Background/Purpose: Janus kinases (JAKs) play critical roles in mediating various cytokine signaling. First-generation non-selective JAK inhibitors such as tofacitinib and baricitinib are widely used for rheumatoid arthritis (RA). However, safety concerns such as anemia, thrombosis, and infection are raised for these therapeutics primarily linked with insufficient selectivity for JAK subfamily. The second-generation selective JAK1 inhibitor, filgotinib, exhibits a better safety profile, but testicular toxicity issue remains to be resolved. In the present study, we demonstrate that CJ-15314, a novel highly selective JAK1 inhibitor, exhibits robust efficacy in RA animal models with a preferable safety profile.

Methods: Biochemical, cell-based, human whole blood assay were performed to determine the inhibition potency and selectivity for JAK subfamily kinases. In vivo efficacy was evaluated in rat adjuvant-induced arthritis (rAIA) and collagen-induced arthritis (rCIA) models following oral administration (q.d.) for 2 weeks. A 2-weeks rat repeated dose toxicity study was performed to directly compare the toxicity between CJ-15314 and filgotinib.

Results: In biochemical analysis, CJ-15314 inhibited the JAK kinase family in a concentration – dependent manner, and the IC₅₀ value of JAK1 was 3.8 nM, showing 18 fold more highly selectivity over JAK2 and 83 fold over JAK 3. Accordingly, in human whole blood assays, CJ-15314 is 11 fold more potent against IL6-induced pSTAT1 inhibition through JAK1 (IC₅₀ value: 70 nM) than GM-CSF-induced pSTAT5 inhibition (JAK2) whereas bricitinib and filgotinib exhibited only 2-fold and 7 fold respectively. In an in vivo efficacy model, CJ-15314 inhibited disease severity scores in a dose dependent manner. In the rAIA model, relative to vehicle-treated animals, CJ-15314 at 30 mg/kg showed 95.3% decrease in disease activity score, 51.2% in figotinib at 30 mg/kg, baricitinib at 10 mg/kg showed 97.7%. CJ-15314 showed superior anti-arthritic efficacy than filgotinib and similar efficacy to baricitinib. Although baricitinib induced a significant decrease in hematocrit, RBC, and reticulocyte count, CJ-15314 minimally affected anemia-related parameters at end of the 2-week treatment. In the rats CIA model, like 10 mg/kg of bricitinib, 30 mg/kg of CJ-15314 also had a similar effect, with a significant reduction in histopathological scores and plasma IL-1 beta level. In an acute 5-day repeated dose study in mice, CJ-15314 demonstrates relatively low responses to drug-induced platelet counts increase in 10, 30, 90 mg/kg treated groups compared with that of other JAK inhibitors, suggesting a low risk of thrombosis due to inhibition of peripheral thrombopoietin signal. In a rat 2 weeks repeated dose toxicity study, CJ-15314 exhibited a preferable safety profile, whereas tubular atrophy and luminal cell debris were observed testis and epididymis for filgotinib-treated groups.

Conclusion: CJ-15314 is a highly selective JAK1 inhibitor, demonstrates robust efficacy in RA animal models, exhibits differentiated toxicity profiles.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-cj-15314-a-novel-highly-selective-jak1-inhibitor-for-the-treatment-of-rheumatoid-arthritis/