Zilucoplan for Myasthenia Gravis

By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

Dr. Rubin reports he is a consultant for Merck Sharp & Dohme Corp.

SYNOPSIS: Zilucoplan, a macrocyclic peptide that binds complement component C5, showed promise as an effective agent for treatment of generalized myasthenia gravis in a Phase II trial.

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

Upward of 85% of patients with generalized myasthenia gravis (gMG) have detectable anti-acetylcholine receptor antibodies (AchR-Ab). Evidence indicates that these antibodies, as opposed to anti-muscle-specific kinase (MuSK) antibodies, activate the classic complement cascade. Post-synaptic membrane simplification, with associated reduced AchR density, is the ultrastructural correlate of impaired neuromuscular transmission in gMG, and it appears that the terminal complement cascade plays a role. Eculizumab, a monoclonal antibody to complement component 5 (C5) inhibitor, was shown to be effective in treating gMG patients previously refractory to other therapies, supporting complement inhibition as a new therapeutic approach in gMG. Zilucoplan, a macrocyclic peptide that binds C5 with high affinity and specificity, is thus the subject of this study to determine its efficacy in gMG.

Between December 2017 and August 2018, MG patients, ages 18 to 85 years, were recruited from 25 North American study sites to participate in this randomized, double-blind, placebo-controlled, Phase II clinical trial. Inclusion criteria required a clinically confirmed diagnosis of MG (Myasthenia Gravis Foundation of America [MGFA] Class II-IVa), AchR-Ab positivity, Quantitative MG (QMG) score of 12 or greater, with no intravenous immunoglobulin (IVIg), plasma exchange (PLEX), or change in therapy for four weeks prior to randomization, and no thymectomy or rituximab in the prior six months. Patients were assigned randomly, in a 1:1:1 ratio, to daily subcutaneous self-injection of zilucoplan 0.1 mg/kg, zilucoplan 0.3 mg/kg, or placebo, for 12 weeks.

No change in ongoing therapy was permitted during the 12-week trial, and patients were evaluated at baseline and weeks 1, 2, 4, 8, and 12. IVIg or PLEX was allowed in the event of worsening, based on investigator discretion. A change in QMG score, a 13-item scale evaluating muscle strength, ranging from 0 (normal) to 39 (severe weakness), was the primary endpoint, with improvement of two to three points considered clinically meaningful, depending on baseline disease. Pyridostigmine was not allowed in the 10 hours prior to QMG measurements. Secondary endpoints included the MG Composite (MGC) and the 15-item Myasthenia Gravis Quality-of-Life Revised Scale (MG-QoL15r). The key secondary endpoint was the change in MG Activities of Daily Living (MG-ADL) score, an eight-item scale assessing daily functions, ranging from 0 (normal) to 24 (severely affected), by study completion. Statistical analysis used an analysis of covariance model and least squares means, with Fisher exact test used to analyze categorical endpoints.

Among 57 patients assessed for eligibility, 12 did not meet inclusion criteria, leaving 45 patients for randomization (15 per arm of the trial). All but one received the study drug, with the exception lost to follow-up when he did not return for the dosing visit. Rapid, clinically meaningful, and statistically significant improvement in the QMG score was seen in the 0.3 mg/kg zilucoplan arm compared to placebo, with a score change of -6.0 points in the former, compared to -3.2 in the latter, and improvement beginning after one week. Beginning after four weeks, a less pronounced and slower but clinically meaningful and statistically significant improvement also was appreciated with 0.1 mg/kg zilucoplan. MG-ADL showed similar results, favoring zilucoplan over placebo, and 0.3 mg/kg over 0.1 mg/kg, at week 12. MG-QoL15r and MGC followed a similar pattern, although the former favored the 0.1 mg/kg zilucoplan arm, perhaps because of its higher baseline scores. No significance was found in the analysis of the covariance model for age, sex, duration of disease, treatment history, prior thymectomy, or history of thymoma.

Three patients in the placebo arm required rescue therapy with IVIg or PLEX, one patient in the 0.1 mg/kg zilucoplan arm, and none in the 0.3 mg/kg zilucoplan arm. The study drug was well-tolerated, with a moderate injection-site reaction (ISR) in only one placebo patient, all other ISRs being mild. Other adverse events were mostly mild, were considered unrelated to study drug, and resolved spontaneously. No meningococcal infections, life-threatening adverse events, or deaths occurred during the trial, and no anti-zilucoplan antibodies were detected. Zilucoplan appears safe and effective for the treatment of AchR-Ab positive gMG.

COMMENTARY

Like eculizumab, zilucoplan is a terminal complement inhibitor, but, unlike the former, it is administered subcutaneously. A synthetic macrocyclic peptide, zilucoplan binds C5, preventing its cleavage into C5a and C5b, and preventing the production of the membrane attack complex. Complement inhibition increases the risk for meningococcal infection since the complement system ordinarily protects against encapsulated bacterial infections, and prior vaccination may be required.

The results of this study are promising, and preparations for a Phase III trial are underway.