THU0195 Preferential Inhibition of IL-6 Relative To IL-7 Signaling Pathways by ABT-494: Exposure-Response Analysis of ex-Vivo Data from Two Phase 1 Clinical Trials and Comparison To Tofacitinib
Authors: M.-E. Mohamed, D. Koenig, H.S. Camp, S. Jungerwirth, A.A. Othman
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> ABT-494 is a Janus activated kinase (JAK) inhibitor that demonstrated robust efficacy in Phase 2 clinical trials in rheumatoid arthritis and is currently being evaluated in Phase 3. ABT-494 has a higher in vitro potency against JAK1 compared to JAK2 and JAK3 isoforms. Selectivity of ABT-494 towards JAK1 has the potential to provide an improved safety profile compared to less selective JAK inhibitors. <h3>Objectives</h3> The objective of this work was to characterize the effects of ABT-494 on IL-6 and IL-7 signaling pathways and to compare the in-vivo potency of ABT-494 versus tofacitinib in inhibiting these different pathways in humans. <h3>Methods</h3> Data from two Phase 1 clinical studies of ABT-494 immediate-release capsules were included in this analysis. In the first study, single doses of ABT-494 (1, 3, 6, 12, 24, 36, and 48 mg) or placebo were administered to healthy subjects. In the second study, multiple doses of ABT-494 (3, 6, 12, and 24 mg), placebo, or tofacitinib (5 mg) were administered to healthy subjects twice daily for 14 days and multiple doses of ABT-494 (6, 12, and 24 mg) or placebo were administered twice daily to subjects with mild to moderate rheumatoid arthritis. Blood samples were collected to measure plasma concentrations of ABT-494 or tofacitinib and the degree of inhibition of IL-6-induced STAT3 phosphorylation (pSTAT3) and IL-7-induced STAT5 phosphorylation (p-STAT5) as measures of in-vivo inhibition of JAK1 and JAK1/JAK3, respectively, in whole blood. Non-linear mixed-effects modeling was conducted to characterize the relationships between ABT-494 or tofacitinib pharmacokinetics and ex-vivo IL-6-induced pSTAT3 and IL-7-induced pSTAT5. The dataset included 68 subjects who received ABT-494, 23 subjects who received placebo, and 9 subjects who received tofacitinib. <h3>Results</h3> Dose dependent inhibition of IL-6-induced pSTAT3 and IL-7-induced pSTAT5 relative to baseline was observed, with maximum inhibition occurring at 1 hour after ABT-494 dose administration. The relationships between ABT-494 or tofacitinib plasma concentrations and IL-6-induced pSTAT3 and IL-7-induced pSTAT5 were adequately described using direct E<sub>max</sub> models. The relationship between ABT-494 plasma concentrations and the ex-vivo pharmacodynamic effects were consistent in healthy volunteers and rheumatoid arthritis patients. The model-estimated plasma EC<sub>50</sub> [95% bootstrap confidence interval] values for inhibition of IL-6-induced pSTAT3 and inhibition of IL-7-induced pSTAT5 were 61 [48 to 77] nM and 125 [106 to 143] nM, respectively, for ABT-494 versus 119 [87 to 160] nM and 79 [69 to 91] nM, respectively, for tofacitinib. <h3>Conclusions</h3> ABT-494 is more potent than tofacitinib in inhibiting IL-6-induced pSTAT3 (mediated predominantly through JAK1) and is less potent than tofacitinib in inhibiting IL-7-induced pSTAT5 (mediated through JAK1 and JAK3). These results are consistent with higher in vitro potency of ABT-494 against JAK1 compared to JAK3. Results from the ongoing Phase 3 trials will determine whether the improved selectivity profile of ABT-494 will translate into improved benefit to risk profile compared to less selective JAK inhibitors. <h3>Disclosure of Interest</h3> M.-E. Mohamed Shareholder of: AbbVie, Employee of: AbbVie, D. Koenig Shareholder of: AbbVie, Employee of: AbbVie, H. Camp Shareholder of: AbbVie, Employee of: AbbVie, S. Jungerwirth Shareholder of: AbbVie, Employee of: AbbVie, A. Othman Shareholder of: AbbVie, Employee of: AbbVie