Comparing Clinical Efficacy of C5, C3 and Factor B Inhibition in Paroxysmal Nocturnal Hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, deadly, hematological disease that arises from the body’s inability to regulate the complement system’s attack on PNH RBCs which lack the ability to regulate ongoing complement activity resulting in RBC hemolysis, persistent anemia, extreme lethargy, and elevated risk for thrombosis. Among the treatment options available to patients and their physicians, three therapeutics specifically targeting the complement system are available on the market: ravulizumab, pegcetacoplan, and iptacopan. Each of these three treatments blocks a different portion of the complement cascade, C5, C3 and factor B respectively, resulting in variable efficacy. This paper explores and assesses the clinical efficacy of these three therapeutics through a collective analysis of each asset’s pivotal phase 3 trials through: 1) a collection of primary and key secondary endpoints from each trial and 2) a table-based comparison of common reported PNH biomarkers drawn from the collective analysis. Both points of methodology are conducted in patients who had never received complement inhibition therapy previously and patients who had been switched from one form of complement inhibition to another. Based on the alternative pathway’s ability to amplify convertase production, reasoning is provided as to why blocking certain nodes of the complement pathway displays higher efficacy than other nodes. Recommendations are put forward to further pursue research within these nodes for development of future therapeutics. Lastly, development of new complement-based therapeutics for PNH, such as Voydeya, is discussed.