Nomacopan inhibits terminal complement activation by binding tightly to C5 (KD 1nM) and preventing activation of C5 by the C5 convertase of all three complement activation pathways (classical, lectin and alternative). Akari is also evaluating compounds that inhibit the complement system by different mechanisms.
Role of complement system in inflammation and disease
The complement system, in evolutionary terms one of the oldest parts of the immune system, is considered to underpin and bridge innate and adaptive immunity, working with the immune system to disable and clear out foreign invaders and unwanted cells. It acts by triggering one or all of three processes: inflammation, cell destruction by lysis, or thrombosis through interactions with the coagulation system. Together with white blood cells and antibodies, it marks organisms recognized as pathogenic for destruction, and then assists in this process by recruiting white blood cells and mounting a direct lytic (destructive) attack on foreign cells or on the body’s own cells that appear to be foreign due to dysregulation of the complement system or some other homeostatic mechanism.
Dysregulation or inappropriate activation of the complement system underlies the life-threatening inflammatory and autoimmune conditions that Akari is planning to treat with nomacopan.
When activated, the complement system produces a cascade of proteins with each step in the complement system activated by a highly specific protease. C5, near the end of the complement cascade, is split into the anaphylatoxin C5a, a powerful inflammatory substance that engages two cell surface G-protein coupled receptors, and into C5b, which is the basis for formation of the membrane attack complex (MAC). The MAC can directly lyse cells causing tissue damage seen in many autoimmune diseases. Furthermore, sublytic deposition of MAC on self-cells induces inflammatory signals independently of C5a.
To prevent complement running out of control and causing autoimmune disease, the system includes a number of regulatory proteins, and it is usually when these proteins are deficient for genetic or other reasons that the complement system becomes dysregulated, and may start to directly attack the body’s own healthy organs and tissues. In other circumstances, the complement system may run out of control in response to a relatively mild infection which results in a “cytokine storm,” in which an uncontrolled inflammatory reaction or thrombotic event endangers the body’s own survival.
Mode of action
The atomic details of the binding interaction between nomacopan and C5 have been established through crystallographic studies (Fredslund et al, 2008, Jore et al., 2016). Three external regions of nomacopan interact with the C5d, CUB and C5-C345C domains of complement C5. The tight binding locks C5 into a rigid conformation that cannot be activated by engagement with the complement C5 convertase, thereby preventing generation of C5a and the MAC.