Pegcetacoplan

PNH is due to a mutation in the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) gene. The mutation in the PIGA gene prevents an early step in the formation of glycosyl phosphatidyl inositol (GPI). Under normal circumstances, GPI connects cell surface proteins to the cell. In patients with PNH, complement inhibiting cell surface proteins, such as CD55 and CD59, are not anchored to the surface of red blood cells. In cases with reduced or absent CD55 and CD59, complement is not appropriately inhibited, leading to activation of the complement system and complement-mediated hemolysis. As a result of complement-mediated hemolysis, patients with PNH may experience anemia, fatigue, asthenia, and dyspnea.

The alternative complement system pathway is spontaneously activated due to the absence of CD55, leading to activation of a C3 convertase that that cleaves C3 into C3a and C3b. C3b binds to factor B, which is cleaved by factor D into the smaller Ba and larger Bb. The resulting C3bBb can bind to other C3 proteins, leading to a positive feedback loop of complement activation. C3b proteins can also bind directly to a target cell, marking it as a target for phagocytosis. CD55, also known as decay-accelerating factor (DAF) disrupts the formation of C3bBb, preventing spontaneous activation of the alternative complement pathway.

C3b cleaves C5 into C5a and C5b. C5b combines with complement proteins C6, C7, C8, and C9 to form the membrane attack complex (MAC). The MAC is a pore formed in the cell by 16 C9 proteins associated with C5b, C6, C7, and C8. Formation of pores destroys the cell membrane leading to cell death. CD59 disrupts the formation of the MAC, preventing hemolysis.

In patients with PNH, extravascular hemolysis is mediated by C3b marking red blood cells for phagocytosis, and intravascular hemolysis is mediated by the MAC. Pegcetacoplan binds to C3 and C3b, reducing cleavage and activation of complement pathways, reducing both extravascular and intravascular hemolysis.