Pegcetacoplan

Empaveli / Syfovre / Aspaveli

Pegcetacoplan is a therapeutic built around two identical cyclic peptides — each a compstatin derivative that binds and inhibits complement component C3 — linked to a polyethylene glycol (PEG) chain that extends its half-life. C3 sits at a central hub of the complement system, the innate-immune cascade that tags and destroys cells. By blocking C3, pegcetacoplan acts at a more proximal, broader point than C5-targeting drugs, controlling both the terminal 'membrane attack' pathway and the upstream deposition of C3 fragments that mark cells for destruction. In paroxysmal nocturnal hemoglobinuria (PNH) — a rare acquired blood disorder in which red cells lack the protective surface proteins that normally restrain complement — this dual control matters. C5 inhibitors like eculizumab prevent complement from bursting red cells inside blood vessels (intravascular hemolysis), but complement C3 fragments can still coat surviving red cells and lead to their destruction in the spleen and liver (extravascular hemolysis), leaving some patients anemic despite treatment. By inhibiting C3, pegcetacoplan addresses both mechanisms, and in the head-to-head PEGASUS trial it improved hemoglobin compared with eculizumab. It was approved by the FDA for PNH in 2021 (Empaveli), given by subcutaneous infusion. A separate formulation of the same molecule (Syfovre) was approved in 2023 as an intravitreal (into-the-eye) injection to slow the progression of geographic atrophy secondary to age-related macular degeneration, a leading cause of irreversible vision loss where complement overactivity contributes to retinal cell death. Because inhibiting complement raises the risk of infection by encapsulated bacteria (such as meningococcus), PNH patients require meningococcal and other vaccinations before starting, and the eye formulation carries risks including intraocular inflammation. It is a specialist prescription medicine, and its two very different uses share only the underlying C3-inhibitory mechanism.