232 Nipocalimab Pharmacokinetic/pharmacodynamic and Exposure-Response Modeling in Pregnancies at Risk for Early-Onset Severe (EOS) HDFN

Hemolytic disease of the fetus and newborn (HDFN) is a rare, immune-mediated red blood cell (RBC) disorder, where maternal IgG alloantibodies attack fetal RBCs. Nipocalimab is a fully human monoclonal antibody designed to selectively block the IgG binding site on neonatal Fc receptors (FcRn). Modeling approaches were used to characterize the pharmacokinetic/pharmacodynamic (PK/PD) and exposure-response (E-R) relationships of nipocalimab in the Phase 2 UNITY study in pregnancies at risk for EOS-HDFN. UNITY is a multicenter, open-label, single-arm study evaluating the safety, efficacy, and PK/PD of nipocalimab in pregnant individuals at risk for EOS-HDFN. Data from three Phase 1 studies in healthy volunteers and the UNITY study were combined and utilized for the PK/PD and E-R modeling. Nipocalimab PK and FcRn occupancy (RO) were characterized by a 2-compartment target-mediated-drug-disposition (TMDD) model following intravenous (IV) doses. A PK/PD model was established to describe the observed longitudinal IgG data following IV doses. E-R relationships were explored to correlate nipocalimab PK or total IgG with efficacy and safety endpoints. Nipocalimab PK exhibited nonlinear behavior. The developed TMDD PK model characterized the time courses of nipocalimab PK and FcRn RO. The PK/PD model indicated high potency of nipocalimab to reduce the maternal total IgG levels. Similar to total IgG, maternal alloantibodies decreased and showed a correlation with maternal total IgG. At the studied dose levels in UNITY, nipocalimab fully saturated FcRn, leading to decreased maternal alloantibodies and inhibition of their placental transfer. E-R modeling for primary efficacy and selected safety (ie, infection) endpoints showed that optimal responses have been achieved in EOS-HDFN participants. This study demonstrates the correlation of nipocalimab PK and FcRn RO with reduction in total IgG and alloantibodies, as well as with clinical efficacy and safety endpoints. These relationships inform the appropriate dose regimen for evaluation in the pivotal Phase 3 study in EOS-HDFN.