Pharmacokinetics and pharmacodynamics across infusion rates of intravenously administered nipocalimab: results of a phase 1, placebo-controlled study

Abstract

IntroductionNipocalimab is a high-affinity, fully human, aglycosylated, effectorless, immunoglobulin G (IgG) 1 monoclonal antibody that targets the neonatal Fc receptor (FcRn), decreases systemic IgG including autoantibodies, and is under development in several IgG autoantibody- and alloantibody-mediated diseases, including generalized myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, maternal-fetal medicine, and multiple other therapeutic areas. An initial phase 1 study with single and multiple ascending doses of nipocalimab infused intravenously (IV) over 2 h demonstrated dose-dependent serum pharmacokinetics and IgG reductions, with an adverse event (AE) profile comparable to placebo.MethodsThe current investigation evaluates the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of nipocalimab across various IV infusion rates in a randomized, double-blind, placebo-controlled, sequential-dose study. Forty participants were randomized to receive nipocalimab 30 mg/kg over 60, 30, 15 or 7.5 min (0.5, 1, 2, or 4 mg/kg/min); nipocalimab 60 mg/kg over 15 min (4 mg/kg/min); or matching placebo.ResultsAt doses up to 60 mg/kg and infusion rates up to 4 mg/kg/min (maximum clinically feasible rate), single doses of nipocalimab were tolerable, with 12 (40%) participants experiencing AEs across nipocalimab cohorts compared with 1 (10%) participant in the placebo cohort. AEs deemed treatment related occurred in 6 (20%) participants receiving nipocalimab and 1 (10%) participant receiving placebo. None of the AEs were severe, and no participants discontinued treatment due to AEs. Nipocalimab provided consistent, dose-dependent serum pharmacokinetics and IgG reductions, regardless of infusion rate.DiscussionThis study supports the use of shortened durations of nipocalimab infusion for future studies.

Differential effects of FcRn antagonists on the subcellular trafficking of FcRn and albumin

“…The diverse roles and multiple ligands of FcRn need consideration when evaluating therapeutic antagonists targeting this receptor, as alterations in the homeostasis of serum albumin in parallel with the desired reductions in IgG levels have been associated with their use. For example, during a phase I trial, the mAb nipocalimab demonstrated a transient decline in albumin (3.6 to 2.8 g/dL) in patients receiving 30 mg/ kg weekly doses for 4 weeks (40), and this transient decline in albumin level was observed in another single-dose phase I study, ranging from 4.4% to 8.2% for 30 mg/kg infusion cohorts and 14.6% for the 60 mg/kg infusion cohort (48). In a phase II clinical trial using another mAb, batoclimab, for treatment of myasthenia gravis, serum albumin declined in a dose-dependent fashion before returning to normal levels 6 weeks after discontinuation of the study drug.…”