Pegcetacoplan

A PEGylated dimer of two cyclic 15-amino-acid compstatin-family peptides that binds complement C3, FDA approved as a subcutaneous infusion for paroxysmal nocturnal hemoglobinuria (2021) and C3 glomerulopathy / primary IC-MPGN (2025) and as an intravitreal injection for geographic atrophy (2023).

Also referenced as: APL-2, APL2, Empaveli, Syfovre, Aspaveli

Also appears in: Other

COA Public product evidence No certificate records are bound to a tracked Pegcetacoplan product page A record counts here only when a vendor publishes a certificate against one of its own tracked Pegcetacoplan product pages. Other certificates naming this compound may still exist — search the wider certificate database. →

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What is Pegcetacoplan?

Pegcetacoplan is a synthetic complement inhibitor built from two identical cyclic pentadecapeptides, descendants of the compstatin family of C3-binding peptides, each covalently attached to one end of a linear 40 kDa polyethylene glycol chain. The whole conjugate weighs about 43.5 kDa, so although the active elements are 15-amino-acid peptides, most of the molecule’s mass is PEG, which is what gives it a half-life long enough for twice-weekly subcutaneous dosing. It was developed by Apellis under the code APL-2 and is marketed in the U.S. as Empaveli (subcutaneous, approved May 14, 2021 for paroxysmal nocturnal hemoglobinuria and on July 28, 2025 for C3 glomerulopathy and primary immune-complex membranoproliferative glomerulonephritis) and as Syfovre (intravitreal, approved February 17, 2023 for geographic atrophy secondary to age-related macular degeneration). Apellis itself was acquired by Biogen in May 2026; Sobi holds rights to the systemic product outside the U.S. under the name Aspaveli.

It appears in peptide reference listings almost entirely because of that clinical record: it was the first C3-targeted complement inhibitor to reach approval and the first drug approved for geographic atrophy. It is not a classic research-market peptide; the active compound is a large PEG conjugate manufactured under pharmaceutical conditions, and the interest it attracts comes from complement biology, rare hematologic and renal disease, and retinal degeneration rather than from any wellness or performance framing.

How it works

Pegcetacoplan acts at C3, the point where the classical, lectin, and alternative complement pathways converge, which puts it one step upstream of the C5 inhibitors (eculizumab, ravulizumab) it is most often compared with.

• Binding C3 and C3b blocks convertase activity — the compstatin peptides bind native C3 and its activation fragment C3b and prevent their cleavage by the C3 convertases, so downstream generation of C3a, C5a, and the membrane attack complex is suppressed. In pegcetacoplan two compstatin-derived units are bridged by the 40 kDa PEG to slow renal clearance and extend exposure (Kolev et al., Immunological Reviews, 2023, 313(1):358–375)
• Upstream blockade controls both intravascular and extravascular hemolysis in PNH — C5 inhibitors stop membrane-attack-complex lysis of PNH red cells, but surviving cells still become coated with C3 fragments and are cleared in the liver and spleen, which is why many patients remain anemic on eculizumab. In a Phase 1b study of patients with suboptimal response to eculizumab, adding pegcetacoplan raised hemoglobin and lowered reticulocyte count and bilirubin in all six long-term subjects, consistent with inhibition of that C3-mediated extravascular process (de Castro et al., American Journal of Hematology, 2020, 95(11):1334–1343; reviewed in Risitano et al., Seminars in Immunology, 2022, 59:101618)
• Head-to-head superiority over eculizumab on hemoglobin — in the PEGASUS trial, patients with hemoglobin below 10.5 g/dL despite eculizumab were randomized to pegcetacoplan monotherapy or continued eculizumab; the adjusted mean difference in hemoglobin change at week 16 was 3.84 g/dL in favor of pegcetacoplan (P < 0.001), and 85% versus 15% of patients avoided transfusion (Hillmen et al., New England Journal of Medicine, 2021, 384(11):1028–1037)
• Local complement inhibition slows retinal atrophy — complement components including C3 accumulate in drusen and at the margins of geographic atrophy lesions. In the Phase 2 FILLY trial, intravitreal pegcetacoplan given monthly or every other month reduced the growth rate of GA lesions at 12 months relative to sham, at the cost of a higher rate of new exudative AMD (Liao et al., Ophthalmology, 2020, 127(2):186–195)

Research status

Pegcetacoplan has three completed pivotal programs, one well-documented Phase 2 failure, and a safety signal and a regulatory refusal that both belong in any honest summary.

PNH: PEGASUS (NCT03500549) and PRINCE (NCT04085601). PEGASUS enrolled 80 adults with PNH who remained anemic on eculizumab. After a 4-week run-in on both drugs, 41 continued on pegcetacoplan alone and 39 on eculizumab. Pegcetacoplan was superior on the primary hemoglobin endpoint and noninferior on reticulocyte count but did not show noninferiority on lactate dehydrogenase change; injection-site reactions were more common with pegcetacoplan (37% versus 3%) and breakthrough hemolysis less common (10% versus 23%) (Hillmen et al., New England Journal of Medicine, 2021, 384(11):1028–1037). PRINCE randomized 53 complement-inhibitor-naive patients roughly 2:1 (35 versus 18) to pegcetacoplan or supportive care for 26 weeks: hemoglobin stabilization was achieved by 85.7% versus 0%, and LDH fell substantially more on treatment (Wong et al., Blood Advances, 2023, 7(11):2468–2478). Together these supported the broad U.S. indication, which covers adults with PNH regardless of prior therapy; the European approval of Aspaveli on December 13, 2021 was initially limited to adults still anemic after at least three months on a C5 inhibitor, a restriction the CHMP recommended lifting in January 2024.

Geographic atrophy: OAKS (NCT03525613) and DERBY (NCT03525600). Two identically designed 24-month sham-controlled Phase 3 trials enrolled 1,258 patients aged 60 and older (637 and 621 respectively), randomized to monthly injection, every-other-month injection, or sham. At 12 months OAKS met its primary endpoint (lesion growth slowed by 21% monthly and 16% every other month) while DERBY did not (12% and 11%). By 24 months the reductions were 22% and 18% in OAKS and 19% and 16% in DERBY, with the treatment effect widening over time; the U.S. label reports the 24-month figures as 21.9%/18.1% (OAKS) and 18.1%/17.4% (DERBY). No visual-function benefit was demonstrated, and new-onset exudative AMD was more frequent on treatment (Heier et al., Lancet, 2023, 402(10411):1434–1448). The open-label GALE extension (NCT04770545), which carries the OAKS/DERBY population to 36 months of continuous treatment against a projected rather than concurrent sham, reported a continued and larger reduction in lesion growth in its third year (Wykoff et al., American Journal of Ophthalmology, 2025, 276:350–364).

Retinal vasculitis signal (2023). Within months of U.S. launch, retina specialists began reporting cases of retinal vasculitis, frequently occlusive, after Syfovre injections. The ASRS Research and Safety in Therapeutics Committee’s review of voluntarily reported cases confirmed 14 eyes of 13 patients on imaging; every case followed the first injection, presentation was a median of 10.5 days after dosing (range 8 to 23), 11 eyes (79%) had occlusive vasculopathy, 6 eyes (43%) lost more than six lines of acuity, and 2 eyes were enucleated. The committee stated there was no known etiology and advised that continued treatment of affected patients should be avoided (Witkin et al., Journal of Vitreoretinal Diseases, 2024, 8(1):9–20). The U.S. label was revised in November 2023 (labeling supplement approved November 30, 2023) to add a warning that retinal vasculitis and/or retinal vascular occlusion can occur with the first dose and may cause severe vision loss, and that treatment should be discontinued if it develops. The manufacturer pointed to variations in the internal structure of the filter needle supplied in early kits as a possible contributor; the kit’s filter needle was subsequently changed. No single cause has been established.

EMA refusal for geographic atrophy. The CHMP adopted a negative opinion on June 27, 2024, confirmed it on re-examination on September 19, 2024, and marketing authorization for Syfovre was refused on December 16, 2024. The committee accepted that lesion growth was slowed but concluded that this had not been shown to translate into a benefit patients could notice in daily functioning, and that regular intravitreal injections carried significant risks including exudative AMD and intraocular inflammation. The drug remains approved for GA in the U.S.

C3G and primary IC-MPGN: VALIANT (NCT05067127). A 26-week randomized, double-blind, placebo-controlled Phase 3 trial enrolled 124 patients aged 12 and older with native or post-transplant C3 glomerulopathy or primary immune-complex MPGN. Pegcetacoplan reduced proteinuria by 68% relative to placebo (geometric mean urine protein-to-creatinine ratio at week 26 of 0.33 versus 1.03 times baseline; P < 0.0001), produced a least-squares mean eGFR difference of 6.31 mL/min/1.73 m², and sharply reduced C3 staining on repeat biopsy in most treated patients (74% versus 12% with at least a two-order-of-magnitude decrease) (Fakhouri et al., New England Journal of Medicine, 2025, 393(22):2210–2220). The FDA approval of July 28, 2025 was the first for either disease in the U.S.; an efficacy-labeling supplement approved August 20, 2026 added 52-week data, and the current indication reads “to reduce proteinuria and loss of kidney function.” In Europe, the CHMP adopted a positive opinion for the same indications (in combination with a RAS inhibitor) on December 11, 2025, and Aspaveli’s EU authorization now lists them.

Failed and discontinued programs. The Phase 2 MERIDIAN study (NCT04579666) of subcutaneous pegcetacoplan in 249 adults with sporadic amyotrophic lateral sclerosis missed its primary endpoint of Combined Assessment of Function and Survival at week 52 and its key secondary endpoints; the study was terminated and the sponsor discontinued the ALS program in the spring of 2023. Pegcetacoplan is a systemic complement inhibitor, and this result is a reminder that complement activation observed in a disease does not establish that blocking it changes the disease’s course.

Active work. ClinicalTrials.gov lists a Phase 2 study in pediatric PNH (NCT04901936), the VALE long-term extension in C3G/IC-MPGN (NCT05809531), a Sobi-sponsored Phase 3 study for prevention of recurrent C3G or IC-MPGN after kidney transplantation (PRESERVE, NCT07898774, not yet recruiting), a completed Phase 3b safety study of a Syfovre prefilled syringe (NCT07214740), and investigator-initiated oncology combinations at Roswell Park (with pembrolizumab in recurrent gynecologic cancers, NCT04919629; with modified FOLFIRINOX in metastatic pancreatic cancer, NCT07214298). A Phase 3 study in delayed graft function after kidney transplantation (NCT07020832) was registered and then withdrawn without enrolling. Biogen agreed to acquire Apellis on March 31, 2026 ($41.00 per share in cash plus a contingent value right) and completed the acquisition on May 14, 2026; the transaction does not change the regulatory status of either product.

Common dosage forms

• Subcutaneous solution (Empaveli / Aspaveli) — a 20 mL single-dose vial containing 1,080 mg (54 mg/mL), administered as a subcutaneous infusion through a commercially available infusion pump with a reservoir of at least 20 mL or through a dedicated single-use on-body injector. Stored refrigerated.
• Intravitreal solution (Syfovre) — a single-dose glass vial of 150 mg/mL that delivers one 0.1 mL (15 mg) dose, supplied either as the vial alone or as a kit with a 5-micron filter needle, a 1 mL Luer-lock syringe, and a 29-gauge injection needle. The dose is drawn from the vial immediately before injection into the affected eye. A prefilled syringe has completed a Phase 3b safety study but is not an approved presentation.
• Research supply — pegcetacoplan is not a standard lyophilized research-peptide item. Where it is listed at all, it is as a reference-standard quantity of the full PEG conjugate; an unconjugated compstatin-type peptide is a different, short-lived molecule and should not be described as pegcetacoplan.

Key considerations

• Approved in two routes for three diseases, with a boxed warning on the systemic product. The FDA Approved status reflects the approved Empaveli and Syfovre indications. Empaveli carries a boxed warning for serious and potentially fatal infections caused by encapsulated bacteria (Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae type b), requires vaccination at least two weeks before the first dose unless delay is riskier, and is dispensed only through a REMS program. The label also warns of infusion-related reactions including anaphylaxis, requires at least eight weeks of monitoring for hemolysis after discontinuation in PNH, and notes that silica-based coagulation reagents can falsely prolong aPTT. The intravitreal product has no boxed warning but its own list of ocular risks.
• The retinal vasculitis signal is real and remains unexplained. The 2023 post-marketing cases of occlusive retinal vasculitis after a first Syfovre injection led to a label change, and no definitive cause has been identified. The label also quantifies the conversion to neovascular AMD over 24 months at 12% with monthly dosing, 7% every other month, and 3% in sham-treated eyes, and intraocular inflammation, raised intraocular pressure, and ischemic optic neuropathy (1.7% monthly) are listed adverse reactions.
• Lesion-growth slowing has not been shown to preserve vision. OAKS and DERBY were powered on an anatomic endpoint and did not demonstrate a visual-function benefit; DERBY missed its 12-month primary endpoint. European regulators refused the GA application on exactly this point. Readers should treat the anatomic effect and the clinical meaning of that effect as two different questions, and should note that the 36-month GALE data rely on a projected rather than concurrent control.
• It is a peptide, but mostly polymer by weight. Each pegcetacoplan molecule contains two 15-residue cyclic peptides and a 40 kDa PEG chain. Properties such as half-life, route, and immunogenicity are governed as much by the PEG as by the peptides, and results from the approved products do not transfer to unconjugated compstatin analogs or to any material of unknown composition.
• Naming and classification. Empaveli, Aspaveli, and Syfovre contain the same molecule but are different concentrations for different routes and are not interchangeable; APL-2 is the development code. Pegcetacoplan should not be confused with avacincaptad pegol (also PEGylated, also approved for GA, but an RNA aptamer that targets C5) or with the oral factor B inhibitor iptacopan, which is approved for PNH and C3G through a different mechanism.