Background
Phase III open-label RCT. 80 adult PNH patients with Hgb <10.5 g/dL despite stable eculizumab therapy for ≥3 months. 4-week run-in with eculizumab continuation, then randomized 1:1 to pegcetacoplan vs continued eculizumab for 16 weeks. Pegcetacoplan (APL-2; Empaveli/Aspaveli) is a PEGylated cyclic peptide targeting complement C3, the central complement node upstream of both the terminal (C5) and opsonin pathways, thereby inhibiting both intravascular (C5b-9-mediated) and extravascular (C3-opsonized) hemolysis. Designed to address the 30–35% of eculizumab-treated PNH patients with persistent anemia due to extravascular hemolysis.
Interventions and follow up
Arm A: Pegcetacoplan 1080 mg SC twice weekly
Arm B: Eculizumab (current dose) IV q2w (continuing)
Primary endpoint: Change in hemoglobin from baseline to week 16 (superiority)
Median follow-up: 16 weeks (randomized phase); 48-week open-label extension
Arm B: Eculizumab (current dose) IV q2w (continuing)
Primary endpoint: Change in hemoglobin from baseline to week 16 (superiority)
Median follow-up: 16 weeks (randomized phase); 48-week open-label extension
Results
Hgb change at 16 weeks: +3.84 g/dL (pegcetacoplan) vs −0.50 g/dL (eculizumab); difference +4.34 g/dL (95% CI 3.47–5.21), P<.001
Transfusion avoidance (prior-transfusion subgroup): 85% (pegcetacoplan) vs 15% (eculizumab)
LDH normalization: 54% (pegcetacoplan) vs 0% (eculizumab) among non-normalizers at baseline
Reticulocyte count: decreased (pegcetacoplan) vs increased (eculizumab)
Transfusion avoidance (prior-transfusion subgroup): 85% (pegcetacoplan) vs 15% (eculizumab)
LDH normalization: 54% (pegcetacoplan) vs 0% (eculizumab) among non-normalizers at baseline
Reticulocyte count: decreased (pegcetacoplan) vs increased (eculizumab)
Adverse events
Common AEs: injection site reactions 37% (pegcetacoplan) vs 3% (eculizumab); headache 20% vs 21%; breakthrough hemolysis seen on pegcetacoplan withdrawal
Serious events/mortality: grade ≥3 AEs 29% vs 21%; serious AEs 29% vs 15% (including pneumococcal pneumonia in 2 pegcetacoplan patients); twice-weekly SC injection required
Serious events/mortality: grade ≥3 AEs 29% vs 21%; serious AEs 29% vs 15% (including pneumococcal pneumonia in 2 pegcetacoplan patients); twice-weekly SC injection required
Conclusions
Pegcetacoplan significantly improved hemoglobin by +4.34 g/dL compared to eculizumab in patients with persistent anemia despite C5 inhibition, by addressing extravascular hemolysis through proximal C3 inhibition.
Key Limitations
Short 16-week randomized phase; long-term efficacy and safety require extension data. Serious AEs numerically higher on pegcetacoplan (29% vs 15%), including encapsulated-organism infections (C3 inhibition blocks opsonization broadly), requiring prophylaxis against meningococcus, pneumococcus, and Haemophilus. Twice-weekly SC injections are burdensome. PNH clone can expand as proximal inhibition shifts clone selection pressure. Higher discontinuation risk due to injection burden.
Clinical Context
FDA approved pegcetacoplan (Empaveli) for PNH in May 2021 as the first proximal C3 inhibitor; EMA approval (Aspaveli) followed in 2021. It is positioned for patients with persistent anemia on C5 inhibitors (the extravascular hemolysis phenotype) and requires more comprehensive infectious prophylaxis than C5 inhibitors. Iptacopan (oral factor B inhibitor, APPLY-PNH 2023) subsequently showed superior hemoglobin improvement vs C5 inhibitors and was FDA-approved in December 2023 as a more convenient once-daily oral option for the same population.