Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050

Journal of Immunology 2010; 184(9):5298-307

This preclinical characterisation study examined the efficacy and tolerability of the small molecule INCB028050 (now known as baricitinib), an orally bioavailable, selective Janus kinase (JAK) 1/JAK2 inhibitor, in rodent models of arthritis. The decision to investigate its effects of INCB028050 followed positive evidence for the related compound ruxolitinib, the JAK inhibitor tofacitinib and the IL-6 inhibitor tocilizumab in rheumatoid arthritis (RA). In this preclinical study, INCB028050 was shown to inhibit intracellular signalling of multiple pro-inflammatory cytokines including IL-6 and IL-23. It produced significant improvements in efficacy for clinical, histologic and radiographic signs of disease in rat adjuvant arthritis models through partial and/or periodic inhibition of JAK1/JAK2, with no inhibition of JAK3. Levels of inflammatory Th1- and Th17-associated cytokine mRNA in the draining lymph nodes of treated rats decreased following administration of INCB028050. This small molecule was also effective in multiple murine models of arthritis, with no evidence of suppression of humoral immunity or adverse haematological effects. The data reported in this paper indicated that fractional inhibition of JAK1 and JAK2 with INCB028050 is sufficient to produce significant activity in autoimmune disease models and resulted in continued clinical evaluation of its role in the treatment of RA.