In vitro and in vivo characterization of the JAK1 selectivity of upadacitinib (ABT-494)

Abstract

Background Anti-cytokine therapies such as adalimumab, tocilizumab, and the small molecule JAK inhibitor tofacitinib have proven that cytokines and their subsequent downstream signaling processes are important in the pathogenesis of rheumatoid arthritis. Tofacitinib, a pan-JAK inhibitor, is the first approved JAK inhibitor for the treatment of RA and has been shown to be effective in managing disease. However, in phase 2 dose-ranging studies tofacitinib was associated with dose-limiting tolerability and safety issues such as anemia. Upadacitinib (ABT-494) is a selective JAK1 inhibitor that was engineered to address the hypothesis that greater JAK1 selectivity over other JAK family members will translate into a more favorable benefit:risk profile. Upadacitinib selectively targets JAK1 dependent disease drivers such as IL-6 and IFNγ, while reducing effects on reticulocytes and natural killer (NK) cells, which potentially contributed to the tolerability issues of tofacitinib. Methods Structure-based hypotheses were used to design the JAK1 selective inhibitor upadacitinib. JAK family selectivity was defined with in vitro assays including biochemical assessments, engineered cell lines, and cytokine stimulation. In vivo selectivity was defined by the efficacy of upadacitinib and tofacitinib in a rat adjuvant induced arthritis model, activity on reticulocyte deployment, and effect on circulating NK cells. The translation of the preclinical JAK1 selectivity was assessed in healthy volunteers using ex vivo stimulation with JAK-dependent cytokines. Results Here, we show the structural basis for the JAK1 selectivity of upadacitinib, along with the in vitro JAK family selectivity profile and subsequent in vivo physiological consequences. Upadacitinib is ~ 60 fold selective for JAK1 over JAK2, and > 100 fold selective over JAK3 in cellular assays. While both upadacitinib and tofacitinib demonstrated efficacy in a rat model of arthritis, the increased selectivity of upadacitinib for JAK1 resulted in a reduced effect on reticulocyte deployment and NK cell depletion relative to efficacy. Ex vivo pharmacodynamic data obtained from Phase I healthy volunteers confirmed the JAK1 selectivity of upadactinib in a clinical setting. Conclusions The data presented here highlight the JAK1 selectivity of upadacinitinib and supports its use as an effective therapy for the treatment of RA with the potential for an improved benefit:risk profile. Electronic supplementary material The online version of this article (10.1186/s41927-018-0031-x) contains supplementary material, which is available to authorized users.

Clinical Pharmacokinetics of Upadacitinib: Review of Data Relevant to the Rheumatoid Arthritis Indication

“…Upadacitinib is currently under regulatory review by other agencies around the world and is being evaluated in clinical trials for the treatment of other inflammatory conditions [7][8][9][10]. Upadacitinib potently inhibits JAK1 and is less potent against the other isoforms, JAK2, JAK3, and TYK2 [11]. The hypothesis behind the development of upadacitinib is that higher potency against JAK1 has the potential to maximize efficacy in RA while limiting the effects on physiological functions that involve JAK enzymes (e.g., hematopoiesis and immune function) [11,12].…”

Exposure–Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit–Risk Assessment in Rheumatoid Arthritis

“…14 Upadacitinib potently inhibits JAK1, but is less potent against the other isoforms, such as JAK2, JAK3, and tyrosine kinase 2 (Tyk2). 15,16 The enhanced selectivity of upadacitinib against JAK1 may offer an improved benefit-risk profile compared with less selective JAK inhibitors. 17,18 Upadacitinib demonstrated robust efficacy and acceptable safety in two phase II and in five phase III studies in subjects with moderate to severe RA.…”

Characterization of the Effect of Renal Impairment on Upadacitinib Pharmacokinetics

“…Upadacitinib (ABT‐494) is a novel, Janus kinase (JAK) inhibitor with preferential selectivity toward JAK1. Upadacitinib potently inhibits JAK1 but is less potent against the other isoforms, JAK2, JAK3, and tyrosine kinase 2 . The enhanced selectivity of upadacitinib against JAK1 may offer an improved benefit‐risk profile in patients with inflammatory disease, including limiting the adverse effects on immune function and erythropoietin signaling .…”

“…Upadacitinib potently inhibits JAK1 but is less potent against the other isoforms, JAK2, JAK3, and tyrosine kinase 2. 1 The enhanced selectivity of upadacitinib against JAK1 may offer an improved benefit-risk profile in patients with inflammatory disease, including limiting the adverse effects on immune function and erythropoietin signaling. 2,3 Upadacitinib is being developed for the treatment of rheumatoid arthritis (RA) as well as for other immune-mediated inflammatory diseases.…”