Anti-complement antibody therapy for CFH c.3514G>T (p.Glu1172Ter): pegcetacoplan and avacincaptad pegol for complement-driven AMD with CFH loss-of-function

For CFH c.3514G>T (p.Glu1172Ter), a pathogenic nonsense variant in the C-terminal SCR20 domain of complement factor H (CFH) that abolishes cell-surface complement regulation, intravitreal anti-complement antibody/inhibitor therapy represents the most immediately actionable treatment approach. CFH is the primary negative regulator of the alternative complement pathway on host cell surfaces; p.Glu1172Ter truncates the protein before the critical C3b/heparan sulfate binding domain in SCR19-20, eliminating its ability to protect retinal pigment epithelium (RPE) from complement-mediated damage. Pegcetacoplan (Syfovre, targeting C3) and avacincaptad pegol (Izervay, targeting C5) are FDA-approved intravitreal complement inhibitors that directly address the downstream consequence of CFH deficiency — uncontrolled complement activation at the RPE/Bruch membrane interface.

Pegcetacoplan received FDA approval in 2023 for geographic atrophy (GA) secondary to AMD based on the OAKS and DERBY Phase 3 trials, demonstrating a 22% reduction in GA lesion growth over 24 months (Liao et al., Ophthalmology 2024; PMID:37321400). Avacincaptad pegol (anti-C5 aptamer) was approved in 2023 based on the GATHER1/GATHER2 trials showing 35% reduction in GA growth (Jaffe et al., Ophthalmology 2021; PMID:33207274). These approvals validate complement inhibition as a therapeutic strategy for AMD. For CFH p.Glu1172Ter specifically, genetic evidence strongly supports complement dysregulation as the pathogenic mechanism: the CFH locus (1q31.3) harbors the strongest genetic risk factor for AMD (Y402H, rs1061170), and rare CFH loss-of-function variants like p.Glu1172Ter confer high penetrance risk for AMD and related complement-mediated maculopathies. ClinVar classifies this variant as Pathogenic. The SCR20 domain truncated by this variant is essential for CFH binding to glycosaminoglycans on RPE cell surfaces, meaning complement regulation is lost specifically at the retinal target tissue.

Current complement inhibitors slow GA progression but do not reverse existing geographic atrophy or restore lost vision — they are disease-modifying but not curative. Monthly intravitreal injections impose substantial treatment burden. Both pegcetacoplan and avacincaptad pegol carry a signal for increased risk of exudative (wet) AMD conversion, potentially from complement-mediated anti-angiogenic effects being disrupted. These therapies are approved for GA regardless of CFH genotype, so the variant-specific therapeutic advantage for p.Glu1172Ter carriers is primarily in the strength of the mechanistic rationale rather than a unique treatment option. For a null CFH variant like p.Glu1172Ter, systemic complement dysregulation may also predispose to atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, which intravitreal therapy does not address — systemic complement inhibition with eculizumab or ravulizumab may be needed for renal involvement. Gene replacement (AAV-CFH to RPE) is in preclinical development and could provide continuous local complement regulation without repeated injections, but is years from clinical availability.