(T-051) Mechanistic model-based analysis of Total IgG kinetics and pathogenic autoantibody pharmacodynamics in autoimmune diseases

Jia Zhou, PhD – Sr Scientist, Janssen R&D; Angelia Wang, PhD – Scientist, Janssen R&D; Edwin Lam, PharmD – Sr Scientist, Janssen R&D; Yuan Xiong, PhD – Director, Janssen R&D; Jocelyn Leu, PharmD, PhD – Sr Director, Janssen R&D; Weirong Wang, PhD – Sr Director, Janssen R&D; Mahesh Samtani, PhD – Sr Director, Janssen R&D; Vivaswath Ayyar, PhD – Associate Director, Janssen R&D

Objectives/

Background: The neonatal Fc receptor (FcRn) salvages Immunoglobulin G (IgG) from lysosomal degradation consequently extending its half-life. FcRn inhibitors accelerate IgG catabolism to lower circulating total IgG (IgGtot) concentrations, thus serving as treatment options across diverse pathogenic autoantibody (PAA)-mediated diseases. A mechanism-based model was developed to capture and relate total serum IgG kinetics with endogenous IgG/PAA lowering.

Methods: A target-mediated drug disposition model was developed to characterize efficiency of IgG salvage. Model calibration was performed using reported serum IgGtot kinetics across multiple studies of subjects dosed with exogenous IgG. Model simulations were qualified against additional reported measurements of serum IgGtot and PAA lowering. Correlation analysis was conducted between PAA titers and reported clinical measures.

Results: The model adequately captured the relationship between IgGtot elevation and endogenous IgG lowering following intravenous immunoglobulin G (IVIg) treatment. This model characterized total IgG PK reasonably well following IVIg administration. Model-simulated increases in IgGtot at weeks 1 and 2 (224% and 139% of baseline) agreed well with measurements. Further, model simulations of endogenous IgG lowering following IVIg correlated with published PAA lowering at early weeks post-dosing, though it slightly underpredicted PAA lowering at a later timepoint. Correlation analyses suggested that endogenous IgG lowering may be associated with disease activity score (DAS) in subjects treated with IVIg. A limitation of the correlation analysis is that it is based upon limited datasets available publicly in literature, with no well-controlled clinical studies.

Conclusions: The developed mechanism-based model successfully characterized the effects of IVIg on circulating total plus endogenously synthesized IgGs and autoimmune disease-specific PAAs, as reported in published literature.

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2. Kuitwaard, K. et al. Ann Neurol 66, 597-603 (2009).