(W-110) PK/PD Modeling of the Anti-FcRn Monoclonal Antibody Nipocalimab Administered to Healthy Subjects and Participants with Moderate to Severe Active Rheumatoid Arthritis

Yuan Xiong, PhD – Director, Johnson & Johnson; Sophia Liva, PhD – Senior Scientist, Johnson & Johnson; Jocelyn Leu, PhD – Senior Director, Johnson & Johnson; Mahesh Samtani, PhD – Senior Director, Johnson & Johnson

Objectives: Nipocalimab is a fully human, high affinity, aglycosylated, effectorless IgG1 lambda (IgG1) monoclonal antibody designed to selectively block the IgG binding site on endogenous neonatal Fc receptors (FcRn). The inhibition of FcRn-IgG interaction by nipocalimab is expected to inhibit IgG recycling, decrease IgG half-life, and rapidly reduce the circulating levels of IgG, including pathogenic IgG autoantibodies and alloantibodies. Nipocalimab is currently under development for rheumatoid arthritis (RA) indication due to its potential to reduce disease specific autoantibodies involved in RA pathogenesis. A phase 2a study was conducted in participants with moderate to severe active RA receiving either placebo or nipocalimab administered intravenously (IV) at 15 mg/kg q2w. The present analysis aims to characterize the PK of nipocalimab in RA and to assess the PK comparability between healthy volunteers (HV) and RA patients.

Methods: A prior PKPD model was developed using the clinical data collected from 3 Phase 1 studies in HV. A quasi-steady state (QSS) approximation approach incorporating the nipocalimab concentrations and receptor occupancy (RO) data was used to characterize the PK of nipocalimab. Subsequently, an indirect response PK/PD model was developed to describe the observed longitudinal IgG data following IV doses in HV. These two models were used initially for external validation of observed clinical data from a Phase 2a study in RA participants. Subsequently, the models were further developed by including clinical data from RA participants. The combined dataset includes a total of 167 subjects (114 HV and 53 RA) receiving IV placebo or nipocalimab ranging from 0.3 mg/kg to 60 mg/kg.

Results: Nipocalimab PK exhibits TMDD behavior and characterized by a two-compartment QSS TMDD model following IV doses (ranging from 0.3 mg/kg to 60 mg/kg; single or multiple doses). Body weight effects on both clearance and central volume were found to be the only significant covariate affecting nipocalimab PK and included in the model using allometric scaling approach. A semi-mechanistic indirect response PK/PD model linking RO to IgG reduction adequately described the observed longitudinal IgG data following IV doses. These models adequately described week 12 PK and IgG data in RA participants using external validation approach. A separate residual variability term for RA participants was used in the PK model, which improved the VPC performance of the updated model. The typical value PK and PD parameter estimates after including RA data were within 5% difference of estimates from HV data.

Conclusions: The updated models with RA data resulted in similar parameter estimates as from the prior models based on HV only, suggesting that nipocalimab PK and effect on total IgG was consistent between HV and RA. The validated new model can be used for nipocalimab dose selection and optimization in RA patients in future studies.

Citations: None