학술논문
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
Document Type
Article
Author
Howard, James F.; Nowak, Richard J.; Wolfe, Gil I.; Freimer, Miriam L.; Vu, Tuan H.; Hinton, John L.; Benatar, Michael; Duda, Petra W.; MacDougall, James E.; Farzaneh-Far, Ramin; Kaminski, Henry J.; Barohn, Richard; Dimachkie, Mazen; Pasnoor, Mamatha; Farmakidis, Constantine; Liu, Tina; Colgan, Samantha; Benatar, Michael G.; Bertorini, Tulio; Pillai, Rekha; Henegar, Robert; Bromberg, Mark; Gibson, Summer; Janecki, Teresa; Freimer, Miriam; Elsheikh, Bakri; Matisak, Paige; Genge, Angela; Guidon, Amanda; David, William; Habib, Ali A.; Mathew, Veena; Mozaffar, Tahseen; Hinton, John L.; Hewitt, William; Barnett, Deborah; Sullivan, Patricia; Ho, Doreen; Howard, James F.; Traub, Rebecca E.; Chopra, Manisha; Kaminski, Henry J.; Aly, Radwa; Bayat, Elham; Abu-Rub, Mohammad; Khan, Shaida; Lange, Dale; Holzberg, Shara; Khatri, Bhupendra; Lindman, Emily; Olapo, Tayo; Sershon, Lisa M.; Lisak, Robert P.; Bernitsas, Evanthia; Jia, Kelly; Malik, Rabia; Lewis-Collins, Tiffany D.; Nicolle, Michael; Nowak, Richard J.; Sharma, Aditi; Roy, Bhaskar; Nye, Joan; Pulley, Michael; Berger, Alan; Shabbir, Yasmeen; Sachdev, Amit; Patterson, Kimberly; Siddiqi, Zaeem; Sivak, Mark; Bratton, Joan; Small, George; Kohli, Anem; Fetter, Mary; Vu, Tuan; Lam, Lucy; Harvey, Brittany; Wolfe, Gil I.; Silvestri, Nicholas; Patrick, Kara; Zakalik, Karen; Duda, Petra W.; MacDougall, James; Farzaneh-Far, Ramin; Pontius, Angela; Hoarty, Michelle
Source
JAMA Neurology; May 2020, Vol. 77 Issue: 5 p582-592, 11p
Subject
Language
ISSN
21686149; 21686157
Abstract
IMPORTANCE: 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. OBJECTIVE: 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. INTERVENTIONS: 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. RESULTS: 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: ClinicalTrials.gov Identifier: NCT03315130.