Zilucoplan: An Investigational Complement C5 Inhibitor for the Treatment of Acetylcholine Receptor Autoantibody–Positive Generalized Myasthenia Gravis

James F. Howard*, John Vissing, Nils E. Gilhus, M. Isabel Leite, Kimiaki Utsugisawa, Petra W. Duda, Ramin Farzaneh-Far, Hiroyuki Murai, Heinz Wiendl

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

44 Citations (Scopus)
29 Downloads (Pure)

Abstract

Introduction: Generalized myasthenia gravis (gMG) is an autoimmune disorder in which pathogenic autoantibodies damage the neuromuscular junction, causing disabling or life-threatening muscle weakness. Most treatments nonspecifically inhibit aspects of the immune system, do not directly address the causal mechanisms of tissue damage, and often have side-effect profiles that negatively impact patients. Understanding of the central pathogenic role of the complement cascade in gMG is advancing, and a new complement-targeting treatment is under investigation. Areas covered: We provide an overview of gMG etiology, the complement cascade, current treatments, and the investigational gMG therapy zilucoplan. Zilucoplan is a small, subcutaneously administered, macrocyclic peptide that inhibits cleavage of complement component C5 and the subsequent formation of the membrane attack complex. Expert opinion: In a randomized, double-blind, placebo-controlled, phase 2 clinical trial, zilucoplan demonstrated clinically meaningful complement inhibition in patients with acetylcholine receptor-positive gMG. Zilucoplan, a first-of-its-kind cyclic peptide targeting C5, appears to be a therapeutic option for the treatment of gMG based on available pharmacokinetic/pharmacodynamic data and phase 1 and 2 efficacy, safety, and tolerability data with limited long-term follow-up. Zilucoplan use earlier in the treatment paradigm would be suitable in this population should phase 3 efficacy and safety data be equally favorable.

Original languageEnglish
JournalExpert Opinion on Investigational Drugs
Volume30
Issue number5
Pages (from-to)483-493
ISSN1354-3784
DOIs
Publication statusPublished - 2021

Keywords

  • Autoimmune diseases
  • complement activation
  • complement C5
  • corticosteroids
  • generalized myasthenia gravis
  • membrane attack complex
  • neuromuscular junction

Cite this