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PeptideAI
Approved drugimmuneinflammation

Pegcetacoplan

A pegylated cyclic peptide that blocks complement C3, controlling paroxysmal nocturnal haemoglobinuria systemically and slowing geographic atrophy when injected into the eye.

Also known as Empaveli, Syfovre, Aspaveli, APL-2, pegcetacoplan injection, Empaveli, Aspaveli, Syfovre, APL-2

Approved drug — Licensed by a major regulator for human use, with phase-3 trial data behind it.

FDA-approved for PNH in 2021 on the PEGASUS trial, where it beat eculizumab on haemoglobin change at 16 weeks, and for geographic atrophy in 2023 on the DERBY and OAKS trials. The geographic atrophy approval is genuinely contested: lesion growth slows by roughly 15-20 percent but no visual function benefit has been demonstrated, and EMA has repeatedly declined the ophthalmic indication.

How it works

Pegcetacoplan is two identical 13-amino-acid cyclic peptides derived from compstatin, joined by a 40 kDa linear PEG chain that gives it a usable half-life. It binds C3 and C3b with high affinity, preventing C3 convertase from cleaving C3 into C3a and C3b. Because C3 sits at the junction of the classical, lectin and alternative pathways, this blocks both the terminal lytic pathway and the C3b opsonisation that drives extravascular haemolysis. That extravascular component is precisely what C5 inhibitors like eculizumab leave untreated in PNH, which is why pegcetacoplan raises haemoglobin further in patients already on a C5 blocker. In geographic atrophy the same C3 blockade, delivered intravitreally as Syfovre, slows the enlargement of retinal atrophic lesions.

Targets: Complement component C3, C3b, C3 convertase, Alternative and classical complement pathways

Dosing

ProtocolDoseFrequencyRoute
Paroxysmal nocturnal haemoglobinuria (Empaveli label protocol)Infused over about 30 minutes via a syringe pump, typically to the abdomen, thigh, hip or upper arm.1080 mgtwice weeklysubcutaneous
Geographic atrophy secondary to AMD (Syfovre)Administered in a retina clinic as an intravitreal injection under sterile conditions.15 mgmonthly or every other monthsubcutaneous
  • · 1,080 mg subcutaneous infusion twice weekly. Some patients need 1,080 mg every third day. Patients switching from eculizumab overlap both drugs for the first 4 weeks to avoid a haemolytic rebound.
  • · 15 mg (0.1 mL) intravitreally into the affected eye. Intravitreal is not a general self-administration route and does not appear in this site's route list - it is an in-office ophthalmic procedure only.

Titration

No dose titration. The main adjustment is moving from twice-weekly to every-third-day dosing when LDH stays above about twice the upper limit of normal.

Cycling

Continuous indefinite therapy. Stopping systemic pegcetacoplan in PNH can trigger severe rebound haemolysis, so patients are monitored closely for at least 8 weeks after any discontinuation.

Work out your exact syringe units →

Pharmacology

Half-life
Roughly 8 days after subcutaneous infusion.
Onset
Haemoglobin and LDH begin improving within the first weeks of systemic therapy; geographic atrophy lesion-growth benefit is measured over 12-24 months.
Routes
subcutaneous
Molecule
Pegylated cyclic peptide dimer (two 13-residue macrocycles on a 40 kDa PEG linker)
Sequence length
13 amino acids
Molecular weight
43500 Da

Handling

Diluent
Not applicable - supplied as a ready-to-use solution
Lyophilised
Not supplied lyophilised.
Reconstituted
Refrigerate vials at 2-8 C in the original carton. Empaveli may be kept at room temperature for up to 30 days.
Light sensitive
Yes — keep it out of the light

Mixing

Empaveli comes as 1,080 mg/20 mL single-dose vials drawn into an infusion pump reservoir. Syfovre comes as a 15 mg/0.1 mL single-dose vial for intravitreal use.

Side effects

  • very commonInjection-site reaction— The 30-minute subcutaneous infusion produces local swelling and erythema in most patients.
  • commonDiarrhoea and abdominal pain
  • commonHaemolysis on discontinuation— Rebound intravascular haemolysis after stopping is a genuine hazard in PNH.
  • commonIncreased risk of exudative conversion in geographic atrophy (intravitreal use)— Syfovre roughly doubles the rate of conversion to wet AMD compared with sham.
  • uncommonSerious infection with encapsulated bacteria— Boxed warning covering Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae type B. C3 blockade removes opsonisation as well as lysis, so the exposure is broader than with C5 inhibitors.
  • uncommonIntraocular inflammation and endophthalmitis (intravitreal use)— Specific to Syfovre; retinal vasculitis has also been reported post-marketing.

Do not use if

  • Unresolved infection with encapsulated bacteria at the time of initiation.
  • Patients not vaccinated against meningococcus, pneumococcus and Haemophilus influenzae type B, unless the delay would be more dangerous than the risk.
  • Active ocular or periocular infection, for the intravitreal formulation.
  • Known hypersensitivity to pegcetacoplan or PEG.

Combining it

  • cautioneculizumab — Deliberately overlapped for 4 weeks when switching to prevent haemolytic rebound, then stopped - not a long-term combination.
  • cautionravulizumab — Same switching consideration as eculizumab, with a longer washout because of ravulizumab's half-life.
  • cautionlive attenuated vaccines — Vaccinate before initiating wherever possible.

What to monitor

  • · LDH, haemoglobin, reticulocyte count and bilirubin regularly during PNH therapy, and for at least 8 weeks after any discontinuation.
  • · Documented vaccination against meningococcus, pneumococcus and Hib, plus a patient safety card.
  • · Immediate assessment of fever or systemic infection symptoms.
  • · Ophthalmic examination and intraocular pressure check after each intravitreal injection.

Legal status

FDA-approved as Empaveli for PNH and Syfovre for geographic atrophy; approved in the EU as Aspaveli for PNH only. Specialty prescription drug.

References

  • Empaveli (pegcetacoplan) FDA prescribing information (label)
  • Hillmen et al. 2021, PEGASUS trial of pegcetacoplan versus eculizumab in PNH, NEJM (trial)
  • Heier et al. 2023, DERBY and OAKS trials of intravitreal pegcetacoplan in geographic atrophy, Lancet (trial)

Mechanism in depth

Pegcetacoplan binds complement C3 and its activation fragment C3b, which puts it upstream of every C5 inhibitor and is the entire point. In paroxysmal nocturnal haemoglobinuria the PNH clone lacks GPI-anchored CD55 and CD59. Losing CD59 exposes red cells to the membrane attack complex, causing intravascular haemolysis, and that is what eculizumab and other C5 inhibitors fix. But losing CD55 also allows unrestrained C3 convertase activity, so surviving red cells accumulate C3b on their surface and get eaten in the liver and spleen. That is extravascular haemolysis, and it is precisely what C5 blockade cannot touch: by rescuing cells from intravascular lysis, C5 inhibitors let them live long enough to become opsonised, so a substantial fraction of eculizumab-treated PNH patients remain anaemic and transfusion-dependent with a high reticulocyte count and a normal LDH. Blocking C3 stops the opsonisation and the membrane attack complex simultaneously, which is why PEGASUS showed a 3.84 g/dL haemoglobin advantage over eculizumab in exactly those patients. The cost of blocking the cascade at C3 rather than C5 is that you lose more of the immune system: C3b opsonisation is central to defence against encapsulated bacteria, so the infection risk extends to Streptococcus pneumoniae and Haemophilus influenzae type B and not just Neisseria. In geographic atrophy the logic is different again: local complement overactivation drives photoreceptor and RPE loss, and intravitreal pegcetacoplan slows lesion growth by roughly 16 to 21 percent at 12 months without, so far, any demonstrated benefit to visual function.

What usually goes wrong

Two things dominate. First, infection: blocking C3 removes opsonisation as well as the membrane attack complex, so the susceptibility extends to pneumococcus and Haemophilus as well as meningococcus, and the drug is REMS-restricted for that reason. Second, discontinuation: stopping pegcetacoplan in PNH can unmask catastrophic haemolysis, because the patient has a large clone of red cells that have been protected and are now abruptly exposed. The label requires monitoring for at least 8 weeks after stopping, and patients keep their safety card for 2 months because infection risk also persists. Breakthrough haemolysis during treatment, signalled by LDH rising above twice normal, is managed by increasing frequency to every three days rather than by adding another drug. Injection site reactions are common and the twice-weekly 20 mL pump infusion is a genuine adherence burden. In the eye, the contested point is real: EMA has repeatedly declined the geographic atrophy indication because slowing lesion growth without demonstrated visual benefit is not obviously worth monthly intravitreal injections and their attendant endophthalmitis and neovascular AMD conversion risk.

Titration ladder

  1. 1080 mgWeeks 1 to 4 (transition period) — 1,080 mg subcutaneously twice weekly, given alongside the patient's existing C5 inhibitor for the first 4 weeks. The overlap exists to prevent a haemolytic crisis during the switch, not to add efficacy.
  2. 1080 mgWeek 5 onwards — Stop the C5 inhibitor and continue pegcetacoplan 1,080 mg twice weekly as monotherapy. Steady state is reached at about 4 to 6 weeks.
  3. 1080 mgAny time, if LDH exceeds twice the upper limit of normal — Increase frequency to 1,080 mg every three days. Monitor LDH twice weekly for at least 4 weeks after the change.

Bloodwork worth running

MarkerWhenWhy it matters
Lactate dehydrogenase (LDH)Baseline, then regularly during treatment; twice weekly for at least 4 weeks after any dose increase.The marker of intravascular haemolysis and the one the label uses to make a dosing decision. On pegcetacoplan, LDH should normalise; a rise means breakthrough haemolysis.Act if: LDH above twice the upper limit of normal is the labelled trigger to increase the dosing frequency from 1,080 mg twice weekly to 1,080 mg every three days.
HaemoglobinBaseline, week 4, week 16, then periodically.The primary efficacy endpoint of PEGASUS and the number the patient actually feels. C3 inhibition addresses the extravascular haemolysis that leaves C5-inhibited patients anaemic.Act if: Failure to gain haemoglobin by week 16 with a normal LDH suggests a non-haemolytic cause of anaemia such as iron deficiency or marrow failure.
Absolute reticulocyte countWith each haemoglobin check.Falls as haemolysis is controlled. A persistently high reticulocyte count with a normal LDH is the fingerprint of ongoing extravascular haemolysis, which is exactly the problem pegcetacoplan is meant to solve.Act if: A rising reticulocyte count with rising LDH means breakthrough; check for infection or a missed dose first.
PNH clone size by flow cytometryBaseline and periodically; specifically during any monitoring period after discontinuation.A sudden fall in clone size alongside a rise in LDH after stopping the drug is the signature of catastrophic haemolysis, and clone size also tracks disease evolution.Act if: A sudden drop in clone size with rising LDH after discontinuation means severe haemolysis is happening and restarting should be considered.
Vaccination status for encapsulated bacteria (pneumococcus, meningococcus ACWY and B, Haemophilus influenzae type B)At least 2 weeks before the first dose, per current ACIP recommendations for patients on complement inhibitors.C3 blockade removes opsonisation, so the infection risk is broader than with C5 inhibitors. This drug is only available through a REMS programme because of it.Act if: Missing vaccination is a reason to delay unless the risk of delay is greater; if treatment cannot wait, vaccinate and cover with antibiotics.
aPTT, with attention to the reagent usedWhenever a coagulation screen is ordered.Silica reagents in coagulation panels interact with pegcetacoplan and produce an artificially prolonged aPTT. This is a laboratory artefact that has led to unnecessary investigation.Act if: An unexpectedly prolonged aPTT on pegcetacoplan should be repeated with a non-silica reagent before anything else is done.

Pharmacokinetics

Tmax
126 h
Volume of distribution
3.98 L
Time to steady state
35 days
Crosses blood-brain barrier
no
Accumulates
Yes — doses stack before steady state
Metabolism
Catabolised into small peptides and amino acids. The PEG moiety is not metabolised in any meaningful sense and is cleared slowly.
Elimination
Catabolic. No dose adjustment is needed for age, sex, race, renal impairment or hepatic function as assessed by bilirubin, albumin, AST or ALT.

Receptor targets

  • Complement C3

    Binds C3 and blocks its cleavage by C3 convertase, shutting down amplification of the whole cascade and preventing generation of all downstream effectors including C5a and the membrane attack complex.

  • Complement C3b

    Binds the activation fragment already deposited on cell surfaces, preventing opsonisation-driven extravascular haemolysis and preventing C3b from participating in further convertase assembly.

Trials

  • PEGASUS Phase 3 · n=80 · 16 weeks · 2021

    Mean change in haemoglobin from baseline to week 16 in PNH patients still anaemic on eculizumab. Pegcetacoplan was superior with an adjusted mean difference of 3.84 g/dL (p<0.001) after a 4-week run-in on both drugs.

  • OAKS and DERBY Phase 3 · n=1258 · 104 weeks · 2023

    Change from baseline to month 12 in total geographic atrophy lesion area. In OAKS, monthly and every-other-month intravitreal pegcetacoplan slowed lesion growth by 21 and 16 percent respectively versus sham; in DERBY the same comparisons did not reach significance at 12 months. No visual function benefit was demonstrated.

  • PEGASUS 48-week follow-up Phase 3 open-label extension · n=80 · 48 weeks · 2022

    Durability of haemoglobin and haemolysis control through 48 weeks, including patients who crossed over from eculizumab.

What to expect, and when

Haemolysis markers respond within the first two weeks and robust biomarker response is present by 4 weeks. Steady-state serum concentrations are reached at 4 to 6 weeks, with median trough around 700 mcg/mL. In geographic atrophy, separation from sham on lesion area is a 12-month readout, not something a patient perceives.

Stacking and comparisons

The only deliberate combination is the 4-week overlap with a C5 inhibitor when switching, which is a safety measure against transition haemolysis rather than a therapeutic stack. Do not run pegcetacoplan alongside eculizumab or ravulizumab beyond that window. Iron and folate supplementation is usually needed because sustained haemolysis depletes both, and iron status should be rechecked once haemolysis is controlled since iron overload can follow transfusion history. Anticoagulation decisions in PNH are separate and should not be relaxed just because LDH normalises. Live vaccines are problematic under C3 blockade.

Against eculizumab and ravulizumab: pegcetacoplan blocks one step higher in the cascade, which fixes the extravascular haemolysis those drugs leave behind and cost a broader infection risk. Against iptacopan and danicopan, the newer oral factor B and factor D inhibitors that also act proximally: those are tablets rather than a twice-weekly subcutaneous pump infusion, which is a very large practical difference. Against intravitreal avacincaptad pegol in geographic atrophy: same complement logic applied to the eye, same absence of a demonstrated functional visual benefit. The systemic and ophthalmic products share a molecule and share almost nothing else clinically.

Rough cost

A REMS-restricted complement inhibitor for a rare disease; US list pricing for this class is in the hundreds of thousands of dollars per year. I did not verify a current figure.

Genuinely uncertain

  • The 15-residue peptide sequence is described in the label only by its modifications, not written out, and I did not verify the compstatin-derived sequence letter by letter, so the sequence object is marked unverified.
  • Plasma protein binding is not published.
  • The exact tmax value of 126 hours entered here is the midpoint of the label's stated 108 to 144 hour range for a single dose, not a single reported figure.
  • Whether the modest geographic atrophy lesion-growth effect will eventually translate into a visual function benefit with longer follow-up is unresolved, and the EMA and FDA have reached different conclusions on it.

Papers