Revisiting Faricimab and Earlier Randomized Controlled Trials for Diabetic Macular Edema in Light of Newly Defined Pathogeneses
Main Article Content
Abstract
The primary aim of therapy for center-involved diabetic macular edema (DME) is to achieve a long-lasting dry macula. High therapeutic efficacy correlates with targeting the underlying pathogenesis. Recent discoveries have identified two additional tractional pathogeneses that are undetectable by standard optical coherence tomography (OCT). These indicated that all “diffuse” DME in non-ischemic maculae is tractional in origin. Consequently, DME may be classified by pathogenesis as tractional DME and microaneurysm-related DME.
Faricimab (Vabysmo) inhibits vascular endothelial growth factor-A and angiopoietin-2, and is highly effective in abolishing leaking microaneurysms, altering their turnover. In the pivotal YOSEMITE and RHINE trials, two outcome assessments were reported. The first applied a numerical definition in which central subfield thickness <325µm was considered “no DME” ("dry" macula), irrespective of OCT anatomy. Using <325µm and visual criteria, injection intervals were extended to 12 and 16 weeks, and <325µm was found in ~83% of eyes over the 2-year trial. The second assessment was anatomical: at year-1 and -2, approximately half, ~40% and 47%, respectively, achieved ≥8 weeks of dry, fluid-free maculae. Hence, injection intervals were extended in 43% (83%-40%) and 36% of eyes, respectively, with edematous maculae, instead of prompt treatment.
Uniquely, analysis revealed a sharp clinical separation between two response patterns: (1) anatomical drying for ≥8 weeks, consistent with faricimab’s effect in microaneurysm-related DME, and (2) partial or absent response, consistent with tractional DME. Had DME been stratified before treatment and faricimab used only for microaneurysm-related disease, dryness could likely have been achieved for ≥8 weeks, while futile injections could have been avoided in tractional DME. Concerns regarding outcomes following missed stratification might also be relevant, in retrospect, to most earlier trials and real-world practice.
In conclusion, the well-defined clinical separation between the two DME pathogeneses supports identical earlier claims, and seems a landmark moment for DME therapy after decades. It follows the conduct: Never mix two different items for calculations. After excluding microaneurysm-related DME, the benchmarks for long-lasting resolution remain pars plana vitrectomy in treatment-naïve eyes or following failed grid laser photocoagulation; grid laser photocoagulation is efficacious in specific early conditions. Aligning future trials and clinical practice with pathogenetic enrollment, consistent with the Declaration of Helsinki, and anatomy-based endpoints is essential to move toward an effective, potentially curative therapy.
Keywords:
Dry diabetic macular edema, Curative DME, Faricimab, Microaneurysm-related DME, Tractional DME, Diffuse DME, Focal DME, DME pathogenesis, DME classifications, Extrafoveal traction, 3D-OCT, Transitional-phase DME, Anti-VEGF
Article Details
How to Cite
OPHIR, Avinoam.
Revisiting Faricimab and Earlier Randomized Controlled Trials for Diabetic Macular Edema in Light of Newly Defined Pathogeneses.
Medical Research Archives, [S.l.], v. 14, n. 2, feb. 2026.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/7210>. Date accessed: 02 mar. 2026.
doi: https://doi.org/10.18103/mra.v14i2.7210.
Section
Editorial
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Cennamo G, Montorio D, Fossataro F, Fossataro C, Tranfa F. Evaluation of vessel density in disorganization of retinal inner layers after resolved diabetic macular edema using optical coherence tomography. PLoS One. 2021;16(1):e0244789. doi: 10.1371/journal.pone.0244789.
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6. Wong TY, Haskova Z, Asik K, Ba µm al CR, Csaky KG, Eter N, et al. Faricimab treat-and-extend for Diabetic Macular Edema: Two-year results from the randomized phase 3 YOSEMITE and RHINE trials. Ophthalmology. 2024;131(6):708-723. doi: 10.1016/j.ophtha.2023.12.026.
7. Ferro Desideri L, Traverso CE, Nicolò M. The emerging role of the Angiopoietin-Tie pathway as therapeutic target for treating retinal diseases. Expert Opin Ther Targets. 2022;26(2):145-154. doi: 10.1080/ 14728222.2022.2036121.
8. Heier JS, Singh RP, Wykoff CC, Csaky KG, Lai TYY, Loewenstein A, et al. The angiopoietin/tie pathway in retinal vascular diseases: A Review. Retina. 2021 Jan 1;41(1):1-19. doi: 10.1097/IAE.0000000000003003.
9. Takamura Y, Yamada Y, Morioka M, Gozawa M, Mats µm ura T, Inatani M. Turnover of microaneurysms after intravitreal injections of faricimab for diabetic macular edema. Invest Ophthalmol Vis Sci. 2023 Oct 3;64(13):31. doi: 10.1167/iovs.64.13.31.
10. Takamura, Y, Yamada, Y, Inatani, M. Role of microaneurysms in the pathogenesis and therapy of diabetic macular edema: A descriptive review. Medicina 2023,59, 435. https://doi.org/10.3390/medicina59030435
11. The DRCR.net, Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064-1077. doi:10.1016/j.ophtha.2010.02.031.
12. Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE Study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4): 615-625. doi: 10.1016/j.ophtha.2011.01.031.
13. DRCR.net; Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. New Eng J Med. 2015;372(13):1193-1203. doi: 10.1056/NEJMoa1414264.
14. Bressler SB, Barve A, Ganapathi PC, Beckmann K, Apte RS, Marcus DM, et al. Aflibercept biosimilar MYL-1701P vs. reference aflibercept in diabetic macular edema: The INSIGHT randomized clinical trial. Jama Ophthalmol. 2024:142(10):952-960. doi:10.1001/jamaophthalmol.2024.3458.
15. Gillies MC, McAllister IL, Zhu M, Wong W, Louis D, Arnold JJ, Wong TY. Intravitreal triamcinolone prior to laser treatment of diabetic macular edema: 24-month results of a randomized controlled trial. Ophthalmology 2011;118:866-872. doi: 10.1016/j.ophtha.2010.09.029.
16. Glassman AR, Wells III JA, Josic K, Maguire MG, Antoszyk AN, Baker C, et al. Five-year outcomes after initial Aflibercept, Bevacizumab, or Ranibizumab treatment for diabetic macular edema (Protocol T Extension Study). Ophthalmology. 2020;127(9): 1201-1210. doi: 10.1016/j.ophtha.2020.03.021.
17. Jhaveri CD, Glassman AR, Ferris FL 3rd, Liu D, Maguire MG, Allen JB, et al. Aflibercept monotherapy or bevacizumab first for diabetic macular edema. New Engl J Med. 2022; 387(8):692-703. doi: 10.1056/NEJMoa2204225.
18. Sensoy E, Citirik M. Current biosimilar anti-VEGF drugs in retinal diseases. Eur Eye Res. 2024;4(3):237-244 | doi: 10.14744/eer.2024.29291.
19. Blindbaek SL, Peto T, Grauslund J. Aflibercept and navigated versus conventional laser in diabetic macular oedema: a 12-month randomized clinical trial. Acta Ophthalmol. 2020 Jun;98(4):347-352. doi: 10.1111/aos.14266. Epub 2019 Oct 10. PMID: 31602811.
20. Zhang J, Wang M, Chen L, Radke N. Diabetic blindness remains a big challenge despite all recent advancements in diagnostics and treatments. Asia Pac J Ophthalmol. 2024;13(5):100105. doi: 10.1016/j.apjo/2024/100105.
21. Ophir A, Martinez MR, Mosqueda P, Trevino A. Vitreous traction and epiretinal membranes in diabetic macular edema using spectral-domain optical coherence tomography. Eye (London). 2010;24(10):1545-1553. doi: 10.1038/eye.2010.80.
22. Ophir A, Trevino A, Fatum S. Extrafoveal vitreous traction associated with diabetic diffuse macular oedema. Eye (Lond). 2010;24(2):347-353. doi: 10.1038/eye.2009.106.
23. Karatas M, Ramirez JA, Ophir A. Diabetic vitreopapillary traction and macular edema. Eye (London). 2005;19(6):676-682. doi:10.1038/sj.eye.6701622.
24. Ophir A, Martinez MR. Epiretinal membranes and incomplete posterior vitreous detachment in diabetic macular edema, detected by spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2011;52(9):6414-6420. doi: https://doi.org/10.1167/iovs.10-6781.
25. Ophir A. Full-field 3-D optical coherence tomography imaging and treatment decision in diffuse diabetic macular edema. Letter. Invest Ophthalmol Vis Sci. 2014;55(5):3052-3053. doi: 10.1167/iovs.14-14414.
26. Adhi M, Badaro E, Liu JJ, Kraus MF, Ba µm al CR, Witkin AJ, et al. Three-dimensional enhanced imaging of vitreoretinal interface in diabetic retinopathy using swept-source optical coherence tomography. Am J Ophthalmol. 2016;162:140-149.e1. doi:10.1016/j.ajo.2015.10.025.
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