FDA Approves Complement C5 Inhibitor Zilucoplan as Treatment for Myasthenia Gravis


With the approval, zilucoplan becomes the first once-daily subcutaneous C5 complement inhibitor available for adults with generalized myasthenia gravis.

James F. Howard, MD, Distinguished Professor of Neuromuscular Disease and professor of neurology at The University of North Carolina at Chapel Hill School of Medicine

James F. Howard, MD

According to an announcement, the FDA has approved UCB Pharma’s investigational agent zilucoplan, a complement C5 inhibitor, to treat patients with myasthenia gravis (MG). Approved under the market name Zilbrysq, the subcutaneously delivered medication is indicated for those with acetylcholine receptor antibody positive (AChR-Ab+) generalized MG, further expanding the toolbox of options for patients with the disease.1

Data from the large-scale, double-blind, placebo-controlled, phase 3 RAISE study (NCT04115293) was the basis for the approval, in which zilucoplan demonstrated rapid and clinically meaningful improvements in MG-specific efficacy outcomes. After 12 weeks of treatment, zilucoplan met its primary end point, showing a placebo-corrected mean improvement of 2.09 points on Myasthenia Gravis Activities of Daily Living (MG-ADL) score.2

"For people with gMG, the unpredictable nature of the severity and frequency of symptoms can be debilitating and can have a substantial impact on many aspects of their day-to-day lives. In addition to muscle weakness, people living with gMG experience fatigue, affecting their overall quality of life,” lead investigator James F. Howard, MD, Distinguished Professor of Neuromuscular Disease and professor of neurology at The University of North Carolina at Chapel Hill School of Medicine, said in a statement.1 "Zilucoplan demonstrated rapid improvements in gMG symptoms at Week 12, with differences seen as early as one week, and provides a new treatment option for a broad population of AChR antibody-positive gMG patients. Zilucoplan is designed for continued daily use."

Conducted from 2019 to 2021, 174 eligible patients were included and randomly assigned to either 0.3 mg/kg or zilucoplan (n = 86) or placebo (n = 88) for a 12-week period, followed by an optional open-label extension study (RAISE-XT; NCT04225871). In secondary efficacy outcomes, investigators observed a clinically meaningful reduction in Quantitative Myasthenia Gravis (QMG) score after 12 weeks with zilucoplan (least squares [LS] mean change, –6.19; 95% CI, –7.29 to –5.08) vs placebo (LS mean change, –3.25; 95% CI, –4.32 to –2.17; LS mean difference, –2.94; 95% CI, –4.39 to –1.49; P <.0001).2

In terms of safety, zilucoplan demonstrated a favorable profile, with treatment-emergent adverse events (TEAEs) occurring in 77% of patients. The most frequently reported TEAEs among treated patients were injection-site bruising (16%), headache (15%), diarrhea (10%), and worsening of MG (10%). Between the 2 groups, the incidence of frequently reported TEAEs were similar, except for injection-site bruising, diarrhea, injection-site pain, and lipase increase, which were more frequent in the zilucoplan group.

In the zilucoplan group, 4 patients discontinued because of a TEAE (one each of aphthous ulcer, mouth ulceration, hepatic enzyme increase, and COVID-19 leading to death) and 2 patients discontinued from the placebo group because of a TEAE (hyperemesis gravidarum and cerebral hemorrhage leading to death). Neither death was considered related to the study drug. Of note, a higher incidence of infections occurred in the zilucoplan group than in the placebo group (27% vs 18%), which was driven by nonserious upper respiratory tract infections (14% vs 7%). No meningococcal or other Neisseria spp infections or anaphylactic reactions occurred in either group.

“This is an important development for the community because, with more FDA-approved treatments for generalized myasthenia gravis, physicians have additional tools to treat this disease in individualized ways that are the right fit for each individual patient,” Samantha Masterson, president and chief executive officer of the Myasthenia Gravis Foundation of America, said in a statement.1 “We are so grateful to UCB for being part of the myasthenia gravis community and their continued commitment to finding solutions for people living with this chronic, autoimmune, neuromuscular disease.”

Earlier this year, interim data from RAISE-XT continued to highlight zilucoplan’s safety and efficacy profile. Presented at the 2023 Muscular Dystrophy Association Clinical and Scientific Conference, the analysis featured 199 patients with MG who participated in previously conducted phase 2 (NCT03315130) and phase 3 (NCT04115293) studies. At the 24-month period, 84.9% (n = 169) of patients experienced a TEAE, and 23.1% (n = 46) documented serious AEs. Between the groups, the most common TEAEs were headache and worsening of MG, both occurring in 16.6% of patients.3

Throughout the study, 4 treatment-emergent deaths occurred, all in patients with multiple cardiovascular risk factors, and none of them were considered treatment related. Cardiac arrest was the cause in 2 patients, 1 patient experienced head injury, and 1 had severe pneumonia 2 days prior to death. Infections were reported in nearly half (49.2%) of the cohort, although most (86%) were non-serious.

From double-blind study baseline, zilucoplan-treated individuals achieved least square mean changes in MG-ADL score of –6.30 (95% CI, –7.44 to –5.15). These results were similar for the placebo-switch group, with score reductions of –6.32 (95% CI, –8.00 to –4.65). Scores on key secondary outcomes such as QMG score, Myasthenia Gravis Composite score, and Myasthenia Gravis Quality of Life 15-item-revised, were similar across both treatment groups as well.

1. UCB announces US FDA approval of Zilbrysq (zilucoplan) for the treatment of adults with generalized myasthenia gravis. News release. October 17, 2023. Accessed October 17, 2023. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-US-FDA-approval-of-ZILBRYSQR-zilucoplan-for-the-treatment-of-adults-with-generalized-myasthenia-gravis
2. Howard JF, Bresch S, Genge A, et al. Safety and efficacy of zilucoplan in patients with generalized myasthia gravis (RAISE): a randomized, double-blind, placebo-controlled, phase 3 study. 2023;22(5):395-406. doi:10.1016/S1474-4422(23)00080-7
3. Genge A, Hussain Y, Kaminski HJ, et al. Safety and tolerability of zilucoplan in RAISE-XT: a multicenter, open-label extension study in patients with myasthenia gravis. Presented at: MDA 2023; February 19-22; Dallas, TX. Abstract 145.
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