Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Anti-TWEAK Monoclonal Antibody in Patients With Rheumatoid Arthritis.

BACKGROUND: Persistent upregulation of signaling by cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) through its receptor fibroblast growth factor-inducible molecule-14 (Fn14) promotes chronic inflammation and tissue destruction. OBJECTIVE: The aim of this study was to explore the safety and tolerability of the TWEAK-blocking mono-clonal antibody BIIB023 and determine its pharma-cokinetics and effects on TWEAK pathway pharmacodynamic markers in rheumatoid arthritis (RA). METHODS: Phase I, first-in-human, 2-part, multi- center, double-blind, dose-escalation study. Patients were randomized to a single dose of BIIB023 (0.03-20 mg/kg) (n = 38) or placebo (n = 15) as an add-on to methotrexate. Three open-label cohorts of RA patients taking background disease-modifying antirheumatic drugs and stable tumor necrosis factor (TNF) inhibitor therapy (n = 12) received a single-dose of BIIB023 of 2, 10, or 20 mg/kg and were assessed over 70 days. RESULTS: The incidence of treatment-emergent ad-verse events for the BIIB023 monotherapy cohorts and open-label cohorts of BIIB023 as add-on therapy to TNF inhibitors compared with placebo were 47% and 50% versus 33%, respectively. Serum exposure to BIIB023 increased in a dose-dependent manner from 0.03 to 20 mg/kg, but not in direct proportion to dose level. After administration, the time course of BIIB023 serum concentration was multiphasic and showed expedited elimination when levels decreased to < 10 mg/mL. Serum-soluble TWEAK levels were suppressed at all dose levels by 6 hours post-dose and recovered to baseline between days 7 and 28. A trend toward downward modulation of serum biomarkers of in-flammatory response was suggested in monocyte chemoattractant protein 1, inducible protein 10, mac-rophage inflammatory protein 1β, and tissue inhibitor of metalloproteinase 1 in the BIIB023 group versus placebo. CONCLUSIONS: Single-dose BIIB023 showed a favor-able safety and tolerability profile in RA. Suppression of serum-soluble TWEAK for ≤ 28 days was observed and downward trends in serum biomarkers suggested.