Zilucoplan

In generalized myasthenia gravis, autoantibodies damage the neuromuscular junction, where nerves signal muscles, causing weakness that can be disabling³. The complement cascade, a chain of blood proteins that ends in the membrane attack complex (C5b-9), is thought to play a central role in that damage³. Zilucoplan binds C5 and stops it from being split into C5a and C5b, which prevents C5b-9 from forming¹. The label states that its exact therapeutic mechanism is unknown but is presumed to involve less C5b-9 deposition at the neuromuscular junction¹. Chemically, it is a 15-amino-acid cyclic peptide carrying a fatty palmitoyl tail on a long polyethylene-glycol-like linker¹. Because it shuts down the end of the complement pathway, it also weakens a key defense against meningococcal bacteria¹.

Human data come mainly from myasthenia gravis trials. In a phase 2 trial of 44 patients, the higher dose lowered the Quantitative Myasthenia Gravis score by 2.8 points more than placebo⁴. In the phase 3 RAISE trial, 174 adults with AChR antibody-positive generalized disease were randomized for 12 weeks; scores for daily-living function (MG-ADL) fell 4.39 points with zilucoplan versus 2.30 with placebo². Rates of serious adverse events and serious infections were similar between groups².

In the open-label RAISE-XT extension, which had no placebo group (200 patients, median exposure 1.2 years), improvements held through week 60, and patients switching from placebo improved within the first week⁵. Outside myasthenia gravis, a small phase 2 trial in immune-mediated necrotizing myopathy found no meaningful difference from placebo in creatine kinase levels⁶.

FDA-approved in October 2023 as Zilbrysq (UCB) for generalized myasthenia gravis in adults who are anti-acetylcholine receptor antibody positive; because of meningococcal infection risk it is available only through a restricted REMS program.

The label has a boxed warning for serious, sometimes fatal, meningococcal infections, which have occurred with complement inhibitors even in vaccinated people; meningococcal vaccination is required before starting unless delaying treatment carries more risk. Other warnings include other serious infections and pancreatitis or pancreatic cysts. The most common effects (10% or more) were injection-site reactions, upper respiratory infections and diarrhea. In RAISE, injection-site bruising was the most frequent adverse event (16% vs 9% on placebo).

1. FDA label: ZilbrysqFDA label (DailyMed)
2. Howard et al., Lancet Neurol 2023PubMed
3. Howard et al., Expert Opin Investig Drugs 2021PubMed
4. Howard et al., JAMA Neurol 2020PubMed
5. Howard et al., Ther Adv Neurol Disord 2024PubMed
6. Mammen et al., Lancet Rheumatol 2023PubMed