Pegcetacoplan: how it works, uses and risks

What is pegcetacoplan?

Pegcetacoplan is a pegylated cyclic peptide that binds complement factor C3 and its activation fragment C3b. The complement system is part of the innate immune defense. C3 sits at a central point in its chain of reactions, so blocking C3 inhibits many of the steps that follow. The same active substance is used in two different products: Empaveli, given subcutaneously to treat paroxysmal nocturnal hemoglobinuria (PNH), and Syfovre, injected into the eye for geographic atrophy. Its development code was APL-2. Empaveli was approved in 2021 and Syfovre in 2023.

How does pegcetacoplan work?

Pegcetacoplan binds C3 and blocks its activation, along with downstream steps that can lead to cells being destroyed. In PNH, red blood cells lack surface proteins that normally protect them from the complement system. The cells are destroyed inside the blood vessels, and they are also tagged on their surface for breakdown through an earlier, C3-mediated step. Because pegcetacoplan acts on C3, it covers both routes. Its effect therefore reaches further than that of older drugs, which block only factor C5, a later player in the cascade. Source

In the eye, excess complement activity probably contributes to the slow loss of retinal cells in geographic atrophy. Injecting pegcetacoplan into the eye is meant to slow this progression. In the PEGASUS trial in PNH, pegcetacoplan outperformed the C5 inhibitor eculizumab in improving hemoglobin levels over 16 weeks 1.

Is pegcetacoplan FDA-approved?

Yes. The FDA has approved pegcetacoplan under two brand names 2. The table lists the products and their approved uses.

Empaveli carries a prominently highlighted warning, known as a boxed warning, about serious infections caused by encapsulated bacteria. The corresponding vaccinations are therefore required. In the United States, the product is available only through a restricted distribution program.

What is pegcetacoplan prescribed for?

Empaveli is used in adults with paroxysmal nocturnal hemoglobinuria and in people aged 12 and older with C3 glomerulopathy or primary IC-MPGN to reduce the amount of protein lost in the urine. Syfovre is prescribed for geographic atrophy, an advanced form of dry age-related macular degeneration. The eye injection is given by an ophthalmologist.

What side effects have been described?

According to the prescribing information, common side effects include:

• With Empaveli: injection site reactions, infections, diarrhea and abdominal pain.

• With Syfovre: eye discomfort, floating spots or strands in the field of vision (floaters) and bleeding on the surface of the eye.

The more serious risks and warnings include:

• With Empaveli: serious infections caused by encapsulated bacteria, such as meningococci. Vaccinations and a risk management program are required. Hemolysis, meaning increased breakdown of red blood cells, can also occur after the drug is stopped.

• With Syfovre: infections inside the eye (endophthalmitis), retinal detachment, inflammation of the retinal blood vessels and a higher rate of conversion to wet macular degeneration.

Studies at a glance

Year	Product	Approved use
2021	Empaveli	PNH
2023	Syfovre	Geographic atrophy secondary to age-related macular degeneration
2025	Empaveli	C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN), 2 rare kidney diseases

References provided in the source article

Sources: FDA prescribing information for Empaveli and Syfovre; the PEGASUS trial (Hillmen et al., New England Journal of Medicine, 2021, DOI: 10.1056/NEJMoa2029073 1 ), indexed on PubMed.

Provenance and editorial review status

Adapted for Nutrient Desk from the source article. The claims and source attributions in the original text still require clinical review. This draft has not been cleared for indexing.