BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired 
disease characterized by chronic complement-mediated hemolysis. C5 inhibition 
controls intravascular hemolysis in untreated PNH but cannot address 
extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal 
complement protein C3, potentially inhibits both intravascular and extravascular 
hemolysis.
METHODS: We conducted a phase 3 open-label, controlled trial to assess the 
efficacy and safety of pegcetacoplan as compared with eculizumab in adults with 
PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab 
therapy. After a 4-week run-in phase in which all patients received 
pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous 
pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). 
The primary end point was the mean change in hemoglobin level from baseline to 
week 16. Additional clinical and hematologic markers of hemolysis and safety 
were assessed.
RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in 
hemoglobin level from baseline to week 16, with an adjusted (least squares) mean 
difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) 
receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab 
no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab 
was shown for the change in absolute reticulocyte count but not for the change 
in lactate dehydrogenase level. Functional Assessment of Chronic Illness 
Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The 
most common adverse events that occurred during treatment in the pegcetacoplan 
and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% 
vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and 
fatigue (5% vs. 15%). There were no cases of meningitis in either group.
CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin 
and clinical and hematologic outcomes in patients with PNH by providing broad 
hemolysis control, including control of intravascular and extravascular 
hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, 
NCT03500549.).