Pegcetacoplan

Summary

Pegcetacoplan (brand name Empaveli/Aspaveli) is a first-in-class complement C3 inhibitor approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults. It acts upstream of C5 in the complement cascade, providing broader complement inhibition than anti-C5 therapies. It is administered by subcutaneous infusion. It has also been investigated for geographic atrophy (AMD) under the name Syfovre.

Mechanism of Action

Pegcetacoplan is a pegylated synthetic cyclic peptide that binds specifically to complement protein C3 and its activation fragment C3b, thereby inhibiting cleavage of C3 and blocking downstream activation of the complement cascade at both the classical, lectin, and alternative pathways. This prevents formation of C3a, C5a, C3b-opsonins, and the membrane attack complex (MAC), reducing hemolysis and inflammation.

Routes of Administration

Goals & Uses

• Treatment of complement-mediated hemolytic anemiasHematologyModerate
• Reduction of extravascular hemolysis in PNHHematologyHigh
• Treatment of paroxysmal nocturnal hemoglobinuria (PNH)Hematology / Rare DiseaseHigh
• Treatment of geographic atrophy (GA) in AMDOphthalmologyHigh

Contraindications

• Unresolved Neisseria meningitidis infectionInfectious DiseaseHigh
• Hypersensitivity to pegcetacoplan or excipientsAllergy/ImmunologyHigh
• Unvaccinated patients (encapsulated organisms)Infectious DiseaseHigh

Adverse Effects

• Infusion-related reactions (intravitreal: conjunctival hemorrhage, floaters)OphthalmologicCommon
• Serious infections (encapsulated bacteria)Infectious DiseaseUncommon
• Injection site reactionsLocalCommon
• Hemolysis upon discontinuationHematologicUncommon
• FatigueGeneralCommonLow energy or tiredness
• Diarrhea / gastrointestinal symptomsGastrointestinalCommon

Drug Interactions

• Vaccines (live attenuated)Moderate
• Eculizumab / RavulizumabModerate

Population Constraints

• PregnancyReproductive SafetyRelative
• Pediatric patientsAgeRelative
• Patients with active systemic infectionsInfectious DiseaseRelative
• BreastfeedingReproductiveRelative

Regulatory Status

• European UnionApprovedApproved: Paroxysmal nocturnal hemoglobinuria (PNH) in adults (Aspaveli)EMA approved Aspaveli for PNH; geographic atrophy indication under separate review.
• United StatesApprovedApproved: Paroxysmal nocturnal hemoglobinuria (PNH) in adults (Empaveli, May 2021), Geographic atrophy secondary to age-related macular degeneration (Syfovre, February 2023)REMS program required for meningococcal risk (Empaveli). FDA Breakthrough Therapy designation granted.
• United KingdomApprovedApproved: Paroxysmal nocturnal hemoglobinuria (PNH) in adultsMHRA approved following EMA decision; NICE technology appraisal conducted.

FDA approved Empaveli (pegcetacoplan) for PNH in May 2021. FDA approved Syfovre (pegcetacoplan intravitreal injection) for geographic atrophy secondary to age-related macular degeneration (AMD) in February 2023. EMA approved Aspaveli for PNH. Requires vaccination against encapsulated organisms (Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae) prior to initiation due to increased infection risk.

Evidence & Sources

No sources recorded yet.