Background Mavrilimumab is a high-affinity, fully human immunoglobulin G (IgG) monoclonal antibody that selectively binds to the α subunit of GM-CSF receptor (GM-CSFRα). A Phase 2a randomized, double-blind, placebo-controlled, multiple ascending dose study was conducted to evaluate the efficacy, safety, pharmacokinetics (PK) and immunogenicity of mavrilimumab in subjects with at least moderately active rheumatoid arthritis (RA).
Objectives To characterize the PK and immunogenicity of mavrilimumab after multiple subcutaneous administrations to RA patients (10-100 mg Q2W x7).
Methods Serum samples for mavrilimumab concentration determination and the detection of the presence of anti-drug antibodies (ADA) were collected from all RA subjects at pre-designated timepoints, and analyzed using validated electrochemiluminescence assay (PK) or enzyme-linked immunosorbent assay (ADA). Noncompartmental PK data analysis was performed using WinNonlin (Pharsight Corp, St Louis, MO). Exposure-response relationship was assessed using a population modeling approach.
Results Maximum serum mavrilimumab concentrations (Cmax) were observed approximately 3 days following SC administrations. The PK exposure (Cmax and AUC) of mavrilimumab increased more than dose-proportionally across the investigated dose range (10-100 mg). Mavrilimumab was cleared more rapidly at lower dose levels due to the GM-CSF receptor-mediated clearance. The average PK half-life was approximately 13 days at 100 mg dose level when GM-CSFRα was fully occupied by mavrilimumab. Three (3.8%) placebo subjects and 20 (13%) mavrilimumab-treated subjects had positive ADA during the study period. The relationship between PK and RA disease activity was adequately described by a direct Emax model.
Conclusions The observed mavrilimumab PK profiles in this Phase 2a study were consistent with prior projections from a mechanistic population model1. The PK parameters of mavrilimumab following SC dosing are typical of a monoclonal antibody with target-mediated disposition. The PK and immunogenicity properties of mavrilimumab, and the direct exposure-response relationship support further clinical development of mavrilimumab for the treatment of RA.
Wang, B. et. al., Mechanistic Modeling of Antigen Sink Effect for Mavrilimumab Following Intravenous Administration in Patients With Rheumatoid Arthritis. Journal of Clinical Pharmacology (in press), 2012
Disclosure of Interest C.-Y. Wu Employee of: Medimmune, X. Chen Employee of: Medimmune, H. Lu Employee of: Medimmune, E. Esfandiari Employee of: Medimmune, F. Magrini Employee of: Medimmune, A. Godwood Employee of: Medimmune, P. Ryan Employee of: Medimmune, C. Kane Employee of: Medimmune, L. Roskos Employee of: Medimmune, B. Wang Employee of: Medimmune