What Is Zilucoplan (Zilbrysq)? The Complement C5 Blocking Peptide for Myasthenia Gravis and What the RAISE Trial Found

Zilucoplan is a synthetic macrocyclic peptide that blocks complement protein C5, and it is sold as Zilbrysq for generalized myasthenia gravis (gMG). It is a once daily injection under the skin that patients give themselves at home. The [Zilbrysq label](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9f1d53d6-e495-4a3a-8bb9-680a15d25034) lists an initial U.S. approval in 2023 and an indication for adults with gMG who are acetylcholine receptor (AChR) antibody positive.

Myasthenia gravis is an autoimmune disease in which antibodies attack the junction where your nerves signal your muscles. In people with AChR antibodies, those antibodies also switch on the complement system, a part of the immune system that punches holes in the muscle side of that junction, and zilucoplan was built to stop the final step of the attack. If you follow peptide science, zilucoplan is a striking example of a small engineered ring of amino acids doing a job that used to need a large antibody. This article explains how zilucoplan works, what kind of peptide it is, what the phase 2, RAISE and RAISE-XT trials found, how it is dosed, why it carries a boxed warning, and where it has failed. It is educational content about published research, not medical advice.

Myasthenia gravis is an autoimmune disease that causes muscle weakness that worsens with use, and it often starts with drooping eyelids, double vision, slurred speech or trouble swallowing. Generalized myasthenia gravis means the weakness reaches beyond the eye muscles to the limbs, the throat or the breathing muscles.

In most people with gMG, the immune system makes antibodies against the acetylcholine receptor, the docking site on the muscle that receives the nerve's signal. Those AChR antibodies do more than block the receptor, because they also trigger the complement cascade, a chain of blood proteins that ends in a structure called the membrane attack complex, or C5b-9. That complex damages the folded muscle membrane at the junction, and fewer working receptors leave the muscles weaker and quicker to tire.

Complement protein C5 sits near the end of that chain. When C5 is cut into two pieces, C5a and C5b, the attack complex can assemble, so blocking C5 is a way to stop the damage without shutting down the whole immune system. That logic is why C5 inhibitors are used in antibody positive gMG, where the disease mechanism depends on those antibodies.

Zilucoplan binds directly to complement C5 and stops it from being split. The Zilbrysq label states that zilucoplan "binds to the complement protein C5 and inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9."

The label is careful about the next step, noting that the precise mechanism by which zilucoplan helps in gMG is unknown, although it is presumed to involve less C5b-9 deposited at the neuromuscular junction. In the phase 2 trial, complement inhibition was dose dependent, and the investigators concluded that near complete complement inhibition appeared superior to partial inhibition, which is why the higher dose moved forward into phase 3.

Zilucoplan is a 15 amino acid macrocyclic peptide, which means part of the chain is closed into a ring. According to the label, its molecular weight is 3562.23 Daltons in free acid form, and the chemical name shows a lactam ring linking residues 1 and 6, several unnatural building blocks, and a palmitoyl fatty acid group attached to lysine 15 through a long polyethylene glycol spacer.

Each of those design choices has a job. The ring holds the peptide in the shape that grips C5 and makes it harder for enzymes to digest, while the fatty acid tail lets zilucoplan ride on blood proteins, and the label reports that zilucoplan and its main metabolites are more than 99% bound to plasma proteins. The result is a long acting peptide with a mean terminal half life of about 172 hours, or 7 to 8 days.

Zilucoplan was found by screening enormous libraries of ring shaped peptides. A 2025 paper from the discovery team ([Ye and colleagues, Journal of Medicinal Chemistry](https://doi.org/10.1021/acs.jmedchem.5c02537)) describes identifying zilucoplan through "extreme diversity mRNA display" and then refining the early hits for better potency, stability and pharmacokinetics. If you want the broader background on why half life shapes dosing schedules, our guide to [peptide half life and dosing frequency](/articles/peptide-half-life-dosing-frequency) covers the general principles.

The phase 2 trial showed that daily zilucoplan improved muscle strength scores and that the 0.3 mg/kg dose worked better than 0.1 mg/kg. The trial ([Howard and colleagues, JAMA Neurology, 2020](https://doi.org/10.1001/jamaneurol.2019.5125)) enrolled 44 patients with AChR antibody positive gMG at 25 sites in North America and randomized them to placebo, zilucoplan 0.1 mg/kg or zilucoplan 0.3 mg/kg for 12 weeks.

At 0.3 mg/kg, the Quantitative Myasthenia Gravis (QMG) score fell by a mean of 6.0 points, a placebo corrected change of 2.8 points, and the MG-ADL daily living score fell by 3.4 points, a placebo corrected change of 2.3 points. The 0.1 mg/kg dose also helped, although its benefit came more slowly and was smaller. Rescue therapy with intravenous immunoglobulin or plasma exchange tells a similar story, since 3 of 15 patients on placebo needed it, compared with 1 of 15 on the low dose and 0 of 14 on the high dose.

The study was small, and its significance testing used a one sided threshold of .10, so these results justified a phase 3 trial rather than settling the question.

The RAISE trial found that zilucoplan improved daily function and muscle strength more than placebo over 12 weeks. RAISE ([Howard and colleagues, Lancet Neurology, 2023](https://doi.org/10.1016/S1474-4422%2823%2900080-7)) was a randomized, double blind, placebo controlled phase 3 trial at 75 sites in Europe, Japan and North America. It enrolled adults aged 18 to 74 with AChR antibody positive gMG, an MG-ADL score of at least 6 and a QMG score of at least 12, and it assigned 86 patients to zilucoplan 0.3 mg/kg once daily and 88 to placebo.

The primary endpoint was the change in MG-ADL score, a patient reported scale of daily tasks such as talking, chewing, swallowing and breathing, where higher scores mean more impairment. On zilucoplan the MG-ADL score dropped by 4.39 points, compared with 2.30 points on placebo, a difference of 2.09 points (p=0.0004). The QMG strength score, reported in the label, dropped by 6.19 points versus 3.25, a difference of 2.94 points.

The placebo group also improved, which is typical of a disease that fluctuates and of trials that enroll patients while symptoms are active, so the number that matters is the gap between the arms. In the label's responder analysis, 73.1% of patients on zilucoplan improved by at least 3 MG-ADL points, compared with 46.1% on placebo, and 58% versus 33% improved by at least 5 QMG points.

The benefit held through 60 weeks in the open label extension. RAISE-XT ([Howard and colleagues, Therapeutic Advances in Neurological Disorders, 2024](https://doi.org/10.1177/17562864241243186)) enrolled 200 patients who had finished the phase 2 or phase 3 trial, and all of them took zilucoplan 0.3 mg/kg daily, with a median exposure of 1.2 years at the data cutoff.

Patients who had been on zilucoplan from the start kept improving through week 24, reaching an MG-ADL change of 6.06 points from the original double blind baseline, and they held that level at week 60 with a change of 6.04 points. Patients who switched over from placebo improved within the first week of starting zilucoplan and reached a change of 6.46 points by week 24 and 6.51 points by week 60.

Open label extensions have no control group, and the patients who stay in them tend to be the ones doing well, so these numbers support durability without proving it. In the same extension, 94% of patients reported at least one adverse event, most often myasthenia gravis worsening (26%) and COVID-19 (25%).

Zilucoplan is given once daily as an injection under the skin, in one of three fixed doses chosen by actual body weight. The label sets 16.6 mg for people under 56 kg, 23 mg for people from 56 kg to under 77 kg, and 32.4 mg for people at 77 kg and above, and each strength has a different colored plunger so the syringes are easy to tell apart. In the trials, the dose was 0.3 mg/kg once daily.

Before the first dose, the label calls for baseline amylase and lipase blood tests along with meningococcal vaccination. Prefilled syringes can be kept in the refrigerator, or at room temperature in the original carton for up to 3 months. Because zilucoplan is injected every day, technique and site rotation matter, and our guide to [peptide injection sites and subcutaneous technique](/articles/peptide-injection-site-subcutaneous-technique) covers the general principles. Your doses, testing and vaccination schedule should always follow your neurologist's instructions.

Zilucoplan carries a boxed warning because blocking C5 raises the risk of serious infections caused by Neisseria meningitidis, the bacteria behind meningococcal meningitis and sepsis. The complement attack complex is one of the body's main defenses against this germ, and the label states that life threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors.

The label asks for vaccination against meningococcal serogroups A, C, W, Y and B at least 2 weeks before the first dose, unless delaying treatment carries more risk than the infection. It also asks patients and clinicians to watch for early signs of meningococcal infection and to seek evaluation immediately if infection is suspected, even after vaccination. Finally, Zilbrysq is available only through a restricted Risk Evaluation and Mitigation Strategy called the ZILBRYSQ REMS, which prescribers must enroll in.

The most common side effects of zilucoplan are injection site reactions, upper respiratory tract infections and diarrhea. The label lists the adverse reactions seen in at least 5% of RAISE patients on zilucoplan and more often than on placebo, led by injection site reactions in 29% versus 16%.

Beyond the rises in lipase and amylase, the label reports pancreatitis and pancreatic cysts in patients taking zilucoplan, and it says to stop the drug if pancreatitis is suspected until it is ruled out or has resolved. The label also describes morphea, a hardening of patches of skin, which appeared in 10 of 213 patients (5%) in the open label extension studies. Most of those cases began more than a year into treatment and were mild to moderate, and one patient stopped zilucoplan because of it. A 2026 case report ([Auroy and colleagues, JAMA Dermatology](https://doi.org/10.1001/jamadermatol.2026.2321)) described progressive skin induration and fibrosis on the trunk and proximal limbs of a woman with severe, refractory myasthenia gravis who was taking zilucoplan. The label additionally advises caution in anyone with another systemic infection.

In RAISE itself, adverse events of any kind occurred in 77% of patients on zilucoplan and 70% on placebo, serious adverse events and serious infections were similar between the groups, and the single death in each arm was not considered related to the study drug. For a wider view of how to read side effect tables, see our [beginner's guide to peptide side effects](/articles/peptide-side-effects-beginners).

Zilucoplan has not worked in the other diseases where it has been tested in controlled trials. In amyotrophic lateral sclerosis (ALS), zilucoplan was regimen A of the HEALEY ALS Platform Trial ([Paganoni and colleagues, JAMA Network Open, 2025](https://doi.org/10.1001/jamanetworkopen.2024.59058)), in which 122 of 162 randomized participants received zilucoplan for a planned 24 weeks. The estimated disease rate ratio was 1.08, where a value below 1 would have meant benefit, and the trial was stopped early for futility.

In immune mediated necrotizing myopathy (IMNM), an autoimmune muscle disease, a phase 2 trial ([Mammen and colleagues, Lancet Rheumatology, 2023](https://doi.org/10.1016/s2665-9913%2823%2900003-6)) gave 27 participants zilucoplan or placebo for 8 weeks. Creatine kinase, the muscle damage marker used as the primary endpoint, fell by 9.86% on zilucoplan and 20.72% on placebo (p=0.46), and the authors concluded that C5 inhibition does not appear to be an effective treatment for IMNM.

These failures are informative, because complement blockade helps in AChR antibody positive myasthenia gravis, where antibodies drive complement damage at a specific site. Where complement activation follows injury rather than causing it, blocking C5 has not helped.

Zilucoplan is an example of a peptide doing a job that once needed an antibody. Other complement inhibitors used in gMG, such as eculizumab and ravulizumab, are monoclonal antibodies given by infusion, while zilucoplan is a small engineered peptide that patients inject at home. Like [icatibant for hereditary angioedema](/articles/icatibant-firazyr-bradykinin-peptide-hereditary-angioedema), zilucoplan shows how chemical changes such as ring closure and unnatural amino acids can turn a fragile peptide into a usable medicine.

No head to head randomized trial has compared zilucoplan with the antibody C5 inhibitors, so claims that one is better rest on indirect comparisons. Zilucoplan is also not a wellness or recovery peptide, since every trial behind it studied people with a diagnosed autoimmune disease under specialist care.

Zilucoplan (Zilbrysq) is a ring shaped peptide carrying a fatty acid tail that blocks complement C5, and it brings C5 inhibition for AChR antibody positive generalized myasthenia gravis into a daily injection given at home. The RAISE trial showed a clear, moderate improvement over placebo in daily function and strength, and the extension suggests that the effect lasts.

The tradeoffs are real, including a boxed warning for meningococcal infection that requires vaccination and a REMS program, pancreatic enzyme monitoring, and a morphea signal that emerged with longer use. Outside myasthenia gravis, zilucoplan has not worked in trials. Decisions about zilucoplan belong with a neurologist who knows your antibody status and history.