Three Years On: The Role of Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria (PNH) since Its Initial Approval

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients' quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.