Anti-complement antibody therapy (lampalizumab, avacincaptad pegol) for CFH-driven AMD: variant-level rationale for c.2596+1G>C splice donor variant

For CFH c.2596+1G>C, a pathogenic splice donor variant that disrupts the C-terminal complement regulatory domains of factor H, systemic or intravitreal anti-complement antibody and aptamer therapies offer a pharmacologically validated approach to slowing geographic atrophy progression. Avacincaptad pegol (Izervay, anti-C5 aptamer, FDA-approved 2023) and pegcetacoplan (Syfovre, anti-C3 antibody fragment, FDA-approved 2023) both reduce GA lesion growth by inhibiting the terminal complement pathway that is overactivated when CFH function is compromised.

CFH is the primary negative regulator of the alternative complement pathway. The c.2596+1G>C variant disrupts the canonical GT splice donor at the exon 17/intron 17 boundary of CFH, likely causing exon skipping or intron retention that truncates or destabilizes the SCR17-20 region responsible for surface complement regulation at Bruch membrane. Loss of CFH surface-binding capacity leads to uncontrolled C3 convertase activity, C3b deposition, membrane attack complex formation, and chronic inflammatory damage to RPE and choriocapillaris. Avacincaptad pegol (anti-C5 aptamer) showed 14% reduction in GA growth rate vs. sham at 12 months in the GATHER2 Phase 3 trial (NCT04435366). Pegcetacoplan (anti-C3) showed 22% reduction at 24 months in OAKS/DERBY Phase 3 trials (NCT03525600/NCT03525613). Both target complement downstream of the CFH deficiency point, making them mechanism-appropriate for CFH loss-of-function carriers. Earlier, lampalizumab (anti-factor D) failed its Phase 3 SPECTRI trial despite initially promising Phase 2 results in CFH risk-allele stratified patients.

Current anti-complement therapies slow but do not halt GA progression — the 14-22% growth rate reduction is modest, and existing vision loss is not reversed. Monthly or bimonthly intravitreal injections impose significant treatment burden and carry risks of endophthalmitis and retinal vasculitis (a noted adverse event with pegcetacoplan). Lampalizumab's Phase 3 failure despite promising Phase 2 biomarker data in CFI/CFH risk-allele carriers is a cautionary tale about complement pharmacogenomic stratification. The c.2596+1G>C variant is rare — trial populations were not enriched for high-impact CFH variants, so the specific benefit in this genotype is extrapolated from mechanism rather than direct evidence. Systemic complement inhibition is not appropriate for a local ocular disease due to infection risk, so intravitreal delivery constraints apply. Whether patients with monogenic CFH deficiency (like this splice variant) derive greater benefit than common-variant polygenic AMD patients has not been studied.