Current view on the issue of insufficient effectiveness of anti-VEGF therapy for age-related macular degeneration

Close metadata

Recommended articles:

Effectiveness and safety of brolucizumab in the treatment of neovascular age-related macular degeneration. Russian Annals of Ophthalmology. 2024;(4):40-48

Diagnosis of choroidal nevus following multiple intravitreal anti-VEGF injections (case study). Russian Annals of Ophthalmology. 2024;(4):68-72

Efficacy of brolucizumab in the treatment of retinal pathologies: a review of post-marketing studies. Russian Annals of Ophthalmology. 2024;(5):154-161

Analysis of the effectiveness of cataract surgery in neovascular age-related macular degeneration. Russian Annals of Ophthalmology. 2024;(6):7-14

Management of patients with treatment-resistant neovascular age-related macular degeneration. Russian Annals of Ophthalmology. 2024;(6):63-68

Neuroprotective therapy for age-related macular degeneration. Russian Annals of Ophthalmology. 2024;(6):152-158

Choroidal neovascularization associated with choroidal nevi. Russian Annals of Ophthalmology. 2025;(1):104-112

Artificial intelligence in assessment of individual risks of age-related macular degeneration progression. Russian Annals of Ophthalmology. 2025;(2):123-128

Due to the significant medical and social importance of neovascular (wet) age-related macular degeneration (wAMD), increasing the effectiveness of anti-VEGF therapy used to treat this disease is one of the high-priority problems in modern retinology. This article focuses on pathobiological aspects and clinical manifestations of incomplete responses to anti-VEGF therapy of wAMD, considers the proposed ways to improve the terminology and classification of responses to therapy, as well as the assessment of its correctness and effectiveness of the treatment. It also discusses the available ways to optimize anti-VEGF therapy and define the criteria of its termination in cases when the treatment proves to be futile.

Keywords:

age-related macular degeneration

anti-VEGF therapy

neovascularization phenotypes

response to therapy

treatment futility

Authors:

Zaytseva O.V.

Helmholtz National Medical Research Center of Eye Diseases;
A.I. Evdokimov Moscow State University of Medicine and Dentistry

SPIN RSCI: 4962-5446
ORCID: 0000-0002-4975-1310

Neroeva N.V.

Helmholtz National Medical Research Center of Eye Diseases

Okhotsimskaya T.D.

Helmholtz National Medical Research Center of Eye Diseases

Bobykin E.V.

Ural State Medical University

Received:

27.10.2021

Accepted:

25.01.2022

List of references:

Yang S, Zhao J, Sun X. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review. Drug Des Devel Ther. 2016;10:1857-1867. https://doi.org/10.2147/DDDT.S976531
Budzinskaya MV, Plyukhova AA, Andreeva IV, Kuznetsov AV, Shelankova AV, Sorokin PA. Pharmacological Analysis of Resistance to Anti-VEGF Therapy. Ophthalmology in Russia = Oftal’mologiya. 2018;15(4):382-387. (In Russ.). https://doi.org/10.18008/1816-5095-2018-4-382-387
Zaytseva OV, Neroeva NV, Okhotsimskaya TD, Bobykin EV. Anti-VEGF therapy for neovascular age-related macular degeneration: causes of incomplete response. The Russian Annals of Ophthalmology = Vestnik oftal’mologii. 2021;137(5):152-159. (In Russ.). https://doi.org/10.17116/oftalma2021137051152
Stone TW, ed. ASRS 2018 Preferences and Trends Membership Survey. Chicago, IL. American Society of Retina Specialists; 2018. Accessed August 29, 2018. https://www.asrs.org/content/documents/_2018-pat-survey-results-for-website.pdf
Zaytseva O, Neroev V, Zhulev Y, Petrakovskaya V, Paleeva A, Trifonova M, Efimenko I. Semantic analysis of patient voice in wet AMD and diabetic retinal disease: Patients’ journey and healthcare experience. Euretina 2021 Virtual Abstracts. Type Free Paper, No. 38.
Bobykin EV, Korotkih SA, Krokhalev VYa, Buslaev RV, Beresneva NS, Morozova OV. Anti-VEGF therapy of wet age-related macular degeneration: analysis of patients lost to follow-up. The Russian Annals of Ophthalmology = Vestnik oftal’mologii. 2021;137(2):66-74. (In Russ.). https://doi.org/10.17116/oftalma202113702166
Mettu PS, Allingham MJ, Cousins SW. Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities. Prog Retin Eye Res. 2021;82:100906. https://doi.org/10.1016/j.preteyeres.2020.100906
Lad EM, Grunwald L, Mettu PS, Serrano NP, Crowell S, Cousins SW. Lesion Morphology on Indocyanine Green Angiography in Age-Related Macular Degeneration with Classic Choroidal Neovascular Membrane: Implications for Response to anti-VEGF Treatment. Invest Ophthalmol Vis Sci. 2012;53(14):5161.
Mettu PS, Crowell S, Shaw J, Grunwald L, Lad EM, Serrano N, Cousins SW. Neovascular Morphology on ICG Angiography Predicts Response to Anti-VEGF Therapy in Eyes with Serous Pigment Epithelial Detachments and Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2012; 53(14):2654.
Serrano NP, Shaw J, Mettu PS, Lad EM, Crowell S, Cousins SW. High-speed Indocyanine Green Angiography In Age Related Macular Degeneration With Fibrovascular Pigment Epithelial Detachments. Invest Ophthalmol Vis Sci. 2012;53(14):1151.
Mettu PS, Allingham MJ, Nicholas PC, Cousins SW. Neovascular Morphology by ICG Angiography and Response to Loading-Dose Anti-VEGF Therapy in Patients with Neovascular AMD. Invest Ophthalmol Vis Sci. 2016; 57(12):No Pagination Specified.
Ersoz MG, Karacorlu M, Arf S, Sayman Muslubas I, Hocaoglu M. Retinal pigment epithelium tears: Classification, pathogenesis, predictors, and management. Surv Ophthalmol. 2017;62(4):493-505. https://doi.org/10.1016/j.survophthal.2017.03.004
Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Maguire MG, Martin DF, Ying GS, Jaffe GJ, Daniel E, Grunwald JE, Toth CA, Ferris FL 3rd, Fine SL. Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123(8):1751-1761. https://doi.org/10.1016/j.ophtha.2016.03.045
Pauleikhoff D, Löffert D, Spital G, Radermacher M, Dohrmann J, Lommatzsch A, Bird AC. Pigment epithelial detachment in the elderly. Clinical differentiation, natural course and pathogenetic implications. Graefes Arch Clin Exp Ophthalmol. 2002;240(7):533-538. https://doi.org/10.1007/s00417-002-0505-8
Guber J, Praveen A, Saeed MU. Higher incidence of retinal pigment epithelium tears after ranibizumab in neovascular age-related macular degeneration with increasing pigment epithelium detachment height. Br J Ophthalmol. 2013;97(11):1486-1487. https://doi.org/10.1136/bjophthalmol-2013-303978
He X, Hahn P, Iacovelli J, Wong R, King C, Bhisitkul R, Massaro-Giordano M, Dunaief JL. Iron homeostasis and toxicity in retinal degeneration. Prog Retin Eye Res. 2007;26(6):649-673. https://doi.org/10.1016/j.preteyeres.2007.07.004
Avery RL, Fekrat S, Hawkins BS, Bressler NM. Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration. Retina. 1996; 16(3):183-189. https://doi.org/10.1097/00006982-199616030-00001
Altaweel MM, Daniel E, Martin DF, Mittra RA, Grunwald JE, Lai MM, Melamud A, Morse LS, Huang J, Ferris FL 3rd, Fine SL, Maguire MG; Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; Comparison of Age-related Macular Degeneration Treatments Trials CATT Research Group. Outcomes of eyes with lesions composed of >50% blood in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). Ophthalmology. 2015;122(2):391-398.e5. https://doi.org/10.1016/j.ophtha.2014.08.020
Daniel E, Toth CA, Grunwald JE, Jaffe GJ, Martin DF, Fine SL, Huang J, Ying GS, Hagstrom SA, Winter K, Maguire MG; Comparison of Age-related Macular Degeneration Treatments Trials Research Group. Risk of scar in the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2014;121(3):656-666. https://doi.org/10.1016/j.ophtha.2013.10.019
Cousins SW, Bearelly S, Reinoso MA, Chi SL, Espinosa-Heidmann DG. Dynamic indocyanine green angiography-guided focal thermal laser treatment of fibrotic choroidal neovascularization. Graefes Arch Clin Exp Ophthalmol. 2008;246(12):1677-1683. https://doi.org/10.1007/s00417-008-0905-5
Bearelly S, Espinosa-Heidmann DG, Cousins SW. The role of dynamic indocyanine green angiography in the diagnosis and treatment of retinal angiomatous proliferation. Br J Ophthalmol. 2008;92(2):191-196. https://doi.org/10.1136/bjo.2007.118760
Grossniklaus HE, Kang SJ, Berglin L. Animal models of choroidal and retinal neovascularization. Prog Retin Eye Res. 2010;29(6):500-519. https://doi.org/10.1016/j.preteyeres.2010.05.003
Espinosa-Heidmann DG, Suner I, Hernandez EP, Frazier WD, Csaky KG, Cousins SW. Age as an independent risk factor for severity of experimental choroidal neovascularization. Invest Ophthalmol Vis Sci. 2002;43(5): 1567-1573.
Espinosa-Heidmann DG, Malek G, Mettu PS, Caicedo A, Saloupis P, Gach S, Dunnon AK, Hu P, Spiga MG, Cousins SW. Bone marrow transplantation transfers age-related susceptibility to neovascular remodeling in murine laser-induced choroidal neovascularization. Invest Ophthalmol Vis Sci. 2013; 54(12):7439-7449. https://doi.org/10.1167/iovs.13-12546
McLeod DS, Bhutto I, Edwards MM, Silver RE, Seddon JM, Lutty GA. Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2016; 57(14):5843-5855. https://doi.org/10.1167/iovs.16-20049
Kent D, Sheridan C. Choroidal neovascularization: a wound healing perspective. Mol Vis. 2003;9:747-755.
Reddy VM, Zamora RL, Kaplan HJ. Distribution of growth factors in subfoveal neovascular membranes in age-related macular degeneration and presumed ocular histoplasmosis syndrome. Am J Ophthalmol. 1995;120(3): 291-301. https://doi.org/10.1016/s0002-9394(14)72158-0
Miller DM, Espinosa-Heidmann DG, Legra J, et al. The association of prior cytomegalovirus infection with neovascular age-related macular degeneration. Am J Ophthalmol. 2004;138(3):323-328. https://doi.org/10.1016/j.ajo.2004.03.018
Nikitina E, Larionova I, Choinzonov E, Kzhyshkowska J. Monocytes and Macrophages as Viral Targets and Reservoirs. Int J Mol Sci. 2018;19(9):2821. https://doi.org/10.3390/ijms19092821
Mettu PS, Saloupis P, Cousins SW. PAMP Stimulation of Macrophages Promotes Neovascular Remodeling in Experimental Choroidal Neovascularization. Invest Ophthalmol Vis Sci. 2014;55(13):1198.
Yuan F, Fu X, Shi H, Chen G, Dong P, Zhang W. Induction of murine macrophage M2 polarization by cigarette smoke extract via the JAK2/STAT3 pathway. PLoS One. 2014;9(9):e107063. https://doi.org/10.1371/journal.pone.0107063
Yang XF, Yin Y, Wang H. Vascular inflammation and atherogenesis are activated via receptors for PAMPs and suppressed by regulatory T cells. Drug Discov Today Ther Strateg. 2008;5(2):125-142. https://doi.org/10.1016/j.ddstr.2008.11.003
McGeer PL, Sibley J. Sparing of age-related macular degeneration in rheumatoid arthritis. Neurobiol Aging. 2005;26(8):1199-1203. https://doi.org/10.1016/j.neurobiolaging.2005.02.003
Ishibashi T, Miki K, Sorgente N, Patterson R, Ryan SJ. Effects of Intravitreal Administration of Steroids on Experimental Subretinal Neovascularization in the Subhuman Primate. Arch Ophthalmol. 1985;103(5):708-711. https://doi.org/10.1001/archopht.1985.01050050100026
Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol. 2013;13(6):438-451. https://doi.org/10.1038/nri3459
Budzinskaya MV, Gurova IV, Schegoleva IV, Loschenov VB, Shevchik SA, Kuzjmin SG, Vorogtsov GN. Combined modality therapy for exsudative form of age-related macular degeneration. Photodynamic Therapy and Photodyagnosis = Fotodinamicheskaya terapiya i fotodiagnostika. 2013;2(1):20-24 (In Russ.).
Bobykin EV, Morozova OV, Beresneva NS. Treatment of macular diseases: an overview of key randomized clinical trials. Russian Ophthalmological Journal = Rossiyskiy oftal’mologicheskiy zhurnal. 2021;14(4):137-148 (In Russ.). https://doi.org/10.21516/2072-0076-2021-14-4-137-148
Koh A, Lai TYY, Takahashi K, et al. Efficacy and Safety of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: A Randomized Clinical Trial. JAMA Ophthalmol. 2017; 135(11):1206-1213. https://doi.org/10.1001/jamaophthalmol.2017.4030
Wong TY, Ogura Y, Lee WK, et al. Efficacy and safety of intravitreal Aflibercept for polypoidal choroidal vasculopathy: two-year results of the Aflibercept in polypoidal choroidal vasculopathy study. Am J Ophthalmol. 2019; 204:80-89. https://doi.org/10.1016/j.ajo.2019.02.027
Shen J, Frye M, Lee BL, et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014;124(10):4564-4576. https://doi.org/10.1172/JCI74527
Hussain RM, Neiweem AE, Kansara V, Harris A, Ciulla TA. Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease. Expert Opin Investig Drugs. 2019;28(10):861-869. https://doi.org/10.1080/13543784.2019.1667333
Dugel PU, Boyer DS, Antoszyk AN, et al. Phase 1 Study of OPT-302 Inhibition of Vascular Endothelial Growth Factors C and D for Neovascular Age-Related Macular Degeneration. Ophthalmol Retina. 2020;4(3):250-263. https://doi.org/10.1016/j.oret.2019.10.008
Cabral T, Lima LH, Mello LGM, et al. Bevacizumab Injection in Patients with Neovascular Age-Related Macular Degeneration Increases Angiogenic Biomarkers. Ophthalmol Retina. 2018;2(1):31-37. https://doi.org/10.1016/j.oret.2017.04.004
Al-Khersan H, Hussain RM, Ciulla TA, Dugel PU. Innovative therapies for neovascular age-related macular degeneration. Expert Opin Pharmacother. 2019;20(15):1879-1891. https://doi.org/10.1080/14656566.2019.1636031
Peden MC, Suñer IJ, Hammer ME, Grizzard WS. Long-term outcomes in eyes receiving fixed-interval dosing of anti-vascular endothelial growth factor agents for wet age-related macular degeneration. Ophthalmology. 2015; 122(4):803-808. https://doi.org/10.1016/j.ophtha.2014.11.018
Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG; HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2020;127(1):72-84. https://doi.org/10.1016/j.ophtha.2019.04.017
Espinosa-Heidmann DG, Reinoso MA, Pina Y, Csaky KG, Caicedo A, Cousins SW. Quantitative enumeration of vascular smooth muscle cells and endothelial cells derived from bone marrow precursors in experimental choroidal neovascularization. Exp Eye Res. 2005;80(3):369-378. https://doi.org/10.1016/j.exer.2004.10.005
Caicedo A, Espinosa-Heidmann DG, Piña Y, Hernandez EP, Cousins SW. Blood-derived macrophages infiltrate the retina and activate Muller glial cells under experimental choroidal neovascularization. Exp Eye Res. 2005;81(1): 38-47. https://doi.org/10.1016/j.exer.2005.01.013
Lad EM, Cousins SW, Van Arnam JS, Proia AD. Abundance of infiltrating CD163+ cells in the retina of postmortem eyes with dry and neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2015;253 (11):1941-1945. https://doi.org/10.1007/s00417-015-3094-z
Allingham MJ, Mettu PS, Cousins, SW. Elamipretide, a Mitochondrial-Targeted Drug, for the Treatment of Vision Loss in Dry AMD with High Risk Drusen: Results of the Phase 1 ReCLAIM Study. Invest Ophthalmol Vis Sci. 2019;60(9):361.
Cousins SW, Allingham MJ, Mettu PS. Elamipretide, a Mitochondria-Targeted Drug, for the Treatment of Vision Loss in Dry AMD with Noncentral Geographic Atrophy: Results of the Phase 1 ReCLAIM Study. Invest Ophthalmol Vis Sci. 2019;60(9):974.
Mettu PS, Allingham MJ, Cousins SW. Effects of the Mitochondria-Targeted Drug Elamipretide on Leakage-Independent Vision Loss in Fellow Eyes with Neovascular AMD in the ReCLAIM Study. Invest Ophthalmol Vis Sci. 2019;60(9):358.
Fursova AZh, Derbeneva AS, Tarasov MS, Nikulich IF, Devyatkin VA, Telegina DV, Kolosova NG, Kozhevnikova OS. Leukocyte Telomere Length and Response to Antiangiogenic Therapy in Patients with Neovascular Age-Related Macular Degeneration. Advances in Gerontology = Uspekhi gerontologii. 2021;34(6):823-830. https://doi.org/10.34922/AE.2021.34.6.002
Avitabile T, Boscia F, Dell’Erba A, Introini U, Lanzetta P, Locatelli P, Ricci F, Staurenghi G, Varano M, Zotti F. Definition of indicators of appropriateness in the management of neovascular age-related macular degeneration: An expert opinion. Eur J Ophthalmol. 2020;30(4):795-804. https://doi.org/10.1177/1120672120915685
Okada M, Wong TY, Mitchell P, Eldem B, Talks SJ, Aslam T, Daien V, Rodriguez FJ, Gale R, Barratt J, Finger RP, Loewenstein A. Defining Nonadherence and Nonpersistence to Anti-Vascular Endothelial Growth Factor Therapies in Neovascular Age-Related Macular Degeneration. JAMA Ophthalmol. 2021;139(7):769-776. https://doi.org/10.1001/jamaophthalmol.2021.1660
Monés J. Non-responders neovascular AMD concept and spectrum. Presentation at the EURETINA 2021 Virtual (Instructional Course 8: Non-Responders in Neovascular AMD, 09.09.2021).
FDA Approves Genentech’s Port Delivery System, Susvimo, a First-of-Its-Kind Therapeutic Approach for Wet AMD. Accessed October 26, 2021. https://eyewire.news/news/fda-approves-genentechs-port-delivery-system-susvimo-a-first-of-its-kind-therapeutic-approach-for-wet-amd
Wong DT, Lambrou GN, Loewenstein A, Pearce I, Okada AA. Vision Academy Steering Committee. Suspending treatment of neovascular age-related macular degeneration in cases of futility. Retina. 2020;40(6):1010-1020. https://doi.org/10.1097/IAE.0000000000002713
Schneiderman LJ. Defining Medical Futility and Improving Medical Care. J Bioeth Inq. 2011;8(2):123-131. https://doi.org/10.1007/s11673-011-9293-3
The Royal College of Ophthalmologists. Age-related macular degeneration: guidelines for management. September 2013. Accessed October 21, 2021. https://www.rcophth.ac.uk/wp-content/uploads/2014/12/2013-SCI-318-RCOphth-AMD-Guidelines-Sept-2013-FINAL-2.pdf
Ross AH, Downey L, Devonport H, Gale RP, Kotagiri A, Mahmood S, Mehta H, Narendran N, Patel PJ, Parmar N, Jain N. Recommendations by a UK expert panel on an aflibercept treat-and-extend pathway for the treatment of neovascular age-related macular degeneration. Eye (Lond). 2020; 34(10):1825-1834. https://doi.org/10.1038/s41433-019-0747-x

Close metadata