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

Abstract

Introduction: Nipocalimab 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.

Methods: The 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.

Results: At 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.

Discussion: This study supports the use of shortened durations of nipocalimab infusion for future studies.

Keywords: immunoglobulin G; intravenous infusions; monoclonal antibodies; neonatal Fc receptor; pharmacokinetics; phase 1 clinical trial.

Figure 1

Study design of a phase 1, single-dose, sequential escalating-dose, randomized, double-blind, placebo-controlled, infusion rate study. BMI, body mass index; EOI, end of infusion; IgG, immunoglobulin G; IV, intravenous; MOI, middle of infusion; PD, pharmacodynamic; PK, pharmacokinetic. ^aThe PK assessment time points included Day 1 predose, MOI, EOI, EOI + 0.083 h, EOI + 0.25 h, EOI + 1 h; Day 2 (24 h postdose); Day 8 (169 h postdose); and Day 15 (337 h post dose). The PD and safety assessment time points included Day −1, Day 2 (24 h postdose), Day 8 (169 h postdose), Day 15 (337 h postdose), and Day 29 (672 h postdose), with an optional test every 14 days post−Day 29 until clinically significant laboratory test results returned to normal ranges.

Figure 2

Serum nipocalimab concentrations over time were assessed for up to 336 h following single doses of nipocalimab (30 and 60 mg/kg) administered at escalating infusion rates (0.5–4 mg/kg/min). (A) Mean (±SD) serum nipocalimab concentrations over the first 3 h postdose (n = 6). (B) Mean (±SD) serum nipocalimab concentrations over the entire period of 336 h postdose (n = 6). SD, standard deviation.

Figure 3

Total serum IgG concentrations over time were assessed for up to 672 h following single doses of nipocalimab (30 and 60 mg/kg) administered at escalating infusion rates (0.5–4 mg/kg/min). (A) Percent change from baseline of total serum IgG concentration (n = 6 per nipocalimab cohort, n = 10 for placebo cohort). (B) Mean (±SD) total IgG serum concentrations (n = 6 per nipocalimab cohort, n = 10 for placebo cohort). IgG, immunoglobulin G; SD, standard deviation.

Figure 4

Serum albumin concentrations over time were assessed for up to 672 h following single doses of nipocalimab (30 and 60 mg/kg) administered at escalating infusion rates (0.5–4 mg/kg/min). (A) Percent change from baseline of serum albumin concentration (n = 6 per nipocalimab cohort, n = 10 for placebo cohort). (B) Mean (±SD) serum albumin concentrations (n = 6 per nipocalimab cohort, n = 10 for placebo cohort). SD, standard deviation.