Description
Pegcetacoplan: a pegylated complement C3 inhibitor peptide.
Pegcetacoplan is a complement inhibitor indicated in treating paroxysmal nocturnal hemoglobinuria (PNH). Before its FDA approval, patients with PNH were typically treated with the C5-inhibiting monoclonal antibody eculizumab. Patients given eculizumab experienced less hemolysis caused by the membrane attack complex but were still somewhat susceptible to hemolysis caused by C3b opsonization. Pegcetacoplan was developed out of a need for an inhibitor of complement-mediated hemolysis further upstream of C5. Pegcetacoplan is a pegylated C3 inhibitor that can disrupt the processes, leading to both forms of hemolysis that threaten patients with PNH. Pegcetacoplan for subcutaneous use was granted FDA approval on 14 May 2021.7 In February 2023, the FDA approved pegcetacoplan for intravitreal use for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration.
Mode of action
Pegcetacoplan is a pegylated complement C3 inhibitor peptide that inhibits the C3 convertase, preventing cleavage of C3 into C3a and C3b, which prevent an inflammatory response and opsonization, respectively. C3b also supports the enzyme needed to cleave C5 into C5a and C5b, which promotes inflammatory reaction and the membrane attack complex responsible for cellular destruction and death. Therefore, inhibiting the complement systems at the level of C3 is suspected to be therapeutically beneficial to manage GA. Pegcetacoplan is a 15–amino acid cyclic peptide conjugated to each end of a linear polyethylene glycol molecule that binds to C3 and inhibits C3 activation. In addition, pegcetacoplan binds to and prevents the activity of C3b. As such, it inhibits the activities of the C3 and C5 convertases, even in the setting of a C3 or C5 nephritic factor.
Research
Currently, pegcetacoplan is in phase 2 development for C3G, IgAN, LN, and primary membranous nephropathy (Study APL2-201, DISCOVERY). Pegcetacoplan is also being developed for multiple nonrenal indications, including PNH (phase 3) and autoimmune hemolytic anemias (phase 2). In these indications, pegcetacoplan is administered via subcutaneous infusion. Pegcetacoplan is also in development for managing geographic atrophy secondary to age-related macular degeneration (AMD). Phase 3 clinical trials in geographic atrophy are ongoing in which intravitreal administration of pegcetacoplan is used.
