Anti-complement C3/C5 antibody therapy for CFH-deficient AMD: pegcetacoplan and avacincaptad pegol for geographic atrophy

For CFH c.2596+1G>C, a pathogenic splice donor variant that disrupts complement factor H production and leads to uncontrolled alternative complement pathway activation in the retina, anti-complement antibody and aptamer therapies represent the first FDA-approved treatments for geographic atrophy (GA), the advanced form of dry AMD. Pegcetacoplan (Syfovre, Apellis, anti-C3) and avacincaptad pegol (Izervay, Astellas, anti-C5) received FDA approval in 2023 for GA secondary to AMD. CFH loss-of-function variants like c.2596+1G>C cause constitutive overactivation of complement C3 convertase on retinal surfaces, leading to membrane attack complex deposition and progressive RPE/photoreceptor death. Complement inhibition directly addresses this pathogenic mechanism.

The OAKS and DERBY Phase 3 trials for pegcetacoplan (intravitreal anti-C3 cyclic peptide-PEG conjugate) demonstrated significant reduction in GA lesion growth rate vs sham: 22% reduction at 24 months (monthly dosing) in pooled analysis. The GATHER2 Phase 3 trial for avacincaptad pegol (intravitreal C5 inhibitor) showed 18% reduction in GA growth at 12 months. For patients with rare CFH loss-of-function variants (as opposed to the common Y402H risk polymorphism), the complement dysregulation is more severe and genetically defined, potentially predicting stronger treatment responses — though no variant-stratified efficacy data have been published. Genetic studies confirm that CFH loss-of-function (including splice-site variants) is associated with earlier onset, more aggressive GA progression, and higher complement biomarker levels (elevated Ba, C3a, C5a in aqueous humor). The anti-C5 antibody eculizumab has shown efficacy in CFH-related atypical hemolytic uremic syndrome, validating complement blockade for CFH deficiency in non-ocular tissues.

Current intravitreal complement inhibitors slow but do not halt or reverse GA progression — they reduce lesion growth rate by 18-22%, a statistically significant but clinically modest effect. Treatment requires monthly or every-other-month intravitreal injections indefinitely, creating a substantial treatment burden. Both pegcetacoplan and avacincaptad have been associated with increased risk of exudative (wet) AMD conversion and, rarely, retinal vasculitis/occlusive events. For a splice-site variant like c.2596+1G>C that produces systemic CFH deficiency, intravitreal therapy addresses only the ocular manifestation — these patients may also be at risk for CFH-related renal disease (C3 glomerulopathy, aHUS) requiring systemic complement inhibition. No variant-specific clinical trial data exist for rare CFH loss-of-function carriers; efficacy extrapolation from the broader AMD GA population (driven largely by common variants) remains uncertain. Gene therapy to restore CFH expression (AAV-CFH) is being explored preclinically but faces the challenge of sustained secretion of a large complement regulatory protein.