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

Background 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. Objectives 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. Methods 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. Results 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 max 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 50 [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. Conclusions 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. Disclosure of Interest 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