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JAMA Neurol. 2020 Feb 17. doi: 10.1001/jamaneurol.2019.5125. [Epub ahead of print]

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.

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University of North Carolina, Chapel Hill.
Yale School of Medicine, New Haven, Connecticut.
University at Buffalo, Buffalo, New York.
Ohio State University, Columbus.
University of South Florida, Tampa.
Infirmary Health, Mobile, Alabama.
University of Miami, Miami, Florida.
Ra Pharmaceuticals Inc, Cambridge, Massachusetts.
George Washington University, Washington, DC.
University of Kansas, Fairway.
Wesley Neurology Clinic, Cordova, Tennessee.
University of Utah, Salt Lake City.
Montreal Neurological Institute, Montreal, Quebec, Canada.
Massachusetts General Hospital, Boston.
University of California, Irvine, Orange.
Lahey Hospital, Burlington, Massachusetts.
University of Texas Southwestern, Dallas, Irving.
Hospital for Special Surgery, New York, New York.
Center for Neurological Disorders, St Francis Hospital at Ascension, Milwaukee, Wisconsin.
Wayne State University, Detroit, Michigan.
Rush University, Chicago, Illinois.
London Health Sciences Center, London, Ontario, Canada.
University of Florida, Jacksonville.
Michigan State University, East Lansing.
University of Alberta, Edmonton, Alberta, Canada.
Mount Sinai Hospital, New York, New York.
Allegheny Neurological Associates, Pittsburgh, Pennsylvania.



Many patients with generalized myasthenia gravis (gMG) have substantial clinical disability, persistent disease burden, and adverse effects attributable to chronic immunosuppression. Therefore, there is a significant need for targeted, well-tolerated therapies with the potential to improve disease control and enhance quality of life.


To evaluate the clinical effects of zilucoplan, a subcutaneously (SC) self-administered macrocyclic peptide inhibitor of complement component 5, in a broad population of patients with moderate to severe gMG.

Design, Setting, and Participants:

This randomized, double-blind, placebo-controlled phase 2 clinical trial at 25 study sites across North America recruited participants between December 2017 and August 2018. Fifty-seven patients were screened, of whom 12 did not meet inclusion criteria and 1 was lost to follow-up after randomization but before receiving study drug, resulting in a total of 44 acetylcholine receptor autoantibody (AChR-Ab)-positive patients with gMG with baseline Quantitative Myasthenia Gravis (QMG) scores of at least 12, regardless of treatment history.


Patients were randomized 1:1:1 to a daily SC self-injection of placebo, 0.1-mg/kg zilucoplan, or 0.3-mg/kg zilucoplan for 12 weeks.

Main Outcomes and Measures:

The primary and key secondary end points were the change from baseline to week 12 in QMG and MG Activities of Daily Living scores, respectively. Significance testing was prespecified at a 1-sided α of .10. Safety and tolerability were also assessed.


The study of 44 patients was well balanced across the 3 treatment arms with respect to key demographic and disease-specific variables. The mean age of patients across all 3 treatment groups ranged from 45.5 to 54.6 years and most patients were white (average proportions across 3 treatment groups: 78.6%-86.7%). Clinically meaningful and statistically significant improvements in primary and key secondary efficacy end points were observed. Zilucoplan at a dose of 0.3 mg/kg SC daily resulted in a mean reduction from baseline of 6.0 points in the QMG score (placebo-corrected change, -2.8; P = .05) and 3.4 points in the MG Activities of Daily Living score (placebo-corrected change, -2.3; P = .04). Clinically meaningful and statistically significant improvements were also observed in other secondary end points, the MG Composite and MG Quality-of-Life scores. Outcomes for the 0.1-mg/kg SC daily dose were also statistically significant but slower in onset and less pronounced than with the 0.3-mg/kg dose. Rescue therapy (intravenous immunoglobulin or plasma exchange) was required in 3 of 15, 1 of 15, and 0 of 14 participants in the placebo, 0.1-mg/kg zilucoplan, and 0.3-mg/kg zilucoplan arms, respectively. Zilucoplan was observed to have a favorable safety and tolerability profile.

Conclusions and Relevance:

Zilucoplan yielded rapid, meaningful, and sustained improvements over 12 weeks in a broad population of patients with moderate to severe AChR-Ab-positive gMG. Near-complete complement inhibition appeared superior to submaximal inhibition. The observed safety and tolerability profile of zilucoplan was favorable.

Trial Registration: Identifier: NCT03315130.

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