Abstract
Background:Janus kinases (JAKs) serve as signaling hubs orchestrating inflammation, innate and adaptive immunity and erythropoiesis. Unfortunately, some of these agents cause suppression of JAK-dependent erythropoiesis, thereby exacerbating inflammation-associated anemia, leading to potential under-dosing and reduced therapeutic benefit. We previously showed that the JAKi momelotinib (MMB) can correct anemia in a rat model of RA, an effect that has been clinically reproduced in myelofibrosis patients treated with MMB. Subsequently, the molecular basis for MMB’s anemia benefit was determined to be a consequence of its potent inhibition of Activin Receptor Type 1 (ACVR1), resulting in decreased hepcidin and, as a consequence, increased systemic iron availability and improved erythropoiesis.Objectives:The goal of the current study was to investigate the effects of MMB on arthritis in pre-clinical RA models.Methods:The anti-arthritic activity of daily administration of MMB was assessed in Streptococcus cell wall-induced arthritis in Lewis rats (PG-PS model) and in collagen antibody-induced arthritis (CAIA) in DBA/1 mice. Consecutive assessment of arthritis was performed by joint thickness measurements and paw scoring. Following 3 weeks of treatment, synovial immune cell infiltration and T cell subset differentiation was quantified. Cytokine gene expression was profiled by quantitative rt-PCR. Anemia was assessed by determination of blood hemoglobin and serum, spleen and liver iron levels.Results:MMB reduced inflammatory granulocyte and macrophage infiltration in synovial tissue by more than 60% at all tested doses as compared to vehicle treatment in PG-PS animals. Importantly, MMB treatment effectively decreased arthritogenic Th17 cell differentiation and overall CD4+ T cells in the synovia beginning at the lowest tested dose and coincided with complete remission of joint swelling at 25 mg/kg. Anti-arthritic activity of MMB was confirmed with significant reductions in arthritis scoring, which demonstrated non-inferiority versus the TNF-α inhibitor, etanercept, in the CAIA model. Consistent with its inhibitory activity on the ACVR1-hepcidin axis, MMB reduced circulating hepcidin levels and mobilized systemic iron, resulting in substantial improvement of the RA-associated anemia in rats.Conclusion:MMB is a highly efficacious anti-arthritic agent that ameliorates local joint inflammation and reduces the systemic differentiation of major arthritogenic effector cell population, Th17 lymphocytes. In accord with our previous report, MMB is distinct from other JAKi due to its ability to inhibit ACVR1 signaling leading to decreased plasma hepcidin, improved iron homeostasis and increased erythropoiesis. The dual anti-inflammatory and anemia-improving pharmacologic activities of MMB position it as a promising and differentiated therapeutic agent for the treatment of RA and other inflammatory diseases with an anemia component.Disclosure of Interests:Piotr Tymoszuk: None declared, Verena Petzer: None declared, Malte Asshoff: None declared, Andrea Schroll: None declared, Markus Seifert: None declared, Ryan Hansen Employee of: I’m a former employee of Sierra Oncology, Snezana Milutinovic Employee of: I’m a former employee of Sierra Oncology, Bryan Strouse Employee of: I’m an employee of Sierra Oncology, Christian Hassig Employee of: I am a former employee of Sierra Oncology, Guenter Weiss: None declared, Igor Theurl Grant/research support from: I have received research support from Sierra Oncology, Consultant of: I have consulted for Kymba Ltd.
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