Inhibition of FD proteolytic activity by danicopan. FD participates in C3 convertase generation by cleavage of factor B at 2 steps in the AP cascade: generation of the initial C3 convertase [C3(H₂O)Bb] following spontaneous AP activation (tick-over) in the fluid phase and the production of surface-bound C3 convertase (C3bBb), which mediates dramatic amplification of the initial activation (amplification loop) and activation of the terminal pathway (cleavage of C5 into C5a and C5b by C5 convertase [ie, C3bBb3b]), leading to opsonization of target surfaces by C3b, release of the anaphylatoxins C3a and C5a, and formation of MAC. An erythrocyte is shown to depict the membrane-bound events. Regulatory proteins not shown here can promote (properdin and FH-related proteins) or attenuate (factor H, factor I, multiple membrane-bound proteins, including CD55 and CD59) AP activity. Eculizumab acts directly at the terminal pathway by preventing its activation via binding to C5; danicopan acts upstream by preventing AP activation via inhibition of proteolytic activity of FD. Although the C5 inhibitor is able to block MAC formation regardless of the initiation pathway of complement activation, it has no effect on C3 fragment deposition. FD inhibitor is able to block C3 fragment deposition and MAC formation when the complement activation is initiated via AP, such as in the case of PNH; it should be able to exert the same, although not complete, inhibitory effect when complement activation is initiated via CP or LP through blocking the amplification loop.²⁴