THU0101 ASP015K: A Novel Jak Inhibitor Demonstrated Potent Efficacy in Adjuvant-Induced Arthritis Model in Rats
Authors: S. Yamazaki, H. Morio, M. Inami, M. Ito, Y. Fujii, K. Hanaoka, K. Yamagami, K. Okuma, Y. Morita, S. Shirakami, T. Inoue, S. Miyata, Y. Higashi, N. Seki
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The Janus kinase (JAK) family of enzymes plays a key role in cytokine signaling, which is involved in the pathogenic events of immune-mediated disorders such as rheumatoid arthritis (RA). <h3>Objectives</h3> The aim of this study was to identify pharmacological profiles of a newly synthesized JAK inhibitor, ASP015K, and to estimate its therapeutic potential in the treatment of RA patients using an experimental animal model. <h3>Methods</h3> In vitro enzyme inhibition assays were conducted against JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) enzymes. Cell-based assays were also conducted to assess the selectivity of ASP015K for signaling via JAK1/JAK3 over JAK2/JAK2. JAK1/3 activation was evaluated by interleukin (IL)-2-stimulated T cell proliferation; JAK2/2 action was evaluated by erythropoietin (EPO)-stimulated erythroleukemia cell proliferation. Phosphorylation of signal transducer and activator of transcription5 (STAT5) was quantified by flow cytometry as a biomarker of JAK activity in vitro in human whole blood and ex vivo in rat whole blood. In order to evaluate the potential efficacy of ASP015K to reduce clinical signs and symptoms of RA as well as disease progression, the reduction of paw swelling and ankle bone destruction in adjuvant-induced arthritic (AIA) rats were assessed after both prophylactic and therapeutic dosing regimens of ASP015K. <h3>Results</h3> ASP015K was shown to inhibit JAK enzymes, with moderate selectivity for JAK3. ASP015K suppressed the IL-2-induced proliferation of human T cells with greater potency than EPO-induced proliferation of human erythroleukemia cells. ASP015K inhibited STAT5 phosphorylation (pSTAT5) in human whole blood in a concentration related manner. Additionally, after oral administration, ASP015K also suppressed pSTAT5 in rat whole blood. In the rat AIA model, the hind paw volume gradually increased after adjuvant injection and ankle bone destruction was established. In a prophylactic dosing regimen, the increase in paw volume was significantly decreased by oral administration of ASP015K in a dose-dependent manner. Similar findings in ankle bone destruction score were observed. In a therapeutic dosing regimen, paw swelling and ankle bone destruction score were also suppressed in a dose-dependent manner. <h3>Conclusions</h3> Data from the current study demonstrate that ASP015K inhibits human JAK enzymes with moderate selectivity against JAK1/3 over JAK2/2, which may translate to less hematological side effects observed in the clinic. ASP015K improved paw swelling and ankle bone destruction after both prophylactic and therapeutic dosing regimens in the rat AIA model. These data together with the finding that ASP015K suppressed pSTAT5 in whole blood after oral administration in rats suggest that the effects of ASP015K on AIA model are due to JAK inhibition. These data also suggest that ASP015K has the potential to reduce clinical signs and symptoms as well as prevent disease progression in RA patients and warrants further clinical investigation. <h3>Disclosure of Interest</h3> S. Yamazaki Employee of: Astellas Pharma Inc., H. Morio Employee of: Astellas Pharma Inc., M. Inami Employee of: Astellas Pharma Inc., M. Ito Employee of: Astellas Pharma Inc., Y. Fujii Employee of: Astellas Pharma Inc., K. Hanaoka Employee of: Astellas Pharma Inc., K. Yamagami Employee of: Astellas Pharma Inc., K. Okuma Employee of: Astellas Pharma Inc., Y. Morita Employee of: Astellas Pharma Inc., S. Shirakami Employee of: Astellas Pharma Inc., T. Inoue Employee of: Astellas Pharma Inc., S. Miyata Employee of: Astellas Pharma Inc., Y. Higashi Employee of: Astellas Pharma Inc., N. Seki Employee of: Astellas Pharma Inc.