Progress in the use of biological therapies to treat paroxysmal nocturnal hemoglobinuria: focus on patient profiling

Introduction: Complement inhibition has revolutionized paroxysmal nocturnal hemoglobinuria (PNH) treatment. While eculizumab, the first anti-C5 antibody, reduced intravascular hemolysis (IVH) and thrombotic risk, it required fortnightly infusions and left a significant percentage of patients with persistent anemia. New terminal complement inhibitors, such as long-acting ravulizumab and subcutaneous crovalimab, have allowed for better control of IVH and demonstrated efficacy in patients with specific C5 genetic polymorphisms (crovalimab). Proximal complement inhibitors, including the small molecule pegcetacoplan (C3 inhibitor), the recently approved orally administered iptacopan (factor B inhibitor), and danicopan (factor D inhibitor, in combination with anti-C5), efficiently control C3-mediated extravascular hemolysis. However, these treatments come with an increased risk of serious breakthrough hemolysis events due to reduced half-life and increased sparing of PNH erythrocytes. Areas covered: In this review, we summarize phase III trials and real-world data to support patient-tailored treatment strategies and offer practical guidance for patient profiling and optimal complement inhibitor selection. Expert opinion: In this evolving landscape, treatment choice has become increasingly complex. PNH specialists must now balance multiple factors beyond efficacy alone. Disease characteristics such as previous thrombotic events or transfusion needs, as well as drug administration routes, patient preferences toward oral or parenteral administration and expected compliance, will all influence clinical decisions.