Therapeutic: zilucoplan for myasthenia gravis

Published: 8-Apr-2022

The rare disease myasthenia gravis (MG) is an autoimmune condition that causes muscle weakness, particularly of those in the face, eyes and that control swallowing

Patients experience symptoms such as drooping eyelids, double vision and difficulty with talking and swallowing. The muscles required for respiration can also be affected. It’s the result of antibodies made by the immune system destroying nicotinic acetylcholine receptors at the muscle–nerve junction, preventing the nerves from triggering muscle contractions.

Treatment is typically with acetylcholinesterase inhibitors or immunosuppressants.

An alternative and more specific treatment is being developed by UCB. Complement activation, which is a key mediator of antibody function, is an important driver of the disease’s pathology; the macrocyclic peptide zilucoplan is a complement C5 inhibitor that is under investigation for the treatment of acetylcholine receptor autoantibody positive generalised MG.1

In a randomised, double-blind, placebo-controlled Phase II clinical trial, 44 patients with generalised MG who were acetylcholine receptor autoantibody positive and had moderate to severe disease were given a self-administered subcutaneous injection of 0.1 or 0.3 mg/kg of zilucoplan or a placebo for 12 weeks in a 1:1:1 ratio.2

The endpoints were the change from baseline to week 12 in quantitative myasthenia gravis (QMG) scores and MG activities of daily living scores (MG-ADL). Those in the trial had a QMG of at least 12 at the start of the trial.

Patients given the higher dose had a mean reduction from baseline of at least 6.0 in the QMG score and 3.4 in the MG score. Outcomes for the lower dose were also statistically significant but had a slower onset and were less pronounced. None of the higher dose patients required rescue therapy (intravenous immunoglobulin or plasma exchange), whereas one of those given the lower dose and three of the placebo group did.

The drug was found to have a favourable safety and tolerability profile.

Positive top-line results have also been released via press release for a placebo-controlled Phase III trial in generalised MG patients; they were given daily subcutaneous doses of 0.3 mg/kg of zilucoplan (the higher dose from the Phase II study) or a placebo for 12 weeks, with the primary outcome being change from baseline in the MG-ADL score; secondary endpoints included a QMG score.

The press release reported that the primary endpoint had been met, along with all the secondary endpoints. It was well tolerated with no unexpected safety findings having emerged. As a result, the company now plans to file for regulatory approval.


  1. J.F. Howard, et al., Expert Opin. Investig. Drugs 30, 483 (2021).
  2. J.F. Howard, et al., JAMA Neurol. 77, 582 (2020).

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