The role of the alternative pathway in paroxysmal nocturnal hemoglobinuria and emerging treatments

Abstract

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled activation of the terminal complement pathway, leading to intravascular hemolysis (IVH) and a prothrombotic state. Treatment with terminal complement (C5) inhibitors, the current standard of care, suppresses IVH and reduces the risk of thrombosis and the associated morbidity and mortality. Opportunities exist to further improve care by alternative modes of administration and the reduction of clinically significant anemia and transfusion dependence caused by extravascular hemolysis in some patients.

Areas covered: This review describes the pathophysiology of PNH, provides an overview of the current standard of care, and discusses potential avenues for enhancing patient care, with a focus on the literature describing new and emerging treatments that target the alternative pathway. Emerging treatments include biosimilars and novel C5 inhibitors as well as agents with novel mechanisms of action that target the proximal complement pathways (C3 inhibitors, factor B inhibitors, and factor D inhibitors).

Expert opinion: Alternative complement pathway inhibitors may offer further benefit as long as terminal complement is completely inhibited to reduce IVH and disease activity. This may lead to improvements in adherence and health-related quality of life for patients with PNH.

Keywords: Alternative pathway; anemia; complement inhibitors; extravascular hemolysis; factor D; paroxysmal nocturnal hemoglobinuria.