|The three principal activation pathways of the complement system (the classical, lectin and alternative pathways) converge on complement peptide C3, making it a central target for drug development in the search for immune system modulators for the treatment of complement-mediated disorders. Excessive or uncontrolled activation of the complement system plays a key role in a wide range of autoimmune and inflammatory diseases. Pharmacological inhibition of C3 activation can modify all outcomes of complement cascade activation (opsonization, inflammation and membrane attack complex formation), irrespective of which complement pathway is activated.
Examples of C3 inhibitors in development, all of which are compstatin derivatives:
Apellis is developing peptide drug candidates which act as C3 inhibitors to effect disease control and disease modification, in conditions including paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD) and chronic obstructive pulmonary disease (COPD). APL-1 (previously POT-4), a short-acting inhibitor has completed Phase 1 in AMD and has potential for COPD (inhaled administration). APL-2 (clinical Phase 2) is PEGylated APL-1 formulated for subcutaneous (PNH) and intravitreal administration (AMD). APL-2 is being trialled alone and as an add-on to the approved PNH therapy eculizumab (Phase 1 trial NCT02264639).
AMY-101 (Amyndas Pharmaceuticals) is has been granted Orphan Designation by both the EMA and US FDA for the treatment of C3 glomerulopathy (C3G).
peptide Cp40 [PMID: 25982307] has shown effective C3 inhibition in C3G in vitro .