Hemolysis events in the Phase 3 PEGASUS study of pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) experience complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Pegcetacoplan, a C3 inhibitor, demonstrated sustained improvements in hematological and clinical parameters in the Phase 3 PEGASUS trial in patients with PNH who remained anemic despite C5 inhibitor therapy. The current post-hoc analysis describes 26 hemolysis adverse events (AEs) experienced in 19 patients during pegcetacoplan therapy in PEGASUS and baseline patient characteristics potentially associated with increased hemolysis risk. Lactate dehydrogenase (LDH) ≥2× the upper limit of normal (ULN) was observed in 19 events, including 2 with LDH ≥10× ULN. All patients experienced decreased hemoglobin during hemolysis (mean decrease: 3.0 g/dL). In 16 events (62%) a potential complement-amplifying condition underlying the event could be identified. Hemolysis AEs led to study discontinuation in 5 patients. However, 17 of 26 (65%) hemolysis AEs were manageable without pegcetacoplan discontinuation. A greater proportion of patients with hemolysis AEs (n=19) had key characteristics of higher disease activity at baseline compared to patients without hemolysis AEs (n=61), namely higher-than-label eculizumab dose (53% vs 23%), detectable CH50 (74% vs 54%) and ≥4 transfusions in the previous 12 months (68% vs 51%). These characteristics may be useful predictors of potential future hemolysis events. ClinicalTrials.gov identifier: NCT03500549.