Complement inhibitors are a class of therapeutic agents that block specific components of the complement cascade.
Complement inhibitors are a class of therapeutic agents that block specific components or pathways of the complement system, an innate immune cascade that, when dysregulated, contributes to tissue damage in various autoimmune, inflammatory, and hematologic diseases.
Complement inhibitors target the complement system, a part of the innate immune system consisting of proteins that help fight infections, clear damaged cells, and regulate inflammation.
The complement system is a proteolytic innate immune system that, when inappropriately activated, drives inflammation and tissue damage in numerous diseases.
When dysregulated, the complement system can contribute to tissue damage in various diseases, including rare blood disorders, autoimmune conditions, kidney diseases, and eye disorders.
These drugs target different points in the complement pathway, offering multiple intervention strategies.
The four main classes include:
1. Complement regulator therapies that mimic or replace endogenous regulatory proteins (C1 inhibitor for hereditary angioedema)
2. Complement activation pathway inhibitors that block specific pathways—classical (sutimlimab targeting C1s), lectin (MASP-2 inhibitors), or alternative (Factor B and Factor D inhibitors like iptacopan and danicopan).
3. C3 or C5 inhibitors that prevent generation of downstream effector molecules—including eculizumab (anti-C5 antibody approved for paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder), pegcetacoplan (C3 inhibitor), and newer agents like crovalimab and zilucoplan.
4. Complement effector or receptor inhibitors that block anaphylatoxins or their receptors, such as avacopan (C5aR1 antagonist for ANCA-associated vasculitis).
These inhibitors block specific components or pathways (classical, lectin, or alternative) to prevent excessive activation while ideally preserving some immune function.
These drugs target different points in the complement cascade, offering multiple intervention strategies.
Most are monoclonal antibodies, peptides, or small molecules, administered via infusion, injection, or orally.
Indications: PNH, atypical hemolytic uremic syndrome, expanding to more common conditions including IgA nephropathy (iptacopan) and geographic atrophy (pegcetacoplan).
As of late 2025, approximately 14-15 FDA-approved complement inhibitors exist, primarily for rare diseases.
C1 Inhibitor Berinert, Cinryze, Ruconest (C1-INH concentrates); Enjaymo (sutimlimab, anti-C1s mAb) Hereditary angioedema; Cold agglutinin disease (sutimlimab) IV or subcutaneous; replacement or blockade
C3 Empaveli/Aspaveli (pegcetacoplan); Syfovre/Izervay (pegcetacoplan/avacincaptad pegol intravitreal forms) Paroxysmal nocturnal hemoglobinuria (PNH); Geographic atrophy (age-related macular degeneration) Subcutaneous or intravitreal injection
C5 Soliris (eculizumab); Ultomiris (ravulizumab); Zilbrysq (zilucoplan); PiaSky (crovalimab); Veopoz (pozelimab) PNH, atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), neuromyelitis optica IV infusion (eculizumab/ravulizumab/crovalimab); subcutaneous (zilucoplan)
C5a Receptor Tavneos (avacopan) ANCA-associated vasculitis Oral small molecule
Factor B Fabhalta (iptacopan) PNH; IgA nephropathy (recent approvals) Oral
Factor D Voydeya (danicopan) PNH (add-on for extravascular hemolysis) Oral add-on to C5 inhibitors
These drugs have transformed treatment for conditions like PNH, preventing hemolysis, and aHUS preventing kidney damage.
Proximal inhibitors (C3, Factor B/D) address both intravascular and extravascular hemolysis better than terminal (C5) inhibitors alone in some cases.
Inhibition increases infection risk, especially meningococcal disease, due to impaired bacterial clearance.
Patients require meningococcal vaccination and sometimes prophylaxis.
Efficacy: Highly effective in targeted rare diseases; expanding to kidney diseases, C3 glomerulopathy and others.