Pegcetacoplan (Empaveli, Syfovre)

Pegcetacoplan is a synthetic cyclic peptide, built on a laboratory-discovered peptide called compstatin, that blocks complement protein C3 near the top of the complement cascade — upstream of where antibody drugs like eculizumab act on C5. The same active ingredient is FDA-approved three separate times, under two different brand names, for three unrelated diseases: Empaveli for a rare blood disorder (2021), later a rare kidney disease (2025), and Syfovre, injected directly into the eye, for a leading cause of vision loss (2023) — where a real post-marketing safety signal led to a label update seven months after launch.

A peptide built on a 1990s laboratory discovery

Pegcetacoplan traces back to compstatin, a small cyclic peptide that inhibits complement component C3, discovered by John Lambris's laboratory at the University of Pennsylvania in the early 1990s. A company called Potentia Pharmaceuticals licensed the technology and developed a longer-acting derivative, POT-4 (also called APL-1), initially aimed at wet age-related macular degeneration. Apellis Pharmaceuticals was spun out of Potentia in 2010 to pursue systemic, non-eye indications, and acquired Potentia outright in 2014, bringing a further-modified, PEGylated version — APL-2, now pegcetacoplan — into its own pipeline. The peptide itself is 15 amino acids, closed into a ring, with two branched polyethylene glycol chains attached to slow its clearance; it binds C3 and its active fragment C3b directly, blocking both the C3 convertase and, as a downstream consequence, the C5 convertase — a broader point of interference in the complement cascade than zilucoplan, this site's other peptide-based complement inhibitor, which acts only on C5.

PEGASUS: beating an antibody drug at its own target

Pegcetacoplan's first approval was for paroxysmal nocturnal hemoglobinuria (PNH), a rare disorder in which uncontrolled complement activity destroys red blood cells. The pivotal Phase 3 PEGASUS trial randomized 80 adults with PNH who remained anemic despite treatment with eculizumab (a C5-targeting antibody) to switch to subcutaneous pegcetacoplan or stay on eculizumab for 16 weeks. Pegcetacoplan was superior: hemoglobin rose by an adjusted mean of 2.37 g/dL versus a fall of 1.47 g/dL on eculizumab, a difference of 3.84 g/dL (95% CI 2.33-5.34; p<0.001), and 35 of 41 pegcetacoplan patients (85%) became transfusion-free compared with 6 of 39 (15%) on eculizumab (Hillmen P, Szer J, Weitz I, et al., "Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria," N Engl J Med 2021;384(11):1028-1037, PMID 33730455, DOI: 10.1056/NEJMoa2029073).¹ The FDA approved Empaveli for adult PNH on 14 May 2021 on the strength of that trial — a genuine head-to-head win against an established antibody therapy, in a peptide a patient injects at home rather than receives by IV infusion.

Syfovre: the first approved treatment for geographic atrophy

Geographic atrophy is an advanced, currently irreversible form of dry age-related macular degeneration that gradually destroys the retina and had no approved treatment of any kind before 2023. Apellis ran two identically designed Phase 3 trials, OAKS and DERBY, randomizing a combined 1,258 patients to monthly or every-other-month intravitreal pegcetacoplan or sham injection. Both trials met their primary endpoint — a statistically significant slowing of lesion-growth rate versus sham at 12 months (roughly 16-22% depending on trial and dosing schedule), with the effect size increasing over longer follow-up, reaching a 22% (OAKS) and 19% (DERBY) reduction in growth rate at 24 months with monthly dosing (Heier JS, Lad EM, Holz FG, et al., "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 2023;402(10411):1434-1448, PMID 37865470, DOI: 10.1016/S0140-6736(23)01520-9).² The FDA approved Syfovre on 17 February 2023 as the first treatment ever approved for geographic atrophy — a genuine, if narrow, first: it slows lesion growth, and slowing lesion growth is not the same as restoring vision already lost, and the trials were not designed or powered to show a visual-acuity benefit.

The retinal vasculitis signal that showed up after approval

The cause of the vasculitis is not established; the ReST committee's report explicitly notes it found no confirmed mechanism. Ophthalmologists administering Syfovre are now expected to counsel patients that vision-threatening inflammation, though uncommon, can occur — including after the very first injection — and to monitor accordingly. This is the kind of signal that a controlled trial of roughly 1,200 total patients is not necessarily powered to catch, and it is a real reason for informed caution around the eye-injection formulation specifically, distinct from the PNH/kidney-disease formulation's own separate risk profile (infection risk from complement inhibition generally, and injection-site reactions).

A third approval, in a third disease, in 2025

On 28 July 2025, the FDA approved Empaveli for C3 glomerulopathy (C3G) and primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN) — two rare kidney diseases driven by the same uncontrolled-complement mechanism, in patients 12 and older — making it the first approved treatment for either. The pivotal Phase 3 VALIANT trial randomized 124 patients (the largest single trial ever run in these diseases) to pegcetacoplan or placebo for 26 weeks; the primary endpoint, the ratio of urine protein to creatinine, fell by a mean of 67.3% with pegcetacoplan versus rising 3.2% with placebo, a relative reduction of about 68% (p<0.0001), and significantly more pegcetacoplan patients met a composite of stable kidney function plus at least a 50% drop in that ratio (49% versus 3% on placebo) (Nester CM, Bomback AS, Caravaca-Fontán F, et al., "Trial of Pegcetacoplan in C3 Glomerulopathy and Immune-Complex MPGN," N Engl J Med 2025;393(22):2210-2220, PMID 41337715, DOI: 10.1056/NEJMoa2501510).⁴ This approval used the same twice-weekly self-injected formulation as the original PNH indication, not the eye-injection one — the retinal vasculitis signal described above does not apply to it.

Current status

All three approvals remain active and marketed as of this review: Empaveli for PNH and for C3G/IC-MPGN, and Syfovre for geographic atrophy, both under Apellis in the US and under Swedish Orphan Biovitrum (Sobi) as Aspaveli outside the US for the systemic indications. Not every program succeeded — Apellis discontinued pegcetacoplan development in wet AMD after an early-phase study and, separately, in amyotrophic lateral sclerosis after a Phase 2 trial missed its endpoints — a reminder that this molecule's three real approvals sit alongside genuine failures elsewhere, the same pattern this site's elamipretide page describes for a different peptide. There is no wellness, off-label or grey-market interest in pegcetacoplan that we could find — it is administered either by a treating physician (Syfovre) or under specialist prescription with patient self-injection training (Empaveli), for genuinely rare, serious diseases.