Zilucoplan Effective in Generalized Myasthenia Gravis


In addition to significant improvements compared to placebo on Quantitative QMG scores, zilucoplan improved patients' activities of daily living and quality of life scores.

Dr James Howard

James F. Howard, MD, Distinguished Professor of Neuromuscular Disease, chief, Neuromuscular Disorders Section, University of North Carolina School of Medicine

James F. Howard, MD

Patients with moderate to severe AChR-Ab—positive generalized myasthenia gravis (gMG) who were treated with zilucoplan experienced rapid and sustained improvements over the course of 12 weeks, according to phase 2 study results published in JAMA Neurology. Additionally, observations deemed the treatment was safe and tolerable.

The 44-patient study assessed 3 treatment arms—0.1 mg/kg zilucoplan (n = 15), 0.3 mg/kg zilucoplan (n 14), and placebo (n = 3). Data showed a mean reduction of 6 points on Quantitative Myasthenia Gravis (QMG) scores and 3.4 on the MG Activities of Daily Living scores for the 0.3 mg/kg group compared to reductions of 2.8 (P = .05) and 2.3 (P = .04), respectively, for placebo.

Notably, 0.3-mg/kg zilucoplan achieved near-complete complement inhibition (>97% inhibition at trough) compared to the 0.1-mg/kg zilucoplan dose, which had submaximal inhibition (~88% inhibition at trough). The work was conducted by James F. Howard Jr, MD, Distinguished Professor of Neuromuscular Disease, professor of neurology, and medicine chief, Neuromuscular Disorders Section at the University of North Carolina School of Medicine, and colleagues.

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

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A small number of patients had previously used immunosuppressive therapies, including cyclosporine (n = 4), rituximab (n = 3), methotrexate (n = 2), tacrolimus (n = 2), cyclophosphamide (n = 1), and eculizumab (n = 1; remote history of exposure 8 years before randomization during a clinical trial).

Regardless of prior treatment, there were clinically meaningful and statistically significant improvements observed in other secondary end points: MG Composite and MG Quality of Life scores.

MG Composite scores were reduced significantly for the 0.3 mg/kg dose (—­7.4) compared to placebo ­­(–3.3; difference, 4.1; P = .04), but were not significant for the 0.1 kg/mg group. The 0.3 mg/kg group had a 2.3-point greater reduction compared to placebo (P = .06) on the Myasthenia Gravis Quality of Life Revised Scale scores. For the lower dose group, outcomes were similarly significant (­7.4-point difference; P = .02) but slower in onset and less pronounced.

Rescue therapy of 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.

“Although none of the participants receiving the 0.3-mg/kg dose deteriorated, and most improved significantly, it is interesting that 28% of participants did not improve by the minimal clinically important difference of 3 points on the QMG,” Howard and colleagues wrote. “We speculate that failure to respond to near-complete C5 inhibition in this subset of patients may be attributed to 1 or more of the following factors: insensitivity of the outcome measures to detect clinical improvement; previously unrecognized fixed weakness; or the complement-independent effects of blocking or modulating autoantibodies that sterically hinder binding of ACh to the receptor or decrease AChR density, respectively.”

Notably, this phase 2 work was designed to support dose selection for a phase 3 study, thus 0.3-mg/kg zilucoplan has been selected for further testing in a pivotal phase 3 study (NCT04115293). “Confirmation of the clinical effect of zilucoplan in gMG will be further assessed through the open-label long-term extension of the phase 2 study and an upcoming registrational phase 3 clinical program,” Howard et al. wrote.

In January, the FDA approved an investigational new drug (IND) application for the HEALEY ALS (amyotrophic lateral sclerosis) platform trial, in which zilucoplan will take part as 1 of the first 3 therapies assessed. The trial, which is the first of its kind in the disease, will take place across 54 sites in the Northeast ALS Consortium (NEALS) in conjunction with the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital in Boston.


Howard JF, 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. JAMA Neurol. Published online February 17, 2020. doi:10.1001/jamaneurol.2019.5125.

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