Session Type: Abstract Submissions (ACR)
Jak kinase blockade can effectively manage rheumatoid arthritis (RA) and in some cases achieve remission. However, first generation Jak inhibitors have not met expectations due to dose-limiting tolerability and safety issues. ABT-494 is a second generation Jak inhibitor with high Jak1 selectivity thereby minimizing the potential for Jak2 and Jak3 related side effects. Here we describe preclinical and early clinical data that suggest ABT-494 has potential to address some of the current unmet medical needs of RA patients.
ABT-494 was engineered for increased selectivity for Jak1 using structural predictions indicating the potential for differential binding interactions outside the ATP-binding active site of Jak1 but not Jak2 or Jak3. ABT-494 efficacy and selectivity were tested in a battery of relevant cellular and in vivo pharmacology assays including bone marrow colony formation, adjuvant induced arthritis, erythropoietin (EPO) induced reticulocyte deployment and NK/NKT cell suppression. ABT-494 potency in a variety of complementary pharmacodynamic assays was also assessed at multiple oral dosages in healthy human subjects and patients with RA.
ABT-494 is approximately 74 fold selective for Jak1 over Jak2 in cellular assays dependent on specific, relevant cytokines. The ability of ABT-494 and tofacitinib to inhibit Jak2/EPO signaling in these assays was consistent with their ability to inhibit bone marrow cell differentiation in vitro. Surprisingly, GMCSF (and IL3) signaling in TF1 cells were consistently more sensitive to inhibition than EPO signaling in UT7 cells indicating that Jak2 inhibition in some contexts may over-estimate inhibition of Jak2 via EPO signaling. Accordingly, in whole blood assays, ABT-494 was about 10X more potent against IL6 (Jak1) signaling than GMCSF (Jak2) driven signaling based on free drug concentrations. By contrast, tofacitinib under the same conditions was about 2X more potent. No changes in reticulocyte counts were observed in RA patients after 28 days of ABT-494 dosing.
ABT-494 and tofacitinib inhibited common gamma chain cytokine signaling (IL7, IL15 and IL21) in whole blood with similar potencies and in vivo were similarly potent in driving down NK cell counts in healthy rats. Consistent with its higher potency against IL6 signaling, ABT-494 had substantially greater potency in a rat arthritis model.
ABT-494 is a Jak1-selective inhibitor that demonstrates efficacy in rat arthritis models. Preliminary evidence suggests that compared to tofacitinib, ABT-494 may spare Jak2 and Jak3 dependent signaling. Taken together, these encouraging observations support further testing of ABT-494 in RA patients in Phase II randomized placebo controlled trials and indicate it may have increased potential to address patient needs over existing agents.
« Back to 2014 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/characterization-of-abt-494-a-second-generation-jak1-selective-inhibitor/