Iptacopan monotherapy resulted in increased hemoglobin level in patients with PNH and hemoglobin ≥10 g/dL after anti‐C5 therapy

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Abstract Patients with paroxysmal nocturnal hemoglobinuria (PNH) on anti‐C5 often experience extravascular hemolysis with anemia. Iptacopan, the first oral proximal complement inhibitor targeting factor B, has shown efficacy and safety in PNH patients. APPULSE‐PNH (NCT05630001), a phase 3b, single‑arm, open‐label trial, enrolled adult patients with PNH and hemoglobin ≥10 g/dL on stable anti‐C5 for ≥6 months. Patients switched to iptacopan monotherapy (200 mg twice daily; 24 weeks). Primary endpoint: mean hemoglobin change from baseline across four visits (Days 126–168). At baseline, 57.7% of patients had elevated absolute reticulocyte counts (ARCs; above ULN = 123 × 10 9 /L) and 50% had C3 deposition on red blood cells (RBCs) >10%, indicative of extravascular hemolysis. There was a statistically significant increase in hemoglobin during the trial; adjusted mean change from baseline (95% CI) was +2.0 g/dL (1.7–2.3) overall, and in patients with baseline hemoglobin <12 g/dL and ≥12 g/dL, +2.4 (2.0–2.7) and +1.4 (1.0–1.8), respectively. Patients maintained transfusion independence, 92.7% with hemoglobin ≥12 g/dL. Adjusted mean change from baseline (95% CI) in lactate dehydrogenase and ARC were −1.3% (−6.6 to 4.3) and −89.2 × 10 9 /L (−95.5 to −82.9), respectively. Mean (SD) proportion of C3d+ PNH RBCs, assessed by flow cytometry, decreased from 11.0% (8.6) to 0.2% (0.7) at Day 168. No patients had breakthrough hemolysis or major adverse vascular events. FACIT‐Fatigue and treatment satisfaction scores improved by Days 84 and 168. Safety showed consistency with previous iptacopan PNH trials. Iptacopan improved hematologic outcomes in PNH patients with hemoglobin ≥10 g/dL on anti‐C5, maintaining control of intravascular hemolysis and resolving extravascular hemolysis.

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