- Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, The First Clinical College, Chongqing Medical University, Chongqing 400016, China;
Peng Hui,
Email: pengh9@sina.com
Neovascular age-related macular degeneration (nAMD) is a leading cause of vision loss in the elderly. Despite significant advances in anti-vascular endothelial growth factor (VEGF) therapy, a substantial subset of patients exhibit suboptimal responses to conventional treatments. With the evolution of diagnostic criteria and the integration of multimodal imaging techniques, the definition of refractory nAMD has gradually expanded to encompass anatomical, functional, and therapeutic response parameters. Its pathogenesis is complex, involving adaptive upregulation of the VEGF signaling pathway, compensatory activation of alternative pro-angiogenic pathways, reprogramming of downstream endothelial signaling, development of neutralizing antibodies, elevated angiopoietin-2 (Ang-2) levels, structural remodeling of macular neovascularization, and reduced retinal microvascular density. Faricimab, the first dual-pathway inhibitor targeting both VEGF-A and Ang-2, demonstrates significant advantages by synergistically suppressing abnormal angiogenesis and vascular leakage, modulating the inflammatory microenvironment, and improving choroidal perfusion, thereby enhancing anatomical outcomes and enabling extended dosing intervals. Evidence from clinical trials and real-world studies suggests that faricimab has therapeutic potential in patients with refractory nAMD; however, long-term safety and durability of efficacy require further investigation. Future management of refractory nAMD is likely to emphasize individualized treatment strategies, leveraging dynamic assessment frameworks based on multimodal imaging and biomarkers, as well as artificial intelligence–assisted decision-making models, to transition from reactive, fixed-interval therapy toward predictive, precision-guided interventions.
Citation： Qin Xuefeng, Wang Xing, Peng Hui. Research progress on dual pathway inhibition of vascular endothelial growth factor-A and angiopoietin-2 for refractory neovascular age-related macular degeneration. Chinese Journal of Ocular Fundus Diseases, 2026, 42(9): 807-812. doi: 10.3760/cma.j.cn511434-20251029-00472 Copy
Copyright ? the editorial department of Chinese Journal of Ocular Fundus Diseases of West China Medical Publisher. All rights reserved
| 1. | 中華醫學會眼科學分會眼底病學組, 中國醫師協會眼科醫師分會眼底病學組. 中國年齡相關性黃斑變性臨床診療指南(2023年)[J]. 中華眼科雜志, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649.Ophthalmology Group of the Chinese Medical Association's Ophthalmology Society, and the Ophthalmology Group of the Ophthalmologists' Association of the Chinese Medical Association. Evidence-based guidelines for diagnosis and treatment of age-related macular degeneration in China (2023)[J]. Chin J Ophthalmol, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649. |
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| 5. | 馬志中. 現在如何認識息肉樣脈絡膜血管病變[J]. 中華眼底病雜志, 2024, 40(2): 89-97. DOI: 10.3760/cma.j.cn511434-20240103-00001.Ma ZZ. Present view in understanding of polypoidal choroidal vasculopathy[J]. Chin J Ocul Fundus Dis, 2024, 40(2): 89-97. DOI: 10.3760/cma.j.cn511434-20240103-00001. |
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- 1. 中華醫學會眼科學分會眼底病學組, 中國醫師協會眼科醫師分會眼底病學組. 中國年齡相關性黃斑變性臨床診療指南(2023年)[J]. 中華眼科雜志, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649.Ophthalmology Group of the Chinese Medical Association's Ophthalmology Society, and the Ophthalmology Group of the Ophthalmologists' Association of the Chinese Medical Association. Evidence-based guidelines for diagnosis and treatment of age-related macular degeneration in China (2023)[J]. Chin J Ophthalmol, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649.
- 2. Mettu PS, Allingham MJ, Cousins SW. Incomplete response to anti-VEGF therapy in neovascular AMD: exploring disease mechanisms and therapeutic opportunities[J/OL]. Prog Retin Eye Res, 2021, 82: 100906[2020-10-03]. https://pubmed.ncbi.nlm.nih.gov/33022379/. DOI: 10.1016/j.preteyeres.2020.100906.
- 3. Nicolò M, Ferro Desideri L, Vagge A, et al. Faricimab: an investigational agent targeting the Tie-2/angiopoietin pathway and VEGF-A for the treatment of retinal diseases[J]. Expert Opin Investig Drugs, 2021, 30(3): 193-200. DOI: 10.1080/13543784.2021.1879791.
- 4. 徐君. Faricimab在視網膜血管性疾病治療中的應用[J]. 眼科新進展, 2024, 44(10): 835-840. DOI: 10.13389/j.cnki.rao.2024.0158.Xu J. Application of Faricimab in the treatment of retinal vascular diseases[J]. Rec Adv Ophthalmol, 2024, 44(10): 835-840. DOI: 10.13389/j.cnki.rao.2024.0158.
- 5. 馬志中. 現在如何認識息肉樣脈絡膜血管病變[J]. 中華眼底病雜志, 2024, 40(2): 89-97. DOI: 10.3760/cma.j.cn511434-20240103-00001.Ma ZZ. Present view in understanding of polypoidal choroidal vasculopathy[J]. Chin J Ocul Fundus Dis, 2024, 40(2): 89-97. DOI: 10.3760/cma.j.cn511434-20240103-00001.
- 6. Seguin-Greenstein S, Lightman S, Tomkins-Netzer O. A meta-analysis of studies evaluating visual and anatomical outcomes in patients with treatment resistant neovascular age-related macular degeneration following switching to treatment with aflibercept[J/OL]. J Ophthalmol, 2016, 2016: 4095852[2016-03-06]. https://pubmed.ncbi.nlm.nih.gov/27042342/. DOI: 10.1155/2016/4095852.
- 7. Jang L, Gianniou C, Ambresin A, et al. Refractory subretinal fluid in patients with neovascular age-related macular degeneration treated with intravitreal ranibizumab: visual acuity outcome[J]. Graefe's Arch Clin Exp Ophthalmol, 2015, 253(8): 1211-1216. DOI: 10.1007/s00417-014-2789-x.
- 8. Zola M, D'Alessandro E, Sherif M, et al. Refractory neovascular age-related macular degeneration: time-dependent changes of central retinal thickness with anti-VEGF treatment[J]. Graefe's Arch Clin Exp Ophthalmol, 2021, 259(6): 1477-1486. DOI: 10.1007/s00417-020-05000-3.
- 9. Kishi M, Miki A, Kamimura A, et al. Short-term outcomes of faricimab treatment in aflibercept-refractory eyes with neovascular age-related macular degeneration[J/OL]. J Clin Med, 2023, 12(15): 5145[2023-08-06]. https://pubmed.ncbi.nlm.nih.gov/37568546/. DOI: 10.3390/jcm12155145.
- 10. Holz FG, Tadayoni R, Beatty S, et al. Key drivers of visual acuity gains in neovascular age-related macular degeneration in real life: findings from the AURA study[J]. Br J Ophthalmol, 2016, 100(12): 1623-1628. DOI: 10.1136/bjophthalmol-2015-308166.
- 11. Yeom H, Kwon HJ, Kim YJ, et al. Real-world study to evaluate the efficacy and safety of intravitreal brolucizumab for refractory neovascular age-related macular degeneration[J/OL]. Sci Rep, 2023, 13(1): 11400[2023-07-14]. https://pubmed.ncbi.nlm.nih.gov/37452068/. DOI: 10.1038/s41598-023-38173-y.
- 12. Lee JH, Shin JY, Ahn J. First-year real-world experience of intravitreal brolucizumab injection for refractory neovascular age-related macular degeneration[J]. Jpn J Ophthalmol, 2025, 69(1): 43-48. DOI: 10.1007/s10384-024-01134-7.
- 13. Chang AA, Broadhead GK, Hong T, et al. Intravitreal Aflibercept for treatment-resistant neovascular age-related macular degeneration: 12-month safety and efficacy outcomes[J]. Ophthalmic Res, 2015, 55(2): 84-90. DOI: 10.1159/000440886.
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