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Year : 2014  |  Volume : 4  |  Issue : 1  |  Page : 1-2

The evolution of antivascular endothelial growth factor agents for the treatment of neovascular age-related macular degeneration

Department of Ophthalmology, National University Hospital, 7, Chung-Shan Road, Taipei, Taiwan

Date of Web Publication4-Mar-2014

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Source of Support: None, Conflict of Interest: None

DOI: 10.1016/j.tjo.2014.01.002

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How to cite this article:
Yang CH. The evolution of antivascular endothelial growth factor agents for the treatment of neovascular age-related macular degeneration. Taiwan J Ophthalmol 2014;4:1-2

How to cite this URL:
Yang CH. The evolution of antivascular endothelial growth factor agents for the treatment of neovascular age-related macular degeneration. Taiwan J Ophthalmol [serial online] 2014 [cited 2022 Jan 26];4:1-2. Available from: https://www.e-tjo.org/text.asp?2014/4/1/1/203919

Age-related macular degeneration (AMD) is the leading cause of legal blindness worldwide.[1] Neovascular AMD (nAMD) is characterized by the growth of abnormal choroidal blood vessels beneath the retinal pigment epithelium and/or sensory retina. Most treatment strategies developed for nAMD treatment have targeted choroidal neovascularization (CNV). The pathogenesis of CNV is not completely understood, although the overexpression of vascular endothelial growth factor (VEGF) has been recognized as having a crucial role.[2] The blockade of VEGF effectively inhibits the formation of CNV. Therefore, anti-VEGF therapy has emerged as a promising therapeutic strategy for the treatment of nAMD.

In this issue of the Taiwan Journal of Ophthalmology, Kato and coauthors[3] contribute a comprehensive review of anti-VEGF therapy for nAMD. In 2004, the U.S. Food and Drug Administration (FDA) approved pegaptanib (Macugen; Eyetech Pharmaceuticals, New York, NY, USA) as the first anti-VEGF agent for intravitreal injection to treat nAMD.[4] It is a 28-base RNA aptamer that selectively binds only the VEGF165 isoform of VEGF-A. This limits its efficacy and further clinical application. In 2006, ranibizumab (Lucentis; Genentech, South San Francisco, CA, USA) was the second anti-VEGF agent introduced into the market. It is an antibody fragment that inhibits all VEGF-A isoforms and was designed specifically to treat nAMD. Two landmark clinical studies–the Minimally Classic/Occult Trial of the Anti-VEGFAntibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) and the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) trial–established a paradigm shift in nAMD treatment.[5],[6] Vision was stabilized in 94% of patients receiving ranibizumab with 40% of the patients experiencing improved vision by at least three lines. Bevacizumab (Avastin; Genentech, South San Francisco, CA, USA) is a monoclonal antibody that binds all isoforms of VEGF-A. In 2004, the FDA approved it for the treatment of metastatic colon cancer. However, the intravitreal injection of bevacizumab was applied as an off-label use for the treatment of nAMD worldwide because of its cheaper price. The clinical equivalence of ranibizumab versus bevacizumab was demonstrated by the results of the Age-Related Macular Degeneration Treatment Trial (CATT), which was sponsored by the National Eye Institute of USA.[7] The study results showed that monthly bevacizumab was equivalent to monthly ranibizumab, and bevacizumab p.r.n. was equivalent to ranibizumab p.r.n. Ranibizumab p.r.n. was equivalent to monthly ranibizumab, although the comparison between bevacizumab p.r.n. and monthly bevacizumab was inconclusive.

Most patients with nAMD respond favorably to the aforementioned anti-VEGF agents; however, some patients become less responsive to ranibizumab or bevacizumab after repeated injections. Tachyphylaxis is a contributing factor. It is defined as a progressively diminished therapeutic effectiveness to a drug after repeated administration. Tachyphylaxis has been demonstrated for bevacizumab and for ranibizumab in the treatment of nAMD.[8]

In this issue of the Taiwan Journal of Ophthalmology, Cheng et al[9] report a rapid response to intravitreal aflibercept in the treatment of a patient with nAMD who developed tachyphylaxis to bevacizumab and ranibizumab. Subretinal fluid (SRF) and pigment epithelial detachment persisted in spite of 14 bevacizumab and seven ranibizumab injections. After only one injection of intravitreal aflibercept, marked improvement was observed within 1 week. Four weeks after the first aflibercept injection, complete drying of the SRF and marked subsiding of pigment epithelial detachment were noted and sustained for three consecutive monthly injections. In 2011, the FDA approved aflibercept (Eylea; Regeneron, Tarrytown, PA, USA and Bayer HealthCare, Berlin, Germany) as a new anti-VEGF agent for the treatment of nAMD.[10] It is composed of a recombinant soluble decoy receptor fusion protein that incorporates the second binding domain of the VEGF receptor-1 and the third binding domain of the VEGF receptor-2. The binding affinity of aflibercept to VEGF was higher than that of ranibizumab. Two clinical trials–VEGF Trap-Eye, Investigation of Efficacy and Safety in Wet AMD (VIEW 1 and VIEW 2)–showed that the aflibercept treatment groups were noninferior and clinically equivalent to monthly ranibizumab injections for the primary endpoint.[11] In addition, studies suggest that aflibercept may effectively treat patients with refractory nAMD and persistent fluid, despite repeated intravitreal ranibizumab and/or bevacizumab injections.[12],[13] Unlike currently available anti-VEGF agents, aflibercept binds all isoform of VEGF-A,

VEGF-B, and placental growth factor; the latter is an important factor in angiogenesis.[14] These characteristics could be a contributing factor that enables aflibercept to treat eyes with nAMD that are refractory to ranibizumab or bevacizumab.

In conclusion, in the past decade, a very exciting advance in the treatment of nAMD came with the introduction of anti-VEGF therapy. The advent of anti-VEGF therapy marked a turning point in the treatment of nAMD. The usefulness of bevacizumab, ranibizumab, or aflibercept is supported by large-scale randomized clinical trials. However, the optimal treatment regime remains controversial.[15] Furthermore, these beneficial results come with a drawback. Most anti-VEGF agents are expensive. The cost of frequent clinical visits and examinations is burdensome for the patients, physicians, and health providers (e.g., government). Repeated intravitreal injections raise the risk of endophthalmitis, retinal detachment, vitreous hemorrhages, and cataracts. A sustained rise in intraocular pressure has also been reported after repeated injections of antiVEGF agents.[16] The battle to conquer CNV in nAMD seems to have a long way to go. We look forward to seeing more anti-VEGF agents developed with a higher potency and longer duration for the treatment of nAMD.

  References Top

Bressler NM. Age-related macular degeneration is the leading cause of blindness. JAMA. 2004;291:1900–1901.  Back to cited text no. 1
Miller JW, Le Couter J, Strauss EC, Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology. 2013;120:106–114.  Back to cited text no. 2
Kato A, Yasukawa T, Ogura Y. Antivascular endothelial growth factor therapies for neovascular age-related macular degeneration: search for the optimized treatment regimen. Taiwan J Ophthalmol. 2014;4:3–8.  Back to cited text no. 3
Apte RS, Modi M, Masonson H, Patel M, Whitfield L, Adamis AP. Pegaptanib 1-year systemic safety results from a safety-pharmacokinetic trial in patients with neovascular age-related macular degeneration. Ophthalmology. 2007;114:1702–1712.  Back to cited text no. 4
Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular agerelated macular degeneration. N Engl J Med. 2006;355:1419–1431.  Back to cited text no. 5
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355: 1432–1444.  Back to cited text no. 6
Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897–1908.  Back to cited text no. 7
Binder S. Loss of reactivity in intravitreal anti-VEGF therapy: tachyphylaxis or tolerance? Br J Ophthalmol. 2012;96:1–2.  Back to cited text no. 8
Cheng CK, Chan TY. Rapid response to intravitreal aflibercept in neovascular age-related macular degeneration after development of tachyphylaxis to bevacizumab and ranibizumab. Taiwan J Ophthalmol. 2014;4:40–?44.  Back to cited text no. 9
Stewart MW. Aflibercept (VEGF Trap-Eye) for the treatment of exudative agerelated macular degeneration. Expert Rev Clin Pharmacol. 2013;6:103–113.  Back to cited text no. 10
Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537–2548.  Back to cited text no. 11
Bakall B, Folk JC, Boldt HC, et al. Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol. 2013;156:15–22.  Back to cited text no. 12
Cho H, Shah CP, Weber M, Heier JS. Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol. 2013;97: 1032–1035.  Back to cited text no. 13
Rakic JM, Lambert V, Devy L, et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2003;44:3186–3193.  Back to cited text no. 14
Haller JA. Current anti-vascular endothelial growth factor dosing regimens: benefits and burden. Ophthalmology. 2013;120(5 Suppl.):S3–S7.  Back to cited text no. 15
Tseng JJ, Vance SK, Della Torre KE, et al. Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular age-related macular degeneration. J Glaucoma. 2012;21:241–247.  Back to cited text no. 16

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