Pharmacokinetics, Safety, and Tolerability of the Dual Inhibitor of Tumor Necrosis Factor-α and Interleukin 17A, ABBV-257, in Healthy Volunteers and Patients With Rheumatoid Arthritis.

The dual-variable domain immunoglobulin ABBV-257 binds tumor necrosis factor-α and interleukin 17A. Following single ascending doses ( 0.3, 1.0, and 3.0 mg/kg intravenously; 0.3 and 3.0 mg/kg subcutaneously) in a randomized, double-blind, placebo-controlled study in healthy subjects (n = 40; n = 29 evaluated for pharmacokinetics), maximum observed serum concentration (Cmax ) increased dose-proportionally, whereas area under the serum concentration-versus-time curve trended to more than dose-proportional increase. Absolute subcutaneous bioavailability was ∼80%, and the time to Cmax (tmax ) occurred 6 to 8 days after subcutaneous administration. The terminal-phase harmonic mean elimination half-life (t½ ) ranged from 5.5 to 11 days following intravenous and subcutaneous administration. In another randomized, placebo-controlled study, rheumatoid arthritis (RA) patients (n = 8) received ABBV-257 30 mg/kg subcutaneously every other week for 8 weeks. Following the fourth dose, Cmax was 7.69 μg/mL, and tmax occurred ∼4 days after dosing; t½ was ∼16 days. Most individuals (single-dose study, 97%; multiple-dose study, 83%) developed antidrug antibodies (ADAs). Generally, subjects with higher ADA titers had shorter ABBV-257 t½ and lower exposure. One serious adverse event (cerebral ischemia, considered unrelated to treatment, resolved with interventions) occurred in an RA patient who received ABBV-257. Because of the high incidence of ADA-mediated drug clearance, ABBV-257 is no longer being developed.