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approvedImmune & Inflammation

Pegcetacoplan

Also known as: Empaveli, Syfovre, APL-2, PEGylated compstatin

Pegcetacoplan is a PEGylated cyclic peptide that inhibits complement component C3, sitting at the convergence point of all three complement activation pathways (classical, alternative, and lectin). FDA-approved as Empaveli (2021) for paroxysmal nocturnal hemoglobinuria (PNH) in adults and as Syfovre (2023) for geographic atrophy secondary to age-related macular degeneration (GA/AMD), it represents a new class of complement-targeted therapy. Derived from the compstatin peptide family, pegcetacoplan provides broad complement inhibition upstream of C5, addressing both intravascular and extravascular hemolysis in PNH.

3 cited references·5 researched benefits

Quick Answer

Pegcetacoplan (Empaveli/Syfovre) is a PEGylated cyclic peptide C3 complement inhibitor FDA-approved for paroxysmal nocturnal hemoglobinuria (PNH) and geographic atrophy in age-related macular degeneration. By binding complement C3, it blocks all three complement pathways at their convergence point, providing broader inhibition than C5-targeted therapies like eculizumab. For PNH, it addresses both intravascular and extravascular hemolysis, achieving transfusion independence in clinical trials.

Key Facts

Mechanism
Pegcetacoplan consists of two compstatin-derived cyclic tridecapeptides linked to a 40 kDa branched PEG molecule. The peptide moieties bind to complement C3 and C3b with high affinity, preventing the cleavage of C3 by C3 convertases of all three complement pathways. This blocks generation of the anaphylatoxin C3a, the opsonin C3b (preventing extravascular hemolysis via phagocytosis), and downstream formation of C5a and the membrane attack complex (MAC, C5b-9, responsible for intravascular hemolysis). In PNH, this dual blockade (upstream of C5) addresses the residual extravascular hemolysis that persists with anti-C5 therapy. In geographic atrophy, C3 inhibition reduces complement-mediated damage to retinal pigment epithelium and photoreceptors in the macula.
Research Status
approved
Half-Life
~8 days
Molecular Formula
C₉₅₀H₁₅₀₄N₂₆O₄₅₇S₄ (peptide component, PEG variable)
Primary Use
Immune & Inflammation
Table of Contents

Benefits

  • Superior hemoglobin improvement in PNH — PEGASUS trial showed significant hemoglobin increase vs eculizumab in patients switching from anti-C5 therapystrong
  • Addresses extravascular hemolysis — unlike anti-C5 therapies, C3 inhibition prevents C3b opsonization and subsequent phagocytic destruction of red blood cellsstrong
  • Transfusion independence — over 85% of PNH patients in trials achieved freedom from transfusions at week 16strong
  • Slows geographic atrophy progression — OAKS and DERBY trials showed 22% and 18% reduction in GA lesion growth rate with monthly intravitreal injectionsstrong
  • Subcutaneous self-administration for PNH — allows home-based treatment, unlike IV-only eculizumabmoderate

Dosage Protocols

RouteDosage RangeFrequencyNotes
Subcutaneous infusion (PNH — Empaveli)1,080 mgEvery 3 days (or 1,080 mg weekly in some patients)Self-administered subcutaneous infusion via infusion pump over ~30 minutes. Patients must receive meningococcal vaccination at least 2 weeks before initiation. For patients switching from eculizumab/ravulizumab, a 4-week overlap bridging period is required. Dose may be increased to 1,080 mg every 3 days if weekly dosing is insufficient.
Intravitreal injection (GA/AMD — Syfovre)15 mg/0.1 mLMonthly or every other monthAdministered by retinal specialist via intravitreal injection. Both monthly and every-other-month regimens showed efficacy in phase 3 trials. Treatment is ongoing with no defined stopping point. Patients should be monitored for endophthalmitis, retinal detachment, and ocular inflammation.

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Injection site reactions — erythema, pain, and induration at subcutaneous injection sites in 35-40% of PNH patientscommon
  • Increased infection risk — complement inhibition raises susceptibility to encapsulated bacteria (Neisseria, Streptococcus, Haemophilus); vaccination requiredserious
  • Diarrhea and abdominal pain — gastrointestinal effects reported in 15-22% of patientscommon
  • Breakthrough hemolysis — risk during transition from anti-C5 therapy; careful bridging period requiredserious
  • Endophthalmitis — rare but serious risk with intravitreal injection (Syfovre, GA indication); proper aseptic technique essentialserious
  • Fatigue and headache — reported in 10-15% of PNH patients, usually mildcommon

Frequently Asked Questions

How does pegcetacoplan differ from eculizumab for PNH?
Eculizumab (Soliris) blocks C5, preventing intravascular hemolysis via MAC formation but allowing C3b-mediated extravascular hemolysis to persist. This is why many PNH patients on eculizumab still have anemia and may need transfusions. Pegcetacoplan blocks C3, upstream of C5, preventing both intravascular hemolysis AND extravascular hemolysis. The PEGASUS head-to-head trial showed pegcetacoplan was superior to eculizumab in hemoglobin improvement. Additionally, pegcetacoplan is given subcutaneously at home vs eculizumab IV in clinic.
What is the infection risk with complement C3 inhibition?
Inhibiting C3 broadly suppresses complement-mediated immune defense, increasing susceptibility to infections — particularly encapsulated bacteria (Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae). Patients must receive meningococcal (MenACWY and MenB), pneumococcal, and Haemophilus influenzae type b vaccines at least 2 weeks before starting pegcetacoplan. Patients should carry antibiotics for emergency use and seek immediate medical attention for signs of meningitis or sepsis.
Can Syfovre restore vision lost to geographic atrophy?
No. Pegcetacoplan (Syfovre) slows the progression of geographic atrophy but does not reverse damage already done. It reduces the rate of GA lesion growth by approximately 18-22% compared to sham injection over 12-24 months. This means it preserves remaining vision for longer but does not restore dead retinal cells. Treatment is most beneficial when started earlier in the disease course, before extensive central vision loss has occurred.

References

  1. 1
    Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria (PEGASUS trial)(2021)PubMed ↗
  2. 2
    Pegcetacoplan for geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): phase 3 results(2021)PubMed ↗
  3. 3
    C3 inhibition with pegcetacoplan in subjects with paroxysmal nocturnal hemoglobinuria treated with eculizumab(2020)PubMed ↗

Latest Research

Last updated: 2026-02-19