Background: Geographic atrophy is a leading cause of progressive, irreversible vision loss. The objectives of OAKS and DERBY were to assess the efficacy and safety of pegcetacoplan compared with sham treatment in patients with geographic atrophy., Methods: OAKS and DERBY were two 24-month, multicentre, randomised, double-masked, sham-controlled, phase 3 studies, in which patients aged 60 years and older with geographic atrophy secondary to age-related macular degeneration were enrolled at 110 clinical sites and 122 clinical sites worldwide, respectively. Patients were randomly assigned (2:2:1:1) by central web-based randomisation system to intravitreal 15 mg per 0·1 mL pegcetacoplan monthly or every other month, or sham monthly or every other month using stratified permuted block randomisation (stratified by geographic atrophy lesion area at screening, history or presence of active choroidal neovascularisation in the eye not under assessment, and block size of six). Study site staff, patients, reading centre personnel, evaluating physicians, and the funder were masked to group assignment. Sham groups were pooled for the analyses. The primary endpoint was the change from baseline to month 12 in the total area of geographic atrophy lesions in the study eye based on fundus autofluorescence imaging, in the modified intention-to-treat population (ie, all patients who received one or more injections of pegcetacoplan or sham and had a baseline and at least one post-baseline value of lesion area). Key secondary endpoints (measured at 24 months) were change in monocular maximum reading speed of the study eye, change from baseline in mean functional reading independence index score, change from baseline in normal luminance best-corrected visual acuity score, and change from baseline in the mean threshold sensitivity of all points in the study eye by mesopic microperimetry (OAKS only). Safety analyses included patients who were randomly assigned and received at least one injection of pegcetacoplan or sham. The now completed studies are registered with ClinicalTrials.gov, NCT03525613 (OAKS) and NCT03525600 (DERBY)., Findings: Between Aug 30, 2018, and July 3, 2020, 1258 patients were enrolled in OAKS and DERBY. The modified intention-to-treat populations comprised 614 (96%) of 637 patients in OAKS (202 receiving pegcetacoplan monthly, 205 pegcetacoplan every other month, and 207 sham) and 597 (96%) of 621 patients in DERBY (201 receiving pegcetacoplan monthly, 201 pegcetacoplan every other month, and 195 sham). In OAKS, pegcetacoplan monthly and pegcetacoplan every other month significantly slowed geographic atrophy lesion growth by 21% (absolute difference in least-squares mean -0·41 mm 2 , 95% CI -0·64 to -0·18; p=0·0004) and 16% (-0·32 mm 2 , -0·54 to -0·09; p=0·0055), respectively, compared with sham at 12 months. In DERBY, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth, although it did not reach significance, by 12% (-0·23 mm 2 , -0·47 to 0·01; p=0·062) and 11% (-0·21 mm 2 , -0·44 to 0·03; p=0·085), respectively, compared with sham at 12 months. At 24 months, pegcetacoplan monthly and pegcetacoplan every other month slowed geographic atrophy lesion growth by 22% (-0·90 mm 2 , -1·30 to -0·50; p<0·0001) and 18% (-0·74 mm 2 , -1·13 to -0·36; p=0·0002) in OAKS, and by 19% (-0·75 mm 2 , -1·15 to -0·34; p=0·0004) and 16% (-0·63 mm 2 , -1·05 to -0·22; p=0·0030) in DERBY, respectively, compared with sham. There were no differences in key secondary visual function endpoints at 24 months. Serious ocular treatment-emergent adverse events were reported in five (2%) of 213, four (2%) of 212, and one (<1%) of 211 patients in OAKS, and in four (2%) of 206, two (1%) of 208, and two (1%) of 206 patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months. New-onset exudative age-related macular degeneration was reported in 24 (11%), 16 (8%), and four (2%) patients in OAKS, and in 27 (13%), 12 (6%), and nine (4%) patients in DERBY receiving pegcetacoplan monthly, pegcetacoplan every other month, and sham, respectively, at 24 months., Interpretation: Pegcetacoplan, the first treatment approved by the US Food and Drug Administration for geographic atrophy, slowed geographic atrophy lesion growth with an acceptable safety profile., Funding: Apellis Pharmaceuticals., Competing Interests: Declaration of interests JSH has received grants paid to their institution from Annexon Biosciences, Apellis Pharmaceuticals, AsclepiX Therapeutics, Bayer, Genentech/Roche, Gyroscope Therapeutics, Iveric Bio, jCyte, Kodiak Sciences, NGM Biopharmaceuticals, Notal Vision, Regeneron Pharmaceuticals, and Regenxbio; and consultancy fees from 4DMT, Adverum Biotechnologies, AffaMed, Allegro Ophthalmics, Allergan, Annexon Biosciences, Apellis Pharmaceuticals, AsclepiX Therapeutics, Genentech/Roche, Gyroscope Therapeutics, Iveric, Janssen R&D, Chengdu Kanghong Pharmaceutical Group, NGM Biopharmaceuticals, Novartis, OcuTerra, Regenxbio, Regeneron Pharmaceuticals, RevOpsis, Stealth BioTherapeutics, and Thea Laboratories. EML has received grants paid to their institution from Boehringer Ingelheim; research funding from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Astellas Pharma, Boehringer Ingelheim, Gemini Therapeutics, Janssen, LumiThera, Neurotech, Novartis, and Roche; and consultancy fees from Alexion Pharmaceuticals, Allegro Ophthalmics, Annexon Biosciences, Apellis Pharmaceuticals, EdiGeneBio, Galimedix Therapeutics, Gemini Therapeutics, Iveric Bio, Janssen, LumiThera, Nanoscope Therapeutics, NGM Biopharmaceuticals, Novartis, Perceive Biotherapeutics, Retrotope, Roche, and Thea Laboratories; holds a provisional patent (A System and Method to Predict Progression of Age-Related Macular Degeneration; US patent application number 63162741); holds stock options with Retrotope; and is the recipient of medical writing services from Allegro Ophthalmics, Apellis Pharmaceuticals, and Boehringer Ingelheim. FGH has received grants paid to their institution and consultancy fees from Apellis Pharmaceuticals, Iveric Bio, Genentech/Roche, Pixium Vision, and Heidelberg Engineering; financial support from Apellis Pharmaceuticals, Genentech/Roche, and Heidelberg Engineering; is an executive board member of EURETINA and the German Ophthalmological Society; and is a scientific board member of Pro Retina. PJR has stock options in Apellis Pharmaceuticals. RHG has received consultancy fees from Apellis Pharmaceuticals, Bayer, Genentech/Roche, and Novartis; and financial support from Apellis Pharmaceuticals and Genentech/Roche. DB has received consultancy fees from Alexion Pharmaceuticals, Annexon Biosciences, Apellis Pharmaceuticals, Boehringer Ingelheim, Cell Cure Neurosciences, Gemini Therapeutics, Genentech, Gyroscope Therapeutics, Ionis Pharmaceuticals, Iveric Bio, and Stealth BioTherapeutics; holds stock in Digisight and Ora; and is an equity owner in Apellis Pharmaceuticals. FG is a patent inventor (US patent application number 15/766,795 [Dosing Regimens] and Patent Cooperation Treaty [PCT] application number PCT/US2022/043127 [Treatment of Geographic Atrophy]; the patent rights are assigned to Apellis Pharmaceuticals); is an equity owner in Apellis Pharmaceuticals; and is an employee of Apellis Pharmaceuticals. CRB has received financial support from Apellis Pharmaceuticals; and is the Chief Medical Officer of Apellis Pharmaceuticals. J-FK has received consultancy fees from Apellis Pharmaceuticals, Bayer, Janssen, Nano Retina, Roche, Thea Laboratories, and Carl Zeiss Meditec; and is a member of a data safety monitoring board for Alexion Pharmaceuticals and Novo Nordisk. JSS has received a grant paid to their institution, consultancy fees, and financial support from Apellis Pharmaceuticals; and has stock in Apellis Pharmaceuticals. NKW has received a grant paid to their institution from Nidek, Topcon, and Zeiss; consulting fees from Complement Therapeutics, Hubble Therapeutics, Iolyx Therapeutics, OliX Pharmaceuticals, SalioGen Therapeutics, Syncona, and Topcon; financial support from Nidek; is an officeholder at AGTC; and has an equity interest in Gyroscope Therapeutics and OcuDyne. RM is an employee of Apellis Pharmaceuticals. IP has received consultancy fees from Apellis Pharmaceuticals, Bayer, Novartis, and Roche; and financial support from Apellis Pharmaceuticals, Bayer, and Novartis. NS has received consultancy fees from Apellis Pharmaceuticals, has received speaking honoraria from Apellis Pharmaceuticals, and has participated on a data safety monitoring board and advisory board for Apellis Pharmaceuticals. AAF has received a grant paid to their institution from Novartis and Roche; financial support from Allergan, Novartis, and Roche; holds a patent for Probe for Identification of Ocular Tissues During Surgery (University of California Los Angeles reference number 2020-851-3 PCT); and holds stock in Apellis Pharmaceuticals and Iveric Bio. AH has received a grant paid to their institution and consultancy fees from Apellis Pharmaceuticals; and has stock in Apellis Pharmaceuticals. DRL has received a grant paid to their institution from Annexon Biosciences, Apellis Pharmaceuticals, Iveric Bio, and Stealth BioTherapeutics; consultancy fees from Annexon Biosciences, Apellis Pharmaceuticals, Applied Genetic Technologies Corporation, Iveric Bio, and Stealth BioTherapeutics; financial support from Annexon Biosciences, Apellis Pharmaceuticals, and Iveric Bio; is a steering committee member of Annexon Biosciences and Iveric Bio; and is a medical advisory board member of Applied Genetic Technologies Corporation. PD is an employee of Apellis Pharmaceuticals. PD and CF are inventors of several patents and authors of several patent applications covering pegcetacoplan or relating to methods of treating ophthalmologic indications (US patent numbers 8,168,584 [Methods of Treating Age-related Macular Degeneration by Compstatin and Analogs Thereof], 10,125,171 [Cell-reactive, Long-acting, or Targeted Compstatin Analogs and Uses Thereof], 10,035,822 [Cell-reactive, Long-acting, or Targeted Compstatin Analogs and Related Compositions and Methods]; US patent application number 15/766,795 [Dosing Regimens]; and PCT application number PCT/US2022/043127 [Treatment of Geographic Atrophy]; the patent rights are assigned to Apellis Pharmaceuticals). CF is an equity owner in Apellis Pharmaceuticals, and is an employee of Apellis Pharmaceuticals. CB has stock in Apellis Pharmaceuticals, and is an employee of Apellis Pharmaceuticals. GS has received grants for clinical trials from Apellis Pharmaceuticals, Genentech, and Iveric Bio; financial support from Apellis Pharmaceuticals; and has participated on a data safety monitoring board and advisory board for Apellis Pharmaceuticals, Bayer, Boehringer Ingelheim, Genentech, Iveric Bio, Novartis, and Roche. JM has been an investigator for Apellis Pharmaceuticals, Genentech, Ionis Pharmaceuticals, Iveric Bio, Kodiak Sciences, Novartis, ReNeuron, and Roche; has received consultancy fees from Annexon Biosciences, Apellis Pharmaceuticals, Cell Cure Neurosciences, EyeBio, Genentech, Iveric Bio, Lineage Cell Therapeutics, Maculogix, Novartis, and ReNeuron; financial support from Apellis Pharmaceuticals, Cell Cure Neurosciences, Genentech, Iveric Bio, Lineage Cell Therapeutics, Novartis, ReNeuron, and Roche; has participated on an advisory board for Apellis Pharmaceuticals, Cell Cure Neurosciences, Genentech, Iveric Bio, Kodiak Sciences, Lineage Cell Therapeutics, Novartis, ReNeuron, and Roche; and holds stock in Notal Vision. RPS has received consultancy fees from Alcon, Apellis Pharmaceuticals, AsclepiX Therapeutics, Bausch and Lomb, Genentech, Gyroscope Therapeutics, Novartis, and Regeneron Pharmaceuticals; financial support from Genentech, Novartis, and Regeneron Pharmaceuticals; is a member of the board of directors for the American Society of Retina Specialists; and is an executive board member of the Retina World Congress. RR is an equity owner in Apellis Pharmaceuticals, and an employee of Apellis Pharmaceuticals. CCW has received a grant paid to their institution from 4DMT, Adverum Biotechnologies, Aerie Pharmaceuticals, AffaMed, Aldeyra Therapeutics, Alexion Pharmaceuticals, Alimera Sciences, Alkahest, Allergan, Allgenesis, Amgen, Annexon Biosciences, Apellis Pharmaceuticals, AsclepiX Therapeutics, Bayer, Boehringer Ingelheim, Chengdu Kanghong Pharmaceutical Group, Clearside Biomedical, Curacle, EyePoint Pharmaceuticals, Gemini Therapeutics, Genentech, Graybug Vision, Gyroscope Therapeutics, Ionis Pharmaceuticals, iRenix, Iveric Bio, Kodiak Sciences, The Lowy Medical Research Institute, Nanoscope Therapeutics, Neurotech, NGM Biopharmaceuticals, Novartis, Ocular Therapeutix, Ocuphire Pharma, OcuTerra, Opthea, Oxular, Oxurion, Oyster Point Pharma, RecensMedical, Regeneron Pharmaceuticals, Regenxbio, Roche, SamChunDang Pharm, Sandoz, Taiwan Liposome, Unity Biotechnology, Verily, and Xbrane Biopharma; consultancy fees from 4DMT, AbbVie, Adverum Biotechnologies, Aerie Pharmaceuticals, AGTC, Alcon, Alimera Sciences, Allergan, Allgenesis, Alnylam Pharmaceuticals, Annexon Biosciences, Apellis Pharmaceuticals, Arrowhead Pharmaceuticals, Bausch and Lomb, Bayer, Bionic Vision Technologies, Boehringer Ingelheim, Chengdu Kanghong Pharmaceutical Group, Cholgene Therapeutics, Clearside Biomedical, Curacle, EyePoint Pharmaceuticals, Foresite, Frontera Therapeutics, Genentech, Gyroscope Therapeutics, IACTA Pharmaceuticals, Iveric Bio, Janssen, Kato Pharmaceuticals, Kiora Pharmaceuticals, Kodiak Sciences, Kriya Therapeutics, Merck, Nanoscope Therapeutics, NGM Biopharmaceuticals, Notal Vision, Novartis, OccuRx, Ocular Therapeutix, OcuTerra, OliX Pharmaceuticals, ONL Therapeutics, Opthea, Palatin Technologies, Perceive Biotherapeutics, Perfuse Therapeutics, PolyPhotonix, Ray Therapeutics, RecensMedical, Regeneron Pharmaceuticals, Regenxbio, Resonance Pharma, Roche, SciNeuro Pharmaceuticals, Stealth BioTherapeutics, Surrozen, Thea Laboratories, TissueGen, Valo Therapeutics, Verana Health, and Vitranu; has participated on a data safety monitoring board and advisory board for Aerie Pharmaceuticals and Kato Pharmaceuticals; is a board member of the American Society of Retina Specialists and the Vit-Buckle Society; and holds stock options in ONL Therapeutics, PolyPhotonix, RecensMedical, TissueGen, Visgenx, and Vitranu., (Copyright © 2023 Elsevier Ltd. 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