Session Information
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose:
Non-selective Janus kinase (JAK) inhibitors have shown long-term efficacy in treating rheumatoid arthritis (RA). However, clinical efficacy is limited due to concerns of dose-limiting toxicity related to JAK2/3 inhibition such as anemia, malignancies and infections. The objectives of this study were to reveal pharmacological profiles of a novel JAK1-selective inhibitor, NIP-565, and to estimate its therapeutic potential and safety in the treatment of RA patients.
Methods:
Enzyme assays and cell-based assays were conducted to assess the JAK1 selectivity of NIP-565. As therapeutic activity for RA patients, in vitro JAK1 signaling inhibitory activity was evaluated by IL-6-induced STAT1 phosphorylation using human peripheral blood. In vivo therapeutic potential of NIP-565 was evaluated the reduction of paw swelling in collagen-induced arthritic (CIA) rats. In order to estimate the risk of adverse events caused by JAK3 inhibition, NK cell numbers and NK cell cytotoxic activity were compared in the NIP-565 or tofacitinib treatment animals. The effect on erythropoietin -stimulated erythropoiesis using human bone marrow cells was examined to assume the risk of anemia caused by JAK2 inhibition. Human pharmacokinetics prediction was performed by allometric scaling methods.
Results:
NIP-565 inhibited JAK1 in the nM range, and showed more than 10-fold selectivity towards JAK2, JAK3, and Tyk2. NIP-565 inhibited IL-6-induced phosphorylation of STAT1, at sub-μM IC50 value. This inhibition was 37-fold stronger than the inhibitory effect on GM-CSF-induced STAT5 phosphorylation as cellular JAK2 activity, and 2-fold stronger than the inhibitory effect on IL-15-induced phospho-STAT1 production as cellular JAK1/JAK3 activity. In a rat CIA model, NIP-565 attenuated paw swelling in a dose-dependent manner after repeated oral administration once per day for 15 days. Both NIP-565 and tofacitinib completely suppressed at 30 mg/kg dosing. NK cell numbers in the peripheral blood of CIA model rats were 2-fold higher in the NIP-565-treated group than in the tofacitinib-treated group at 30 mg/kg. In tumor-bearing mice model, NIP-565 (30 mg/kg, 2 weeks) maintained NK cell cytotoxic activity compared with control, while tofacitinib (30 mg/kg) reduced that activity. These data suggest that the risk of adverse events caused by NK cell attenuation with NIP-565 treatment may be lower than that with tofacitinib treatment. Additionally, NIP-565 showed weaker inhibitory effect than other JAK inhibitors (e.g., tofacitinib, baricitinib and peficitinib) in human erythropoiesis assay. As a result of analysis with human pharmacokinetics prediction, NIP-565 could be enough exposure to provide high therapeutic efficacy without anemia in clinical practice by once daily oral administration.
Conclusion:
NIP-565 is a novel JAK1-selective inhibitor, and expected to provide potent anti-inflammatory effects while minimizing the adverse effects that would result from JAK2/3 inhibition in the treatment of RA patients.
To cite this abstract in AMA style:
Hidaka Y, Nakamura T, Igarashi T, Nanya T, Hagiwara S, Takeuchi K, Yaguchi T, Kawakami Y, Naito T. NIP-565, a Novel JAK1-Selective Inhibitor, for the Treatment of Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/nip-565-a-novel-jak1-selective-inhibitor-for-the-treatment-of-rheumatoid-arthritis/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/nip-565-a-novel-jak1-selective-inhibitor-for-the-treatment-of-rheumatoid-arthritis/