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Two identical 13-residue cyclic peptides hung from a 40 kDa PEG — a peptide drug that works by inhibiting a protein, not by activating a receptor.
Also known as: APL-2 · Empaveli · Syfovre · compstatin-derived C3 inhibitor
Part of the Foundational & therapeutic peptides cluster
Overview
Pegcetacoplan is a PEGylated peptide complement inhibitor: two identical 13-amino-acid cyclic compstatin-derived peptides bridged by a 40 kDa polyethylene glycol, which bind complement C3 and C3b. Approved by the EMA and FDA in 2021 for paroxysmal nocturnal haemoglobinuria after beating eculizumab on haemoglobin change (adjusted difference 3.84 g/dL), it has since been studied in geographic atrophy and, in a 2025 phase 3 trial, C3 glomerulopathy.
Source & context
Biological / chemical source: Synthetic cyclic peptides (compstatin family) conjugated to a 40 kDa polyethylene glycol
Primary research or clinical context: Approved (EMA and FDA, 2021) for paroxysmal nocturnal haemoglobinuria; also studied in geographic atrophy, C3 glomerulopathy and immune-complex MPGN
What pegcetacoplan is
Pegcetacoplan is a peptide drug that inhibits a protein rather than activating a receptor. It belongs to the compstatin family — cyclic peptides discovered for their ability to bind complement component C3, the hub of the immune system's complement cascade. Two identical 13-residue cyclic peptides are joined through their C-termini to a 40 kDa polyethylene glycol chain, which keeps the molecule circulating long enough for subcutaneous dosing. It was approved by the EMA and the FDA in 2021 for paroxysmal nocturnal haemoglobinuria (PNH), a rare acquired disease in which complement destroys red blood cells, after orphan designations dating from 2014 (FDA) and 2017 (EMA).
Structure
Each peptide arm is Ac-Ile-Cys-Val-(N-methyl)Trp-Gln-Asp-Trp-Gly-Ala-His-Cys-Thr-NH2, cyclised through a disulfide between its two cysteines, with the N-terminus acetylated and the C-terminus amidated. The N-methyl-tryptophan is a potency-enhancing modification characteristic of later compstatin analogues. Because the drug is a dimer of modified cyclic peptides on a PEG scaffold, it has no meaningful one-letter sequence display and its mass is dominated by the polymer; the peptide chemistry is what confers C3 binding, the PEG what confers duration.
Mechanism: cutting complement at C3
Complement can be triggered by three pathways, but all converge on cleavage of C3 into C3a and C3b. Pegcetacoplan binds C3 and C3b and prevents that cleavage, which shuts down both the membrane-attack complex downstream (intravascular haemolysis) and the C3b opsonisation that marks red cells for destruction in the spleen and liver (extravascular haemolysis). The approved C5 inhibitor eculizumab acts one step later and controls intravascular haemolysis only, which is why PNH patients on eculizumab can remain anaemic — the problem the pegcetacoplan trial was designed to address (Hillmen et al., NEJM 2021).
PEGASUS: pegcetacoplan versus eculizumab
The pivotal phase 3 PEGASUS trial enrolled adults with PNH whose haemoglobin remained below 10.5 g/dL despite eculizumab. After a four-week run-in on both drugs, 41 patients continued subcutaneous pegcetacoplan alone and 39 continued intravenous eculizumab. At week 16 the adjusted mean difference in haemoglobin change favoured pegcetacoplan by 3.84 g/dL, 85% of pegcetacoplan patients versus 15% of eculizumab patients no longer required transfusions, and fatigue scores improved. Non-inferiority was shown for reticulocyte count but not for lactate dehydrogenase (Hillmen et al., NEJM 2021). A later study confirmed control of haemolysis in complement-inhibitor-naive patients (Wong et al., Blood Advances 2023).
| Endpoint | Pegcetacoplan (n = 41) | Eculizumab (n = 39) |
|---|---|---|
| Haemoglobin change vs baseline | Adjusted difference +3.84 g/dL in favour | — |
| Transfusion-free | 85% (35 patients) | 15% (6 patients) |
Beyond PNH: eye and kidney
Because C3 sits upstream of every complement pathway, pegcetacoplan has been tested wherever complement drives tissue damage. In geographic atrophy secondary to age-related macular degeneration, the OAKS and DERBY phase 3 trials gave intravitreal 15 mg monthly or every other month versus sham for 24 months, with lesion growth on fundus autofluorescence as the primary endpoint (Heier et al., Lancet 2023). In a 2025 phase 3 trial of 124 adolescents and adults with C3 glomerulopathy or primary immune-complex MPGN, proteinuria fell by a geometric mean 67.2% with pegcetacoplan versus a 2.9% rise on placebo — a relative reduction of 68.1% — and more patients met the composite renal endpoint (Fakhouri et al., NEJM 2025).
Safety notes from the record
Blocking C3 removes a defence against encapsulated bacteria, and complement inhibitors as a class carry warnings and vaccination requirements for that reason. The LiverTox record notes that serum aminotransferase elevations occur in a proportion of treated patients but that clinically apparent liver injury with jaundice has not been reported. ClinicalTrials.gov lists 34 studies including real-world effectiveness registries and phase 4 work as of the September 2026 snapshot.
Why it is in a peptide directory
Most peptides on this site are hormone mimics. Pegcetacoplan shows the other half of peptide pharmacology: a cyclic peptide evolved in the laboratory to bind a protein surface with high affinity and selectivity, then PEGylated to survive in circulation. Compare it with zilucoplan, a macrocyclic peptide that inhibits the next protein in the cascade, C5, and with the site's cyclic hormone analogues such as octreotide and lanreotide, which use the same disulfide-ring stabilisation for a different purpose.
Structure & chemistry
Molecular identity & reference confidence
Reference mass unavailable
Reference values are taken from the cited molecular record or curated profile. A database match is not independent laboratory verification; modifications, counter-ions, and formulations can change the measured mass.
- Molecular form
- Two identical 13-residue cyclic peptides, Ac-Ile-Cys(1)-Val-(Me)Trp-Gln-Asp-Trp-Gly-Ala-His-Cys(1)-Thr-NH2 (disulfide-cyclised), each attached at its amidated C-terminus to a 40 kDa linear PEG
- Species
- Not established by this molecular identity audit
- Termini (N / C)
- Not specified / Not specified
Average reference mass
Reference policy updated: 2026-10-05
- IUPHAR/BPS source snapshot · 2026-09-07
- Receptors
- No receptor — a protein–protein inhibitor. Binds complement C3 and its activation fragment C3b, preventing C3 cleavage by C3 convertases
- Backbone
- Two identical 13-residue cyclic peptides, Ac-Ile-Cys(1)-Val-(Me)Trp-Gln-Asp-Trp-Gly-Ala-His-Cys(1)-Thr-NH2 (disulfide-cyclised), each attached at its amidated C-terminus to a 40 kDa linear PEG
- Status
- Approved: EMA and FDA, 2021 (paroxysmal nocturnal haemoglobinuria). Orphan designations for C3 glomerulopathy, immune-complex MPGN, autoimmune haemolytic anaemia and ALS
N-terminal acetylation, an N-methyl-tryptophan, a Cys–Cys disulfide ring and C-terminal amidation on each peptide arm; 40 kDa PEG bridge for circulating half-life (IUPHAR record).
- IUPHAR ligand: 13826
- CAS RN: 2019171-69-6
Chemistry values: curated profile, IUPHAR/BPS Guide to Pharmacology · fetched 2026-09-07.
Clinical development snapshot
ClinicalTrials.gov lists 34 registered studies with “Pegcetacoplan” as an intervention (snapshot 2026-10-01). A registry footprint is not evidence of efficacy or approval.
| NCT | Title | Phase | Status | Updated |
|---|---|---|---|---|
| NCT07746895 | Real-World Effectiveness and Safety of Pegcetacoplan in Patients With C3G or IC-MPG: A Multi-Country Study | Phase 4 | recruiting | 2026-09-09 |
| NCT05776472 | A Real World Effectiveness Study of Pegcetacoplan in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) | — | active not recruiting | 2026-09-03 |
| NCT07020832 | Study to Evaluate the Efficacy and Safety of Pegcetacoplan in Adults at High Risk of Delayed Graft Function (D | Phase 3 | withdrawn | 2026-09-02 |
| NCT07214298 | Pegcetacoplan in Combination With Modified FOLFIRINOX for the Treatment of Metastatic Pancreatic Ductal Adenoc | Phase 2 | recruiting | 2026-08-19 |
| NCT06961370 | A Study to Investigate Safety, Tolerability, Pharmacokinetics (PK), Pharmacodynamics (PD), and Immunogenicity | Phase 1 | terminated | 2026-08-10 |
| NCT04901936 | A Study of Pegcetacoplan in Pediatric Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) | Phase 2 | recruiting | 2026-06-26 |
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- IdentifiersCross-linked to IUPHAR ligand 13826.
- TrialsClinicalTrials.gov snapshot added: 34 registered studies, highest phase 4.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about Pegcetacoplan
What is Pegcetacoplan?+
Pegcetacoplan is a PEGylated peptide complement inhibitor: two identical 13-amino-acid cyclic compstatin-derived peptides bridged by a 40 kDa polyethylene glycol, which bind complement C3 and C3b. Approved by the EMA and FDA in 2021 for paroxysmal nocturnal haemoglobinuria after beating eculizumab on haemoglobin change (adjusted difference 3.84 g/dL), it has since been studied in geographic atrophy and, in a 2025 phase 3 trial, C3 glomerulopathy.
What Canadian product status is recorded for Pegcetacoplan?+
Canadian product status for Pegcetacoplan has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the typical length of Pegcetacoplan?+
Pegcetacoplan is commonly described as approximately 13 amino acids (PEGylated cyclic peptide (complement C3 inhibitor)).
What is pegcetacoplan?+
A PEGylated cyclic-peptide inhibitor of complement C3, sold as Empaveli (for PNH) and Syfovre (for geographic atrophy). Two 13-residue compstatin-derived peptides are linked by a 40 kDa PEG.
How does pegcetacoplan differ from eculizumab?+
Pegcetacoplan blocks C3, upstream of all complement pathways, controlling both intravascular and extravascular haemolysis; eculizumab blocks C5 and controls intravascular haemolysis only. In PEGASUS, pegcetacoplan raised haemoglobin by an adjusted 3.84 g/dL more.
Is pegcetacoplan approved?+
Yes — by the EMA and FDA in 2021 for paroxysmal nocturnal haemoglobinuria, with orphan designations in several other complement-mediated diseases.
Is pegcetacoplan a peptide?+
Yes, a modified one: each arm is a 13-amino-acid cyclic peptide with N-methyl-tryptophan, acetylation and amidation, attached to a polyethylene glycol scaffold.
What did the kidney trial show?+
In C3 glomerulopathy and immune-complex MPGN, pegcetacoplan reduced proteinuria by a geometric mean 67.2% versus a 2.9% increase on placebo at 26 weeks (Fakhouri et al., NEJM 2025).
Related peptides
References & further reading
- 1.Hillmen P et al. (2021). Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria. New England Journal of Medicine
- 2.Fakhouri F et al. (2025). Trial of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN. New England Journal of Medicine
- 3.Heier JS et al. (2023). Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY). Lancet
- 4.Wong RSM et al. (2023). Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria. Blood Advances
- 5.LiverTox (2024). Pegcetacoplan. NIDDK