Pegcetacoplan

Hematology / Ophthalmology

Also known as: Empaveli, Syfovre, APL-2, Pegcetacoplan Injection

Complement Inhibitors (Cyclic Peptide)Research phase: FDA-approvedRegulatory: FDA-approved for PNH (Empaveli, 2021, SC infusion) and geographic atrophy secondary to AMD (Syfovre, 2023, intravitreal injection).

Mechanism

Pegcetacoplan is a PEGylated cyclic peptide that blocks complement component C3 — the central hub of the entire complement immune system. By targeting C3, it blocks all downstream complement pathways. It is FDA-approved for two different conditions: as an injection (Empaveli) for paroxysmal nocturnal hemoglobinuria (PNH) where complement destroys red blood cells, and as an eye injection (Syfovre) for geographic atrophy in macular degeneration.

Technical detail

Pegcetacoplan consists of two identical cyclic tridecapeptides conjugated to a 40 kDa branched PEG molecule. The peptide moieties bind complement C3 and C3b with high affinity, preventing cleavage by C3 convertases (both classical and alternative pathway) and blocking C3b opsonization. This proximal complement inhibition prevents generation of C3a (anaphylatoxin), C3b (opsonin), and all downstream effectors including C5a and C5b-9 (MAC). In PNH, this addresses both intravascular (MAC-mediated) and extravascular (C3b-opsonization-mediated) hemolysis. In geographic atrophy, it reduces complement-driven retinal pigment epithelium destruction.

Evidence

Pegcetacoplan versus eculizumab in patients with paroxysmal nocturnal haemoglobinuria (PEGASUS): 48-week follow-up of a randomised, open-label, phase 3, active-comparator, controlled trial
de Latour et al. (2022) — Lancet Haematology — PMID: 36055332
In adults with paroxysmal nocturnal hemoglobinuria and a suboptimal response to eculizumab, pegcetacoplan maintained superior hematologic outcomes through 48 weeks, extending the benefit seen at 16 weeks.
strong
Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial
Liao et al. (2020) — Ophthalmology — PMID: 31474439
In 246 patients with geographic atrophy from age-related macular degeneration, monthly pegcetacoplan reduced lesion growth by 29% versus sham at 12 months, but treatment was associated with more exudative AMD and rare endophthalmitis.
moderate

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