C3 inhibitor · blood, eye, kidney
A complement inhibitor built from two identical short synthetic peptides joined by a long polyethylene glycol chain. It blocks C3, a central protein of the complement system, part of innate immunity. Given under the skin as Empaveli, it treats a rare blood disease and two rare kidney diseases; injected into the eye as Syfovre, it treats geographic atrophy.
The complement system is a cascade of blood proteins that tags and destroys microbes but can also damage the body's own cells. C3 sits where its activation pathways converge. Pegcetacoplan binds C3 and its activated fragment C3b, limiting C3 cleavage and the steps that follow1.
In paroxysmal nocturnal hemoglobinuria (PNH), C3b coating marks red blood cells for destruction outside the blood vessels, while the later membrane attack complex bursts them inside the vessels1. C5 blockers such as eculizumab stop only the second process; acting earlier in the cascade, pegcetacoplan addresses both1,3.
In C3 glomerulopathy it reduces C3 deposits in the kidney's filters1, and in the eye it targets complement activity in geographic atrophy, a cause of progressive, irreversible vision loss in age-related macular degeneration2,4.
In the open-label PEGASUS trial, 80 adults with PNH who were still anemic on eculizumab were randomized to pegcetacoplan or to stay on eculizumab. After 16 weeks, hemoglobin rose substantially more with pegcetacoplan, and 85% versus 15% no longer needed transfusions3.
In the OAKS and DERBY trials, 1,258 people aged 60 or older with geographic atrophy received eye injections or sham; at 24 months lesion growth was slowed by roughly 16% to 22% versus sham (DERBY had missed statistical significance at 12 months), but key measures of visual function did not differ4.
In the VALIANT trial of 124 adolescents and adults with C3 glomerulopathy or primary immune-complex membranoproliferative glomerulonephritis, urine protein fell by about two-thirds at 26 weeks versus a slight rise on placebo, a 68% relative reduction; a kidney-biopsy activity score did not differ significantly5.
FDA-approved as Empaveli in 2021 for adults with PNH; its label now also covers people aged 12 and older with C3 glomerulopathy or primary immune-complex MPGN. Approved as Syfovre in 2023 for geographic atrophy secondary to age-related macular degeneration1,2.
Empaveli carries a boxed warning: by blocking complement it raises the risk of serious, sometimes fatal infections with encapsulated bacteria such as meningococcus and pneumococcus, so vaccination is required and it is available only through a restricted program. Common effects include injection-site reactions, infections, diarrhea, abdominal pain, fatigue and headache1. Syfovre eye injections carry risks of eye infection, retinal detachment, inflammation, raised eye pressure, retinal vasculitis or vessel blockage that can cause severe vision loss, and more frequent wet macular degeneration2.
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