The clinical effect of the self-administered macrocyclic peptide inhibitor was “similar,” the investigators wrote, to what was seen in studies of the intravenously administered complement inhibitor eculizumab, which is approved by the Food and Drug Administration for treatment of gMG.
While eculizumab studies were restricted to patients with refractory gMG, the investigators wrote that their study of zilucoplan included a broader population, including patients who had not failed prior therapies, who were earlier in their disease course, and who had a history of thymoma.
“This observation is important because in gMG, disease severity frequently peaks within the first few years after diagnosis, before all treatment options have been exhausted, and before patients may be formally declared treatment refractory,” wrote, of the University of North Carolina in Chapel Hill, and coauthors.
Complement inhibition is a “targeted approach” that addresses the primary mechanism of tissue damage in gMG, the investigators wrote.
That stands in contrast to conventional gMG treatments including pyridostigmine, corticosteroids, and other immunosuppressants. “These treatments lack strong evidence from clinical trials to support their efficacy, are often poorly tolerated, and can be associated with considerable long-term toxicities,” Dr. Howard and colleagues wrote in their report, which was published in.
A total of 44 adult patients with gMG were randomized to receive daily zilucoplan 0.1 mg/kg, 0.3 mg/kg, or placebo for 12 weeks in this 25-center North American study. All patients had acetylcholine receptor autoantibody–positive disease and a Quantitative Myasthenia Gravis (QMG) score of 12 or higher. The QMG score ranges from 0, indicating no muscle weakness, to 39, or severe weakness.
Per the study protocol, patients had to keep taking their current gMG medication without changing the dose.
Change in QMG score from baseline to 12 weeks, the primary efficacy endpoint of the study, showed a significant and clinically meaningful difference favoring zilucoplan 0.3 mg/kg over placebo, according to the investigators.
The mean change was –6.0 points for zilucoplan 0.3 mg/kg and –3.2 for placebo (P = .05), according to their report, which indicated a rapid onset of action apparent 1 week after starting treatment.
Zilucoplan 0.1 mg/kg also yielded a significant and clinically meaningful improvement versus placebo, but its magnitude was smaller and took 4 weeks to become apparent.
Treatment with zilucoplan also significantly improved MG Activities of Daily Living scores versus placebo, a key secondary endpoint of the trial, according to the researchers.
Treatment-emergent adverse events, which included local injection-site reactions, were mild and judged to be unrelated to the study treatment, according to the report.
Ra Pharmaceuticals funded the study. Dr. Howard reported disclosures related to Ra Pharmaceuticals, Alexion Pharmaceuticals, argenx, Viela Bio, and others.
SOURCE: Howard Jr JF et al. JAMA Neurol. 2020 Feb 17. doi: .