Comparing Clinical Efficacy of C5, C3 and Factor B Inhibition in Paroxysmal Nocturnal Hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematologic disorder that is caused by unregulated complement activation, leading to chronic red blood cell (RBC) hemolysis, anemia, fatigue, and an increased risk of thrombosis. The therapeutic landscape for PNH includes three key complement-targeting agents: ravulizumab (C5 inhibitor), pegcetacoplan (C3 inhibitor), and iptacopan (factor B inhibitor), each acting at different points in the complement cascade and demonstrating variable clinical efficacy. This study evaluates each treatment’s clinical effectiveness through a comparative analysis of six pivotal phase III trials, integrating primary and key secondary endpoints as well as commonly reported PNH biomarkers. The analysis encompasses both treatment-naïve patients and those transitioning between complement inhibitors. Findings suggest that factor B inhibition provides the most robust overall clinical efficacy, while C3 inhibition offers superior protection against hemolysis by blocking complement activation at an earlier stage. Although C5 inhibition remains a viable treatment option, it is associated with a higher likelihood of breakthrough hemolysis. However, limitations of this comparison of pivotal phase III trials include: heterogeneity in patient baseline characteristics, differences in trial design, variability in endpoint selection, and discrepancies in biomarker reporting. Ultimately, this work demonstrates the need for a greater understanding of the complement cascade and the effects of its inhibition at different points of activation in relation to diseases, such as PNH, that arise from its dysregulation.