Pegcetacoplan 1.08g/20ml solution for infusion vials

PNH is due to a mutation in the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) gene.[A234975][A235000] The mutation in the PIGA gene prevents an early step in the formation of glycosyl phosphatidyl inositol (GPI).[A234975] Under normal circumstances, GPI connects cell surface proteins to the cell.[A234975][A235000] In patients with PNH, complement inhibiting cell surface proteins, such as CD55 and CD59, are not anchored to the surface of red blood cells.[A234975][A235000] 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.[A234975][A235000] As a result of complement-mediated hemolysis, patients with PNH may experience anemia, fatigue, asthenia, and dyspnea.[A235000]

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.[A234975] C3b binds to factor B, which is cleaved by factor D into the smaller Ba and larger Bb.[A234980] The resulting C3bBb can bind to other C3 proteins, leading to a positive feedback loop of complement activation.[A234980] C3b proteins can also bind directly to a target cell, marking it as a target for phagocytosis.[A234995] CD55, also known as decay-accelerating factor (DAF) disrupts the formation of C3bBb, preventing spontaneous activation of the alternative complement pathway.[A234980]

C3b cleaves C5 into C5a and C5b.[A234975] C5b combines with complement proteins C6, C7, C8, and C9 to form the membrane attack complex (MAC).[A234980] The MAC is a pore formed in the cell by 16 C9 proteins associated with C5b, C6, C7, and C8.[A234990] Formation of pores destroys the cell membrane leading to cell death.[A234990] CD59 disrupts the formation of the MAC, preventing hemolysis.[A234975]

In patients with PNH, extravascular hemolysis is mediated by C3b marking red blood cells for phagocytosis, and intravascular hemolysis is mediated by the MAC.[A235000][L34095] Pegcetacoplan binds to C3 and C3b, reducing cleavage and activation of complement pathways, reducing both extravascular and intravascular hemolysis.[L34095]