Pegcetacoplan

Pegcetacoplan is a PEGylated cyclic peptide inhibitor of complement component C3, targeting the central convergence point of all complement activation pathways. By blocking C3, it prevents generation of both C3a (anaphylatoxin) and C3b (opsonin), thereby inhibiting all downstream complement effector functions.

The compound received FDA approval for paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired disorder where GPI-anchored complement regulatory proteins are absent from blood cells, leading to complement-mediated hemolysis. While terminal complement blockade (anti-C5) prevents intravascular hemolysis, it leaves C3b-mediated extravascular hemolysis unaddressed - a limitation pegcetacoplan overcomes through upstream blockade.

The 40 kDa PEG conjugation extends plasma half-life sufficiently for twice-weekly subcutaneous self-administration, transforming a rapidly-cleared peptide into a practical chronic therapy. This exemplifies the power of PEGylation to enable peptide therapeutics that would otherwise require continuous infusion.

Pegcetacoplan also received approval for geographic atrophy secondary to age-related macular degeneration (AMD), where complement activation in the retina drives progressive photoreceptor loss. Intravitreal administration provides direct complement inhibition at the disease site, slowing lesion growth. Research continues exploring C3 inhibition in other complement-driven conditions.