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.