Population pharmacokinetic and pharmacodynamic analysis of BIIB023, an anti‐TNF‐like weak inducer of apoptosis (anti‐TWEAK) monoclonal antibody

Abstract

AIMSTumour necrosis factor-like weak inducer of apoptosis (TWEAK) is implicated in the pathogenesis of lupus nephritis. This study evaluated the pharmacokinetics, using the population approach, and pharmacodynamics of BIIB023, an anti-TWEAK monoclonal antibody, in healthy Chinese, Japanese and Caucasian volunteers. METHODSIn this single-dose, randomized, double-blind, phase 1 study of BIIB023 in healthy volunteers, BIIB023 was administered by intravenous infusion (3 or 20 mg kg À1 ) on Day 1; follow-up occurred through Day 71. BIIB023 serum concentration was measured using a validated enzyme-linked immunosorbent assay; BIIB023 concentration-time data were subjected to noncompartmental analysis. Population pharmacokinetic analysis was performed using data from this study and a prior phase 1 study of BIIB023 in subjects with rheumatoid arthritis. Soluble TWEAK and TWEAK:BIIB023 complex were evaluated. RESULTSThere were no differences in BIIB023 pharmacokinetics requiring dose adjustment among the three ethnic groups or between healthy volunteers and arthritis patients. BIIB023 central compartment volume (3050 ml) and clearance (7.42 ml h À1 ) were comparable to those observed for other monoclonal antibody drugs. BIIB023 serum exposure increased in a dose-dependent manner in all groups, but not in direct proportion to dose level; at concentrations below~10 μg ml À1 , nonlinear clearance was observed. Soluble TWEAK levels decreased to below the level of quantitation after BIIB023 treatment, with concomitant changes in TWEAK:BIIB023 complex levels. CONCLUSIONSNo clinically meaningful differences were observed in BIIB023 pharmacokinetic and pharmacodynamic properties in healthy Chinese, Japanese and Caucasian volunteers; pharmacodynamic measures suggested target engagement. TWEAK may be an attractive therapeutic target for lupus nephritis treatment.

Roles of tumour necrosis factor‐related weak inducer of apoptosis/fibroblast growth factor‐inducible 14 pathway in lupus nephritis

“…Fn14‐Fc can block TWEAK/Fn14 pathway, and displays therapeutic benefits in the SLE model of sanroque mice . Moreover, a phase‐two clinical trial with neutralizing anti‐TWEAK antibody (http://www.clinicaltrials.gov, Identifier: NCT01499355) has been conducted recently, and TWEAK/Fn14 pathway is becoming an attractive therapeutic target for LN treatment …”

Systemic lupus erythematosus biomarkers: the challenging quest

“…in kidney proximal tubule cells [152]. However, a pharmaceutical targeting TWEAK (BBIIB023) did not result in significant improvement in an LN proof-of-concept study [153]; therefore, development was recently terminated by Biogen (NCT01499355).…”

Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) in kidney disease: a biomarker or therapeutic target?

“…Furthermore, an ability to modify the cellular pathway mentioned above can constitute a new therapeutic target. In order to clarify this matter, intravenous administration of anti-TWEAK antibodies was started in systemic inflammatory diseases, which caused serum TWEAK concentration to drop down to indeterminate values and the levels of circulating inflammatory markers to be significantly reduced in patients with rheumatoid arthritis (45) . However, in the ATLAS study (Anti-Tweak in Lupus Nephritis Patients), which assessed the efficacy, safety and tolerability of anti-TWEAK antibodies as an add-on therapy in patients with advanced LN in whom standard of care did not produce remission (25) , anti-TWEAK antibodies were not found to be sufficiently effective in comparison to routinely used steroids and mycophenolate mofetil.…”