C3 inhibitors are a class of medications used to treat complement-mediated diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), geographic atrophy (GA), and C3 glomerulopathy (C3G).
They work by blocking the central C3 protein in the complement system, which prevents inflammation and the destruction of healthy cells.
The complement system involves three distinct pathways (classical, lectin, and alternative) that converge at the C3 protein.
C3 inhibitors work by binding to C3 and interfering with the formation and activity of C3 convertases, the enzymes responsible for cleaving C3 into its active fragments, C3a and C3b.
This provides a broad blockade of the entire complement cascade downstream of C3 activation, which helps to: Prevent the amplification of the immune response.
Stop the formation of inflammatory mediators (C3a and C5a).
Inhibit the deposition of C3b fragments on host surfaces and subsequent cell destruction.
This upstream inhibition offers a potentially broader therapeutic effect compared to inhibitors targeting later stages of the cascade, such as C5.
Approved C3 Inhibitors and Indications
Pegcetacoplan (Empaveli, Syfovre)
Indications: Approved for adults with paroxysmal nocturnal hemoglobinuria (PNH), a rare blood disorder, to address both intravascular and extravascular hemolysis.
Approved for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration, administered as an intravitreal injection.
It has also been approved for C3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN).
Typically administered as a subcutaneous injection for PNH or an intravitreal injection for GA.
Iptacopan (Fabhalta)
Indications: An oral factor B inhibitor that acts upstream in the alternative pathway, effectively reducing C3-mediated extravascular hemolysis.
It is FDA-approved for adults with PNH as an oral monotherapy and for the reduction of proteinuria in adults with C3G.
Pozelimab (Veopoz) Indications: A monoclonal antibody that targets C5, but is used to treat CHAPLE disease (CD55-deficient protein-losing enteropathy), a condition involving an overactive immune system.
A primary concern with long-term, systemic C3 inhibition is a potentially compromised ability to fight certain encapsulated bacterial infections (meningococci) due to the broad role of C3 in immune surveillance.
As a result, vaccination protocols against such bacteria are essential before starting treatment.
Clinical trials suggest that with appropriate prophylaxis, prolonged C3 intervention may have a manageable safety profile in adults