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

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.

Between the flags: implementing a safety-net system at scale to recognise and manage deteriorating patients in the New South Wales Public Health System.

QUALITY PROBLEM: In 2005, the Clinical Excellence Commission (CEC) found that unrecognised patient deterioration remained an important problem in New South Wales (NSW) public hospitals. INITIAL ASSESSMENT: The challenge was to design and implement an effective and sustainable safety-net system in all 225 NSW public hospitals. DESIGNING A SOLUTION: The CEC's system was designed in collaboration with a broad coalition of partners, including clinicians, managers, system administrators and collaborating agencies. A five-element system comprising governance, standard calling criteria in standard observation charts, two-level clinical emergency response systems (CERS) in each facility, an education programme and evaluation, was designed for state-wide implementation. This system was called 'Between the Flags' (BTF). IMPLEMENTATION: Implementation was led by the CEC on behalf of a NSW coalition, and commenced in January 2010 with the implementation of the Standard Adult General Observation Chart, awareness training for all staff and a CERS in each facility. EVALUATION: Since the introduction of BTF, the cardiac arrest rate has declined by 42% (P < 0.05) and the Rapid Response rate has increased by 135.9% (P < 0.05) in NSW. The strength of staff support for BTF has grown with the proportion of respondents strongly agreeing that BTF has benefitted patient safety more than doubling from 21% to 44%, and overall agreement rising from 68% to 82% between 2010 and 2012. LESSONS LEARNED: Key success factors are a focus on governance, standardisation of observation charts and striking the right balance between a rule-based approach and individual clinical judgement.

Structure activity optimization of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines as Jak1 kinase inhibitors.

Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2.