Pharmacokinetics of ABT-122, a TNF-α- and IL-17A-Targeted Dual-Variable Domain Immunoglobulin, in Healthy Subjects and Patients with Rheumatoid Arthritis: Results from Three Phase I Trials.

BACKGROUND AND

objectiveABT-122 is a dual-variable domain immunoglobulin that neutralizes both tumor necrosis factor-α and interleukin-17A, with the goal of achieving greater clinical efficacy than can be achieved by blocking either cytokine alone. This work characterized the pharmacokinetics of ABT-122 in healthy subjects and in patients with rheumatoid arthritis.

methodsABT-122 pharmacokinetics was evaluated in three phase I studies. In Study 1, single intravenous (0.1, 0.3, 1, 3, and 10 mg/kg) and subcutaneous (0.3, 1, and 3 mg/kg) doses were evaluated in healthy subjects. In Studies 2 and 3, multiple subcutaneous doses (1 mg/kg every other week or 0.5-3 mg/kg every week) were evaluated for 8 weeks in patients with rheumatoid arthritis on stable methotrexate therapy. Pharmacokinetic data were available from 48 healthy subjects and 31 patients with rheumatoid arthritis.

resultsABT-122 showed multi-exponential disposition with more than dose-proportional exposures at the 0.1-1 mg/kg doses and approximately dose-proportional exposures at doses ≥1 mg/kg. ABT-122 absolute subcutaneous bioavailability was approximately 50% with maximum serum concentrations observed 3-4 days after dosing. Steady state was achieved by week 6 of subcutaneous dosing. ABT-122 maximum serum concentration-to-trough concentration ratio was 2.6 for every other week dosing and 1.3 for every week dosing, corresponding to an effective half-life of 10-18 days. ABT-122 median area under the serum concentration-time curve accumulation ratio was 3.8-4.8 with every week dosing. Measureable antidrug antibodies were observed in all 48 subjects in Study 1 by day 15 post-dose and 19 of 31 ABT-122-treated patients in Studies 2 and 3 [median time to appearance of antidrug antibodies of 64 days (range 15-92 days)]. No dose-limiting toxicities were observed in these studies and the maximum tolerated dose was not identified.

conclusionsResults from these three phase I studies supported testing ABT-122 every week and every other week regimens in phase II trials in subjects with rheumatoid and psoriatic arthritis. Study 2 (EudraCT: 2012-003448-54); Study 3 (NCT01853033).