Current Opinions on the Clinical Utility of Ravulizumab for the Treatment of Paroxysmal Nocturnal Hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder of hematopoietic stem cells genetically defined by the acquisition of somatic mutations in the X-linked phosphatidylinositol glycan anchor biosynthesis, class A (PIGA) gene. PIGA is essential for the synthesis of glycosyl phosphatidylinositol (GPI) anchor proteins and its mutations result in a deficiency of such molecules on the membrane of blood cells derived from the mutant clone. In particular, the lack of the GPI-linked complement regulatory proteins CD55 and CD59 is responsible for the increased sensitivity of PNH erythrocytes to complement-mediated destruction. Indeed, the classical clinical picture of PNH includes signs and symptoms of intravascular hemolysis along with variable degrees of cytopenia and a strong tendency to thrombosis, hallmarks of the disease. Before the introduction of anti-complement inhibitors, PNH was characterized by a high mortality primarily due to thrombotic events. The approval of the terminal anti-complement inhibitor eculizumab in 2007 introduced a paradigm shift in the treatment of the disease with improvement of the chronic hemolytic process and dramatic reduction of the thrombotic rate. However, eculizumab has a relatively short half-life when considering a life-long treatment, with obvious consequences as to the quality of life of treated patients necessitating relatively frequent drug administrations. Moreover, up to 30% of PNH patients undergoing eculizumab therapy show a suboptimal response, continuing to require red cell transfusions because of extravascular hemolysis or breakthrough hemolytic episodes. In 2019, the FDA approved the second-generation C5 inhibitor ravulizumab, a long-lasting agent with a better control of disease manifestations. Herein, we discuss the use of ravulizumab in PNH, its differences with first-generation C5 inhibitors, the research evidence supporting the safety and efficacy of this drug and its impact on costs for health systems and quality of life of PNH patients.

Keywords: anti-complement therapy; paroxysmal nocturnal hemoglobinuria; ravulizumab.

Figure 1

Pathogenesis of hemolysis in paroxysmal nocturnal hemoglobinuria. In the upper panel, the three complement pathways (classic, alternative, and lectin binding) converge to C3 whose activation following formation of C3 convertase and formation of C3b is regulated by CD55. C3b can then join C5b once cleaved from C5 via C5 convertase and form the membrane attack complex (MAC) along with C6, C7, C8 and C9 (a process inhibited by CD59). In PNH, the lack of CD55 and CD59 makes PNH cells (in particular erythrocytes) vulnerable to complement-mediated lysis because of the absence of inhibitory signals. Eculizumab and ravulizumab block C5 cleavage preventing the formation of the MAC. In the lower panel, the excess of C3 fragment in PNH patients treated with C5 inhibitors leads to opsonization of circulating erythrocytes and extravascular hemolysis via macrophage-mediated phagocytosis in the reticuloendothelial system (RES).

Figure 2

Generation of ravulizumab. The figure displays the amino acid sequence of eculizumab and highlights the amino acids substitutions responsible for the increased half-life of the second-generation C5 inhibitor ravulizumab. Figures were generated by means of I-Tasser and pyMOL Software (The PyMOL Molecular Graphics System, Version 1.2r3pre, Schrödinger, LLC).