What is Pegcetacoplan?
Pegcetacoplan (brand name EMPAVELI in the US, ASPAVELI in the EU; development code APL-2) is a pegylated, cyclic peptide derived from compstatin, designed to inhibit complement component C3. It is the first and only approved drug that targets the complement cascade at the C3 level rather than downstream at C5.
Two molecules of a 15-amino-acid cyclic compstatin analogue are conjugated to opposite ends of a branched 40 kDa polyethylene glycol linker. The PEG extends serum half-life and the cyclic peptide moieties bind C3 and C3b with high affinity.
Mechanism of Action
The complement cascade can be activated through three paths (classical, lectin, alternative), all converging on C3 cleavage to C3a and C3b. C3b then drives:
- Opsonization of cells (including red blood cells in PNH)
- Amplification of the alternative pathway (C3 convertase amplification loop)
- Downstream cleavage of C5 → MAC formation
Pegcetacoplan binds C3 and C3b directly, blocking both the C3 cleavage step and downstream C5 cleavage. This produces broader complement inhibition than C5 inhibitors (eculizumab, ravulizumab, zilucoplan), which leave upstream C3-mediated opsonization intact.
In PNH, the consequence is dual: pegcetacoplan controls both intravascular hemolysis (downstream of C5/MAC, also addressed by C5 inhibitors) and extravascular hemolysis (driven by C3b deposition on RBCs and clearance by liver/spleen — not addressed by C5 inhibitors).
Clinical Evidence
PEGASUS Phase 3 (NEJM 2021) — PNH head-to-head vs eculizumab:
- 80 PNH patients with hemoglobin <10.5 g/dL on stable eculizumab
- Switched to pegcetacoplan or continued eculizumab for 16 weeks
- Hemoglobin change: +2.37 g/dL pegcetacoplan vs −1.47 g/dL eculizumab (treatment difference 3.84 g/dL, p<0.001)
- 85% of pegcetacoplan patients achieved transfusion independence vs 15% on eculizumab
VALIANT Phase 3 — C3 glomerulopathy and IC-MPGN:
- Patients with biopsy-proven C3G or IC-MPGN, ages ≥12
- Reduced proteinuria and stabilized/improved eGFR vs placebo at 26 weeks
- Supported the 2025 expansion approval
Approval History
- May 14, 2021 — FDA approval for adults with PNH
- December 2021 — EMA approval (Aspaveli)
- July 28, 2025 — FDA expanded approval for C3 glomerulopathy and immune-complex MPGN in patients ≥12 years
Place in Therapy
Pegcetacoplan is administered as a subcutaneous infusion twice weekly, self-administered with a small pump. In PNH it can be used as initial therapy or after switch from C5 inhibitors when extravascular hemolysis is the dominant issue. In C3G/IC-MPGN, it is the first disease-modifying therapy ever approved for these previously untreated rare kidney diseases.
Safety Profile
The black-box warning, like all complement inhibitors, is for serious meningococcal and other encapsulated organism infections — patients must be vaccinated against N. meningitidis, S. pneumoniae, and H. influenzae before initiation. Other adverse events include injection-site reactions, infusion-site reactions, and respiratory tract infections.
Relationship to Other Peptide Complement Inhibitors
Pegcetacoplan is part of a small, growing class of peptide-based complement therapeutics:
- Pegcetacoplan (Empaveli) — pegylated compstatin cyclic peptide, C3 inhibitor
- Zilucoplan (Zilbrysq) — macrocyclic peptide, C5 inhibitor
These two illustrate the breadth of peptide drug development across complement targets.