Neonatal Fc Receptor Antagonist Efgartigimod Safely and Sustainably Reduces IgGs in Humans

J Clin Invest. 2018 Oct 1;128(10):4372-4386. doi: 10.1172/JCI97911. Epub 2018 Jul 24.

Abstract

Background: Intravenous Ig (IVIg), plasma exchange, and immunoadsorption are frequently used in the management of severe autoimmune diseases mediated by pathogenic IgG autoantibodies. These approaches modulating IgG levels can, however, be associated with some severe adverse reactions and a substantial burden to patients. Targeting the neonatal Fc receptor (FcRn) presents an innovative and potentially more effective, safer, and more convenient alternative for clearing pathogenic IgGs.

Methods: A randomized, double-blind, placebo-controlled first-in-human study was conducted in 62 healthy volunteers to explore single and multiple ascending intravenous doses of the FcRn antagonist efgartigimod. The study objectives were to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity. The findings of this study were compared with the pharmacodynamics profile elicited by efgartigimod in cynomolgus monkeys.

Results: Efgartigimod treatment resulted in a rapid and specific clearance of serum IgG levels in both cynomolgus monkeys and healthy volunteers. In humans, single administration of efgartigimod reduced IgG levels up to 50%, while multiple dosing further lowered IgGs on average by 75% of baseline levels. Approximately 8 weeks following the last administration, IgG levels returned to baseline. Efgartigimod did not alter the homeostasis of albumin or Igs other than IgG, and no serious adverse events related to efgartigimod infusion were observed.

Conclusion: Antagonizing FcRn using efgartigimod is safe and results in a specific, profound, and sustained reduction of serum IgG levels. These results warrant further evaluation of this therapeutic approach in IgG-driven autoimmune diseases.

Trial registration: Clinicaltrials.gov NCT03457649.

Funding: argenx BVBA.

Keywords: Autoimmune diseases; Autoimmunity; Immunoglobulins; Therapeutics.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Autoantibodies / blood
  • Autoimmune Diseases* / blood
  • Autoimmune Diseases* / drug therapy
  • CHO Cells
  • Cricetulus
  • Double-Blind Method
  • Female
  • Histocompatibility Antigens Class I
  • Humans
  • Immunoglobulin Fc Fragments / administration & dosage*
  • Immunoglobulin Fc Fragments / adverse effects
  • Immunoglobulin G / blood*
  • Macaca fascicularis
  • Male
  • Receptors, Fc / antagonists & inhibitors*

Substances

  • Autoantibodies
  • Histocompatibility Antigens Class I
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Receptors, Fc
  • Fc receptor, neonatal

Associated data

  • ClinicalTrials.gov/NCT03457649

Grant support

argenx bvba was sponsor of the phase I study and funded all non-clinical experiments. Authors are consulant or full-time employee of argenx bvba