{"doi":"10.1016/j.xops.2021.100057","title":"Local Complement Inhibition for Geographic Atrophy in Age-Related Macular Degeneration: Prospects, Challenges, and Unanswered Questions","abstract":"Geographic atrophy (GA) in age-related macular degeneration (AMD) represents a common, blinding condition that typically is bilateral and relentlessly progressive.1Keenan T.D. Agron E. Domalpally A. et al.Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16.Ophthalmology. 2018; 125: 1913-1928Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,2Wong W.L. Su X. Li X. et al.Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.Lancet Glob Health. 2014; 2: e106-e116Abstract Full Text Full Text PDF PubMed Scopus (2072) Google Scholar It affects more than 5 million people, with a global prevalence of 0.44%.2Wong W.L. Su X. Li X. et al.Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis.Lancet Glob Health. 2014; 2: e106-e116Abstract Full Text Full Text PDF PubMed Scopus (2072) Google Scholar If the fovea is involved, visual acuity typically is very poor. It represents a substantial public health problem because no drugs are approved to slow GA enlargement or to restore vision. If local complement inhibition obtains approval, the prospect of the first therapy to slow GA enlargement will be highly welcome. In the FILLY phase 2 trial (NCT02503332),3Liao D.S. Grossi F.V. El Mehdi D. et al.Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial.Ophthalmology. 2020; 127: 186-195Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar the C3 inhibitor pegcetacoplan met its primary end point. Geographic atrophy enlargement over 12 months was decreased by 29% (monthly treatment) or 20% (every-other-month treatment). The results of the phase 3 trials DERBY (NCT03525613) and OAKS (NCT03525600) are expected in late 2021. In the GATHER 1 (NCT02686658) phase 2/3 trial, the C5 inhibitor avacincaptad pegol, given monthly, met its primary end point.4Jaffe G.J. Westby K. Csaky K.G. et al.C5 Inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial.Ophthalmology. 2021; 128: 576-586Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Geographic atrophy enlargement over 12 months was decreased by 27% (2 mg) or 28% (4 mg). Currently, a second phase 3 trial, GATHER 2 (NCT04435366), is enrolling patients. It involves 2-mg treatment only (monthly), with a second randomization at 12 months to monthly or every-other-month treatment. However, several challenges present themselves. This degree of slower enlargement will be meaningful clinically over long periods only. This makes the risk-to-benefit balance more nuanced for each patient. Delivery requires intravitreal injection, and monthly dosing seems to be required. Because GA typically is bilateral, many patients will need 2 injections per month. One important risk-to-benefit consideration is the increased risk of neovascular AMD (nAMD). In both trials, treatment caused a dose-dependent increase in exudative disease (17-fold with monthly C3 inhibition and 3-fold with monthly C5 inhibition).3Liao D.S. Grossi F.V. El Mehdi D. et al.Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial.Ophthalmology. 2020; 127: 186-195Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar,4Jaffe G.J. Westby K. Csaky K.G. et al.C5 Inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial.Ophthalmology. 2021; 128: 576-586Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar The eligibility criteria may explain this variation partially: in FILLY, but not in GATHER 1, fellow-eye nAMD was permitted (comprising 39%). In FILLY, with monthly treatment, the rat","journal":"Ophthalmology Science","year":2021,"id":178756,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9635,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":254976,"name":"Tiarnán D L Keenan","orcid":"0000-0002-2253-1772","position":0,"is_corresponding":true}],"reference_count":16,"raw_metadata":null,"created_at":"2026-07-18T23:47:40.592580Z","pmid":"36275191","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}