Pegcetacoplan

APL-2, Empaveli (systemic, US), Aspaveli (systemic, EU/UK), Syfovre (intravitreal, US)

Immune & bioregulators

Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

Note on this profile. Pegcetacoplan is an approved prescription medicine for rare complement-driven diseases. This page explains the published science. It is a hospital- and specialist-prescribed product; community or self-directed use is essentially none documented.

Summary

Class: Pegylated cyclic peptide: two identical 13-amino-acid cyclic peptides (derived from compstatin) joined by a 40 kDa linear polyethylene glycol chain; a complement C3 inhibitor
Mechanism: Binds complement protein C3 and its fragment C3b, blocking all three complement activation pathways at their convergence point
Routes studied: Subcutaneous infusion via pump (systemic diseases); intravitreal injection into the eye (geographic atrophy)
Half-life: Approximately 8 days (systemic subcutaneous)
Storage: Refrigerate vials in original carton; allow to reach room temperature before infusion. Intravitreal vials refrigerated; clinic use only
Regulatory status: Approved medicine (US, EU, UK, Australia for systemic use); intravitreal form approved in US but refused in EU

Doses are as reported in studies or by the community — never recommendations.

1What it is

Pegcetacoplan started life as compstatin, a 13-amino-acid cyclic peptide discovered in the 1990s by screening peptide libraries for molecules that bound complement C3. Compstatin alone is cleared from the body in minutes. The pharmaceutical version joins two improved compstatin peptides to a large PEG chain, which keeps it in the bloodstream for over a week and makes it the first C3-level complement inhibitor to reach the market.

Complement is part of the innate immune system; C3 is the hub through which every activation route passes. Blocking it broadly dampens complement-mediated destruction of cells and tissue, which is the problem in paroxysmal nocturnal haemoglobinuria (PNH), C3 glomerulopathy and, it is thought, in the dry form of advanced age-related macular degeneration.

2How it's thought to work

Pegcetacoplan binds C3 and C3b, preventing C3 from being cleaved by the C3 convertase and so stopping formation of C3a, C3b and all downstream products including C5a and the membrane attack complex.

In PNH this prevents both intravascular haemolysis (which C5 inhibitors like eculizumab also prevent) and extravascular haemolysis caused by C3 fragments coating red cells (which C5 inhibitors do not). This is why it was superior to eculizumab on haemoglobin.

In the eye, local complement over-activation in the retina is implicated in geographic atrophy; intravitreal injection achieves high local concentration with minimal systemic exposure.

Two cyclic peptides on a PEG chain, blocking complement at C3. Stopping the cascade that early also removes C3's role in clearing bacteria, which is the trade-off against C5 inhibition.Schematic — not to scale

3What the research shows

Paroxysmal nocturnal haemoglobinuria

PEGASUS randomised 80 patients with PNH and persistent anaemia on eculizumab to pegcetacoplan or continued eculizumab. At 16 weeks haemoglobin rose by 3.8 g/dL with pegcetacoplan versus a 1.5 g/dL fall with eculizumab, and 85% of pegcetacoplan patients became transfusion-free versus 15% (Hillmen 2021, NEJM). PRINCE confirmed efficacy in complement-inhibitor-naive patients (Wong 2023, Lancet Haematol). [1][2]

C3 glomerulopathy and primary immune-complex MPGN

VALIANT randomised 124 adolescents and adults and reported a 68% reduction in proteinuria versus placebo at 26 weeks, with stabilised kidney function and clearance of C3 deposits on biopsy in a substantial proportion †. FDA approval for these kidney diseases followed in July 2025; the EU indication extension was validated in early 2025 and approved in 2025–2026 †.

Graded A (modest)

Geographic atrophy secondary to AMD

OAKS and DERBY (around 1,250 participants) reported slowing of lesion growth by roughly 17–22% over 24 months with monthly or every-other-month injections, with effects increasing over time (Heier 2023, Lancet). The FDA approved Syfovre in February 2023. The EMA's CHMP gave a negative opinion in 2024, upheld on re-examination, judging that slower lesion growth had not been shown to translate into a benefit for vision. [3]

Graded B/negative

Cold agglutinin disease, ALS, other indications

Phase 2 signals in cold agglutinin disease; a Phase 2 in ALS (MERIDIAN) did not meet its endpoints †.

4Reported side effects and interactions

Literature-reported

Literature (systemic). Injection-site reactions are the most common adverse event (around 37% in PEGASUS). Diarrhoea, headache, fatigue, haemolysis on treatment interruption. Boxed warning: serious infections with encapsulated bacteria (Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae type b); vaccination is required before starting, and in the US the product is dispensed only under a REMS programme. Breakthrough haemolysis can occur with infection, vaccination or missed doses.

Literature (intravitreal). Increased new-onset exudative (wet) AMD in treated eyes (around 6–12% vs 2–4%), intraocular inflammation, and post-marketing reports of retinal vasculitis, including occlusive vasculitis, which led to label updates in 2023–2024. Rare endophthalmitis as with any intravitreal injection.

Community-reported

none documented.

Interactions. no formal drug interactions established; the main interaction is with the immune system's ability to clear encapsulated bacteria.

Markers researchers commonly monitor

Per the labels and trial protocols:

Marker	Why it's watched
Haemoglobin, reticulocytes, LDH, bilirubin	haemolysis markers in PNH; LDH rises sharply with breakthrough haemolysis.
Urine protein:creatinine ratio and eGFR	primary markers in C3G/IC-MPGN.
Serum C3 levels	low in C3G; rise with treatment as C3 is protected from consumption.
Meningococcal, pneumococcal and Hib vaccination status	a prerequisite, not a lab test.
Signs of infection	fever is treated as an emergency on any complement inhibitor.
Retinal imaging (OCT, fundus autofluorescence)	for intravitreal use, to track lesion growth and detect conversion to wet AMD or vasculitis.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Supplied as a ready-to-use solution (1,080 mg/20 mL vials) infused over about 30 minutes via a commercially available infusion pump into the abdomen, thigh or upper arm; patients are trained to self-infuse. The intravitreal product is administered only by an ophthalmologist. No form exists and the calculator does not apply.

6Commonly studied alongside

Compared head-to-head with eculizumab (a C5 antibody, not a peptide). Related peptide complement inhibitors: zilucoplan (profile #224, C5), avacincaptad pegol (a pegylated RNA aptamer, not a peptide, also approved for geographic atrophy). Studied with concurrent meningococcal vaccination.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	FDA-approved: Empaveli for PNH (May 2021) and for C3G/primary IC-MPGN aged 12+ (July 2025); Syfovre for geographic atrophy (February 2023). REMS applies to Empaveli
European Union	EMA-authorised as Aspaveli for PNH (December 2021); C3G/IC-MPGN extension 2025–2026 †. Intravitreal pegcetacoplan refused (negative CHMP opinion 2024, confirmed on re-examination)
United Kingdom	MHRA-licensed as Aspaveli for PNH; NICE-recommended in specific circumstances †. Intravitreal form not licensed
Australia	TGA-registered (Empaveli) for PNH †
South Africa	Not registered †
Sport (WADA)	Not on the Prohibited List; complement inhibitors are not a listed class

8Open questions

Does slowing geographic atrophy growth eventually preserve measurable vision? This is the crux of the US–EU disagreement.
Long-term infection risk with sustained total complement blockade compared with C5-only inhibition.
Mechanism of the intravitreal retinal vasculitis cases.

9References

1Hillmen P et al. (2021). Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria (PEGASUS). NEJM. PubMed · DOI
2Wong RSM et al. (2023). Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria: results from PRINCE. Lancet Haematol [verify journal]. PubMed · DOI
3Heier JS et al. (2023). Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. PubMed · DOI
4Dixon BP et al. (2025). Pegcetacoplan in C3 glomerulopathy and immune-complex membranoproliferative glomerulonephritis (VALIANT). NEJM [verify authorship and journal]. PubMed
5Mastellos DC, Ricklin D, Lambris JD (2019). Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov. PubMed · DOI
6Empaveli and Syfovre US prescribing information (current labels); EMA Aspaveli EPAR. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

Not enough data yet. 0 of the 50 members needed have logged this compound for 4+ weeks. We don't show anything below 50, so no one can be identified.

11Page history

31 Oct 2026Profile published — awaiting medical review

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