The Clinical Effect of Zilucoplan in Patients With Generalized Myasthenia Gravis

insulin into a needle
A patient loads insulin for his routine shot.
Zilucoplan yielded rapid, clinically meaningful, and sustained improvement in patients with moderate to severe generalized myasthenia gravis.

Zilucoplan yielded rapid, clinically meaningful, and sustained improvement in patients with moderate to severe generalized myasthenia gravis (MG), according to phase 2 study results published in JAMA Neurology.

Because generalized MG is well controlled with the available treatment options for many patients, there is a need for better options in this population. In the current study, the researches explored the use of zilucoplan, a subcutaneously self-administered macrocyclic peptide of complement component 5, for patients with moderate to severe generalized MG.

The randomized, double-blind, placebo-controlled phase 2 trial included patients from 25 study sites across North America. Of 57 patients screened, 44 with acetylcholine receptor autoantibody (AChR-Ab)-positive generalized MG were included in the study. Study patients were randomly assigned 1:1:1 to daily self-injection of placebo, 0.1 mg/kg zilucoplan, or 0.3 mg/kg zilucoplan for 12 weeks.

The primary outcome was the change from baseline to week 12 in Quantitative Myasthenia Gravis (QMG) score, a 13-item categoric scale assessing muscle weakness, ranging between 0 and 39.

A total of 44 patients completed the 12-week study period, including 15 patients in the placebo group, 15 patients treated with zilucoplan 0.1 mg/kg, and 14 patients treated with zilucoplan 0.3 mg/kg. Mean QMG scores at baseline were 18.7±4.0, 18.7±4.0, and 19.1±5.1, respectively. The mean age of patients across all 3 groups ranged from 45.5 to 54.6 years.

The mean change from baseline to week 12 in the QMG score was -6.0 points in the zilucoplan 0.3 mg/kg group, compared with -3.2 points in the placebo group (mean difference of –2.8, P=.05). As for zilucoplan 0.1 mg/kg, the magnitude of the response was less pronounced, and compared with the rapid effect of the higher dose, exhibited a slower onset of action, with separation from placebo beginning only after 4 weeks of therapy.

In a similar fashion, there was a clinically meaningful and statistically significant improvement with zilucoplan 0.3 mg/kg in other secondary end points, including a rapid improvement in the key secondary end point, the change in MG Activities of Daily Living scores, with a mean reduction from baseline of 3.4 points (placebo-corrected change, -2.3, P=.04). Once again, zilucoplan 0.1 mg/kg was associated with a statistically significant, albeit less pronounced, effect and with a slower onset of action.

Rescue therapy (intravenous immunoglobulin or plasma exchange only) was administered per investigator’s discretion in 3 of 15 patients (20%) receiving placebo, 1 of 15 (7%) receiving zilucoplan 0.1 mg/kg, and none (0 of 14) receiving zilucoplan 0.3 mg/kg.

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Zilucoplan had a favorable safety and tolerability profile. The study drug was well tolerated, with a low incidence of local injection site reactions. Of the patients evaluated, 39 reported treatment-emergent adverse events, with no apparent pattern across treatment groups. Most events were mild, considered unrelated to the study drug, and resolved spontaneously.

The overall exposure to zilucoplan was too limited to allow for a complete characterization of the risk for Neisseria infection associated with C5 inhibition, and this was one of the study limitations, according to the researchers.

“Our study suggests that complement inhibition appears to be effective across a broad spectrum of patients with moderate to severe AChR-Ab–positive gMG, regardless of prior therapies; that near-complete complement inhibition is superior to submaximal complement inhibition; and that the safety and tolerability profile of zilucoplan in gMG appears to be favorable,” concluded the researchers.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Howard JF Jr, Nowak RJ, Wolfe GI, et al. Clinical effects of the self-administered subcutaneous complement inhibitor zilucoplan in patients with moderate to severe generalized myasthenia gravis: results of a phase 2 randomized, double-blind, placebo-controlled, multicenter clinical trial [published online ahead of print, 2020 Feb 17]. JAMA Neurol. doi:10.1001/jamaneurol.2019.5125