Danicopan

The complement system is an enzyme cascade that plays a role in innate immunity. It helps defend against infection by initiating a local inflammatory response and is the system responsible for producing the terminal membrane attack complex (MAC), which causes lysis of foreign cells. In addition, the components of the complement pathway have other immune functions, including the promotion of phagocytosis, the clearance of immune complexes, and the regulation of antibody production. There are three pathways to complement activation - Lectin, Classical, and Alternative - which converge at complement component C3.

Danicopan reversibly binds to complement factor D, thereby selectively inhibiting the alternative complement pathway. It prevents the formation of complement component C3 convertase (C3bBb), the generation of downstream effectors including C3 fragment opsonization, and the amplification of the terminal pathway. In paroxysmal nocturnal hemoglobinuria, intravascular hemolysis is mediated by the MAC, while extravascular hemolysis is facilitated by C3 fragment opsonization. Danicopan acts proximally in the alternative pathway of the complement cascade to control C3 fragment-mediated EVH, while co-administered ravulizumab or eculizumab is anticipated to maintain control over MAC-mediated IVH.