Journal Article

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

Wisniacki, Nicolas, Galluppi, Gerald R., Amaravadi, Lakshmi, Burkly, Linda C., Zhang, Ray, Zheng, Timothy S., Kong, Jessica

2013

Overview

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. The aim of this study was to explore the safety and tolerability of the TWEAK-blocking monoclonal antibody BIIB023 and determine its pharmacokinetics and effects on TWEAK pathway pharmacodynamic markers in rheumatoid arthritis (RA). Phase I, first-in-human, 2-part, multicenter, 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. The incidence of treatment-emergent adverse 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 µg/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 inflammatory response was suggested in monocyte chemoattractant protein 1, inducible protein 10, macrophage inflammatory protein 1β, and tissue inhibitor of metalloproteinase 1 in the BIIB023 group versus placebo. Single-dose BIIB023 showed a favorable safety and tolerability profile in RA. Suppression of serum-soluble TWEAK for ≤ 28 days was observed and downward trends in serum biomarkers suggested.

• Publisher: EM Inc USA,Elsevier,Elsevier Limited
• Subject: Administration, Intravenous / Adolescent / Adult / Angiogenesis / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal - pharmacokinetics / Antibodies, Monoclonal - therapeutic use / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - adverse effects / Antibodies, Monoclonal, Humanized - pharmacokinetics / Antibodies, Monoclonal, Humanized - therapeutic use / Antibodies, Neutralizing / Antirheumatic Agents - administration & dosage / Antirheumatic Agents - adverse effects / Antirheumatic Agents - pharmacokinetics / Antirheumatic Agents - therapeutic use / Apoptosis / Arthritis, Rheumatoid - drug therapy / Biological and medical sciences / Chemokines / Cytokine TWEAK / Cytokines / Disease / Diseases of the osteoarticular system / Double-Blind Method / Drug Administration Schedule / Drug therapy / Drug Therapy, Combination / Ethics / Female / Fn14 / Humans / Inflammation - drug therapy / Inflammatory joint diseases / Internal Medicine / Lupus / Medical Education / Medical sciences / Methotrexate - pharmacokinetics / Methotrexate - therapeutic use / Middle Aged / Nervous system / pharmacodynamics / pharmacokinetics / Pharmacology. Drug treatments / Proteins / Receptors, Tumor Necrosis Factor - metabolism / Review boards / Rheumatoid arthritis / Rheumatology / Rodents / Skin / TNF inhibitors / Tumor Necrosis Factor-alpha - antagonists & inhibitors / Tumor Necrosis Factors - antagonists & inhibitors / Tumor Necrosis Factors - immunology / Tumor Necrosis Factors - metabolism / TWEAK / TWEAK Receptor / Young Adult