Zilucoplan
A daily self-injected peptide that blocks complement C5, for antibody-positive myasthenia gravis
Zilucoplan is a 15-amino-acid macrocyclic peptide that binds complement component C5 and stops the complement attack on the neuromuscular junction in myasthenia gravis. UCB's Zilbrysq was approved in the US on October 17, 2023 for adults with generalised myasthenia gravis who are anti-acetylcholine receptor antibody positive.
What is it?
In generalised myasthenia gravis, antibodies against the acetylcholine receptor switch on complement, which damages the nerve-muscle junction. Zilucoplan is a 15-amino-acid macrocyclic peptide that binds complement component C5 and stops its cleavage, the step blocked by the intravenous antibodies eculizumab and ravulizumab, but it is a small peptide taken as a daily self-injection. The label gives a terminal half-life of about 172 hours.
The phase 2 trial in 44 patients set the dose: on 0.3 mg/kg daily, improvement was rapid and no patient needed rescue therapy, against 3 of 15 on placebo. In the phase 3 RAISE trial, 174 adults with anti-AChR antibody-positive disease improved more on that dose than on placebo over 12 weeks (MG-ADL change -4.39), with similar rates of serious events and infections. The label doses by weight bands, from 16.6 mg to 32.4 mg a day.
The long-term extension found patients reducing other drugs: 29.8% of those on non-steroidal immunosuppressants cut back or stopped one, though by week 120 9.3% had increased or started corticosteroids.
Real-world use has followed. In France, 48 patients failing current therapy saw MG-ADL scores fall from 7.4 to 2.5 over six months, and in Italy 82.9% of 54 patients were responders at 24 weeks with a mean prednisone cut of 8.3 mg. Patients stable on intravenous C5 antibodies who switched to zilucoplan in a 26-patient study did slightly better on MG-ADL at 12 weeks, with mostly mild adverse events.
How it compares with older treatments is known only indirectly. In RAISE, patients who had never had immunoglobulin or plasma exchange improved as much as those who had, and matching-adjusted comparisons across separate trials favoured zilucoplan over IVIg and eculizumab on several scores, though no head-to-head trial has been run.
Blocking C5 leaves the body exposed to Neisseria meningitidis, so the label carries a boxed warning for serious meningococcal infections, requires vaccination at least two weeks before starting, and limits prescribing to a REMS programme. Injection-site reactions, upper respiratory infections and diarrhoea are the commonest effects, and pancreatitis is a listed warning.
It did not work in ALS: in a 162-patient platform trial it neither slowed function loss nor improved survival, and the arm stopped early for futility.
Zilucoplan is the only peptide among the C5 inhibitors; eculizumab and ravulizumab are antibodies given into a vein.
Mechanism of Action
Zilucoplan stops the complement cascade at C5, before the membrane attack complex can form.
C5 binding
Binds complement C5 with high affinity and prevents its cleavage into C5a and C5b (dataset mechanism).
Protecting the junction
Blocking terminal complement reduces antibody-driven damage at the neuromuscular junction in myasthenia gravis (dataset mechanism).
Daily injection
Terminal half-life about 172 hours (7-8 days), dosed daily by weight band (Zilbrysq label).
Published Research
The trials behind zilucoplan, read from their PubMed abstracts: the phase 2 and phase 3 RAISE trials and their extension, a switch study from intravenous C5 antibodies, French and Italian real-world cohorts, and the ALS trial. Dosing from the Zilbrysq label read October 1, 2026.
RAISE
In 174 adults with generalised myasthenia gravis, zilucoplan 0.3 mg/kg daily reduced the MG-ADL score more than placebo over 12 weeks (least-squares mean change -4.39), with similar rates of serious events and serious infections.
The phase 2 trial
In 44 patients, 0.3 mg/kg daily gave rapid, sustained improvement over 12 weeks, and rescue therapy was needed by 3 of 15 on placebo, 1 of 15 on 0.1 mg/kg and none of 14 on 0.3 mg/kg.
Fewer other drugs
In the long-term extension, 29.8% of patients on non-steroidal immunosuppressants reduced or stopped one, while by week 120 9.3% had increased or started corticosteroids.
Switching from intravenous C5 antibodies
Twenty-six stable patients switched from eculizumab (16) or ravulizumab (10) to daily zilucoplan 0.3 mg/kg; adverse events occurred in 73.1%, mostly mild, and MG-ADL improved slightly by week 12 (-1.15 points).
French early access
In 48 patients with anti-AChR myasthenia gravis failing current therapy, mean MG-ADL fell from 7.4 to 2.5 at six months (30 evaluated), 12 of 30 reached minimal symptom expression, and three stopped for lack of efficacy.
ZILU25: Italian real-world use
In 54 patients followed a mean 26.4 weeks, MG-ADL responder rates were 75.6% at week 12 and 82.9% at week 24, 55.6% reached minimal symptom expression at week 48, and daily prednisone fell by a mean 8.3 mg at week 24.
No effect in ALS
In 162 people with ALS in a platform trial, zilucoplan did not slow function loss or improve survival (disease rate ratio 1.08), and the trial stopped early for futility.
RAISE: with and without prior immunoglobulin
In RAISE, the 54 patients who had never had immunoglobulin or plasma exchange, with milder and shorter disease, improved on zilucoplan as the others did (MG-ADL change -4.22 against -2.61 on placebo; -4.93 against -2.94 in those with prior treatment).
Indirect comparison with IVIg and the antibodies
Matching-adjusted indirect comparisons of phase 3 trials favoured zilucoplan over IVIg on QMG at 2 and 4 weeks and over eculizumab on MG-ADL, QMG and MGC at 24-26 weeks; these are model-based comparisons across separate trials, not head-to-head data.
Dosing Data
Dosed by label after meningococcal vaccination, by body weight, once daily under the skin.
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Side Effects & Contraindications
Reported Side Effects
From the Zilbrysq label (version 13).
Contraindications & Cautions
From the label.
Legal Status
Approved in the US with a REMS programme.
Frequently Asked Questions
?Why is vaccination required?
Complement C5 helps clear Neisseria meningitidis; the label requires meningococcal vaccination at least two weeks before the first dose.
?How long does it last?
The label gives a terminal half-life of about 172 hours, seven to eight days, though it is injected daily.
?Does it work in other diseases?
Not shown: a 2025 ALS trial was stopped for futility.
?How quickly does it work?
In the phase 2 trial improvement on 0.3 mg/kg was rapid, and in RAISE the benefit over placebo was measured at 12 weeks; real-world cohorts saw scores fall from week 4.
?Can patients switch from eculizumab or ravulizumab?
In a 26-patient study, stable patients who switched kept their control and improved slightly on MG-ADL at 12 weeks.
?Does it let patients cut steroids?
In the extension, 29.8% on non-steroidal immunosuppressants reduced or stopped one, and an Italian cohort cut daily prednisone by a mean 8.3 mg at 24 weeks.
?Who is it approved for?
In the US, adults with generalised myasthenia gravis who are anti-acetylcholine receptor antibody positive.
?Is it a peptide or an antibody?
A peptide: a 15-amino-acid macrocycle, unlike the antibody C5 inhibitors eculizumab and ravulizumab.
?Is it better than IVIg or eculizumab?
No head-to-head trial exists. Indirect, model-based comparisons across separate trials favoured zilucoplan on several scores, which is weaker evidence than a direct trial.
References
- [fda-pi] Zilbrysq (zilucoplan) injection US prescribing information (DailyMed version 13, effective February 3, 2026); read October 1, 2026.
- [clinical-trial] Howard JF Jr, et al. "Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study." Lancet Neurol, 2023;22(5):395-406. PMID: 37059508.
- [clinical-trial] Howard JF Jr, et al. "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." JAMA Neurol, 2020;77(5):582-592. PMID: 32065623.
- [clinical-trial] Hewamadduma C, et al. "Changes in corticosteroid and non-steroidal immunosuppressive therapy with long-term zilucoplan treatment in generalized myasthenia gravis." J Neurol, 2025;272(7):457. PMID: 40504283.
- [clinical-trial] Paganoni S, et al. "Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial." JAMA Netw Open, 2025;8(2):e2459058. PMID: 39960672.
- [pubmed] Freimer M, et al. "Switching to subcutaneous zilucoplan from intravenous complement component 5 inhibitors in generalised myasthenia gravis: a phase IIIb, open-label study." Ther Adv Neurol Disord, 2025;18:17562864251347283. PMID: 40620733.
- [pubmed] Tammam G, et al. "Real-world effectiveness and safety of zilucoplan in patients with anti-AChR myasthenia gravis: A retrospective cohort study in France." J Neuromuscul Dis, 2026:22143602261437792. PMID: 41904994.
- [pubmed] Di Stefano V, et al. "Early real-life experience on Zilucoplan for generalized myasthenia gravis: ZILU25 multicenter observational study." J Neurol Sci, 2025;479:125671. PMID: 41314023.
- [pubmed] Utsugisawa K, et al. "Efficacy of zilucoplan in patients with generalised myasthenia gravis who have not previously received immunoglobulin or plasma exchange: A subgroup analysis from the Phase 3 RAISE study." J Neurol Sci, 2025;474:123550. PMID: 40450840.
- [pubmed] Betts A, et al. "Comparative Efficacy of Zilucoplan Versus Intravenous Immunoglobulin, Eculizumab, and Ravulizumab Using Matching-Adjusted Indirect Comparisons." Neurol Ther, 2026. PMID: 42786374.
Sources & Citations
Dosing and warnings from the Zilbrysq label (DailyMed version 13, effective February 3, 2026, read October 1, 2026); approval from Drugs@FDA; studies from PubMed abstracts.
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