Pegcetacoplan (Empaveli) is approved for the treatment of adults with paroxysmal nocturnal hemoglobinuria (PNH) who are treatment naïve and those who are switching from the C5 inhibitors eculizumab (Soliris) and ravulizumab (Ultomiris).
It is the first approved targeted C3 therapy for PNH.
Approved for treatment of patients with C3 glomerularopathy or immune complex membrano proliferative glomerulonephritis.
Pegcetacoplan is a complement inhibitor that binds to complement protein C3 and its activation fragment C3b, thereby regulating complement activation proximally in the cascade.
It is marketed under two brand names: Empaveli for hematologic and renal indications, and Syfovre for ophthalmic use.
FDA-approved indications include treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH), treatment of adult and pediatric patients aged 12 years and older with C3 glomerulopathy (C3G) or primary immune-complex membranoproliferative glomerulonephritis (IC-MPGN) to reduce proteinuria, and treatment of geographic atrophy secondary to age-related macular degeneration.
In PNH, pegcetacoplan controls both C3b-mediated extravascular hemolysis and terminal complement-mediated intravascular hemolysis by acting proximally in the complement cascade.
In C3G and primary IC-MPGN, it inhibits C3 activation, decreasing C3 glomerular fragment deposition and reducing C5 convertase activity and subsequent assembly of C5b-9.
Pegcetacoplan is administered subcutaneously at a dose of 1,080 mg twice weekly for adults with PNH, C3G, or IC-MPGN.
Pediatric patients aged 12 years and older with C3G or IC-MPGN receive weight-based dosing.
In the phase 3 PEGASUS trial, pegcetacoplan demonstrated superiority over eculizumab in adults with PNH who remained anemic despite eculizumab therapy, with significant improvements in hemoglobin levels and reductions in transfusion requirements.
The trial showed that pegcetacoplan raised hemoglobin levels substantially more than eculizumab, while also achieving noninferiority for freedom from transfusion and reticulocyte count reduction.
For complement inhibitor-naïve patients, the phase 3 PRINCE trial demonstrated that pegcetacoplan was superior to supportive care in achieving hemoglobin stabilization and reducing lactate dehydrogenase levels.
These clinical benefits were sustained for up to 48 weeks of treatment, with improvements in both clinical and hematological parameters of hemolysis as well as quality of life outcomes.
In geographic atrophy secondary to age-related macular degeneration, the FDA approved pegcetacoplan.
Intravitreal injection of pegcetacoplan resulted in reductions in geographic atrophy lesional areas compared with sham injection.
Pegcetacoplan showed efficacy in C3 glomerulopathy and primary immune-complex MPGN.
By targeting C3 and C3b, pegcetacoplan inhibits complement activation through all three complement pathways and directly inhibits both C3 and C5 convertases, potentially halting glomerular complement deposition and preventing kidney failure.
Its subcutaneous administration route allows for self-administration, representing a significant advance in drug accessibility and potentially improving patient compliance compared to intravenous therapies.
Phase 3 PEGASUS study, demonstrated superiority to eculizumab for the change from baseline in hemoglobin level at week 16, with an adjusted mean increase of 3.84 g/dL of hemoglobin.
Pegcetacoplan was found to have noninferiority to eculizumab on the end point of transfusion avoidance: 85% of patients who received pegcetacoplan were transfusion free over 16 weeks compared with 15% of those who received eculizumab.
The agent may increase the risk of meningococcal and other serious infections caused by encapsulated bacteria that may become rapidly life threatening or fatal if not recognized and treated early.
The most common serious adverse effect in patients treated with pegcetacoplan was infections (5%).
The most common toxicities: injection site reactions (39%), infections (29%), diarrhea (22%), abdominal pain (20%), respiratory tract infection (15%), viral infection (12%), and fatigue (12%).
No cases of meningitis and no deaths were reported in patients treated with pegcetacoplan.