Advances in Complement Inhibition Therapies for Paroxysmal Nocturnal Hemoglobinuria and Autoimmune Hemolytic Disorders

Abstract

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare hematologic disorder characterized by intravascular hemolysis through complement activation, bone marrow failure, and thrombosis. The advancement of complement biology has enabled better therapeutic approaches that lead to better clinical outcomes in patients with PNH and other complement-driven hemolytic disorders. The terminal complement inhibitor, eculizumab, was the initial drug available which significantly reduced hemolysis and thrombotic events but failed to resolve residual extravascular hemolysis and transfusion requirements. New therapeutic agents which target proximal complement factors C3, factor B and factor D demonstrate better control of intra- and extravascular hemolysis while decreasing transfusion requirements and improving patient quality of life. This review highlights the evolving therapeutic landscape in complement inhibition by summarizing clinical evidence for the terminal complement inhibitors, as well as pegcetacoplan, iptacopan, and danicopan as emerging agents for treatment of PNH and autoimmune hemolytic anemias—warm AIHA and cold agglutinin disease (CAD). The review also examines ongoing clinical trials and proposes future directions to optimize therapeutic outcomes to address remaining clinical challenges.