inhibits immune-receptor signaling in multiple cells through Btk inhibition and these preliminary results suggest that ONO-4059 may be a promising therapeutic approach for patients with rheumatoid arthritis and warrants further investigation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-a-brutons-tyrosine-kinase-btk-inhibitor-ono-4059-efficacy-in-a-collagen-induced-arthritis-cia-model-indicates-potential-treatment-for-rheumatoid-arthritis-ra/