Background/Purpose: 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). The objectives of this study were to identify in vitro and in vivopharmacological profiles of a novel synthesized compound, ASP015K, and to evaluate its therapeutic potential in the treatment of RA patients using an experimental animal model.

Methods: In vitroenzyme inhibition assays were conducted against JAKs 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. 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. Dunnett’s and Steel’s multiple comparison tests were used to compare ASP015K-treated groups with the control group of the paw volume and ankle bone destruction score, respectively.

Results: ASP015K inhibited JAK1, JAK2, JAK3 and TYK2 enzyme activities with IC₅₀ values of 3.9, 5.0, 0.71 and 4.8 nM, respectively. ASP015K inhibited the IL-2-induced proliferation of human T cells with an IC₅₀value of 18 nM. Moreover, ASP015K was 14-fold more potent against JAK1/3 than JAK2/2 on the basis of EPO-induced proliferation of human leukemia cells. This selectivity suggests that ASP015K has the potential to demonstrate JAK1/3-mediated immunomodulatory effects without the occurrence of JAK2-mediated hematopoietic effects. In rat AIA model, the hind paw volume gradually increased starting 10 days after adjuvant injection and ankle bone destruction was established by day 25, the end of the experiment. After once-daily oral administration of ASP015K 1 to 30 mg/kg in prophylactic dosing regimen, the increase in paw volume was significantly (p<0.05) decreased in a dose-dependent manner and was completely suppressed at the highest dose compared to control. Similar findings of dose-dependent reduction in ankle bone destruction score were observed. In therapeutic dosing regimens initiated after paw swelling was established, paw swelling and ankle bone destruction score was also suppressed in a dose-dependent manner.

Conclusion: Data from the current study demonstrates that ASP015K potently 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 such as anemia. In rat AIA model, ASP015K demonstrated a dose-dependent reduction in paw swelling and suppression of ankle bone destruction scores after both prophylactic and therapeutic dosing regimens. The data suggests that ASP015K has the potential to reduce clinical signs and symptoms as well as prevent disease progression in RA patients warranting further clinical investigation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/asp015k-a-novel-jak-inhibitor-demonstrated-potent-efficacy-in-adjuvant-induced-arthritis-model-in-rats/