Listen on the go
CORRECT!
Next question
touchOPHTHALMOLOGY touchOPHTHALMOLOGY
Retina/Vitreous
Read Time: 2 mins

Anti-vascular Endothelial Growth Factor Pharmacotherapy in the Treatment of Subretinal Choroidal Neovascularization

Copy Link
Published Online: Jun 21st 2012 US Ophthalmic Review, 2012;5(2):107–10 DOI: http://doi.org/10.17925/USOR.2012.05.02.107
Authors: Yoreh Barak, Mark A Ihnen, Shlomit Schaal
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

Vascular endothelial growth factor (VEGF) plays a pivotal role in stimulating the growth of pathologic subretinal choroidal neovascularization (CNV). The increased production of VEGF and subsequent CNV formation can occur in degenerative, inflammatory, and vascular diseases of the retina and choroid, often leading to severe visual impairment. Anti-VEGF agents which are readily available today are much better, more potent, and longer acting in comparison with previous treatment modalities, and therefore have dramatically improved the prognosis of patients with CNV. There are four intravitreal anti-VEGF pharmacotherapies proven by large prospective, multicenter, randomized trials to be effective in the treatment of age-related macular degeneration (AMD)-related CNV: pegaptanib (Macugen®, Eyetech Pharmaceuticals, Palm Beach Gardens, FL), ranibizumab (Lucentis®, Genentech, Inc., South San Francisco, CA), bevacizumab (Avastin®, Genentech, Inc., South San Francisco, CA), and VEGF Trap-Eye (Eylea® Regeneron, Tarrytown, NY). However, there are still many challenges and unanswered questions regarding the optimal anti-VEGF pharmacotherapy agent, the best clinical treatment regimen, the most effective dosage, the optimal injection frequency, and the duration of treatment. The heavy burden of frequent injections on the elderly patient population and physicians begs for a simpler way of drug administration or development of more potent compounds.

Keywords

Vascular endothelial growth factor, subretinal choroidal neovascularization, age-related macular degeneration, pegaptanib, ranibizumab, bevacizumab, VEGF Trap-Eye

Article:

Intravitreal anti-vascular endothelial growth factor (VEGF) pharmacotherapy, introduced in 2004,1 has evolved over the last decade to revolutionize the treatment of patients suffering from subretinal choroidal neovascularization (CNV). Anti-VEGF agents, which are readily available today, are much better, more potent, and longer acting in comparison with previous treatment modalities, and therefore have dramatically improved the prognosis of patients with CNV.

Patients losing vision secondary to CNV, such as patients suffering from exudative age-related macular degeneration (AMD), can now expect stabilization and even improvement of their visual acuity, as opposed to the slow and certain visual deterioration that was the rule before the anti-VEGF era.2–6

Vascular Endothelial Growth Factor
VEGF is a diffusible cytokine that promotes angiogenesis and increases vascular permeability. It is a product of a gene family that plays an important role in normal development and angiogenesis.7 The influence of VEGF in retinal diseases is profound. This dimeric glycoprotein of approximately 40 kDa is upregulated in response to hypoxia. It plays a pivotal role in stimulating abnormal growth of pathological new blood vessels in the adult retina and choroid. VEGF is also a potent inducer of vascular permeability and leakage that can lead to retinal edema and thickening.8,9

There is mounting evidence that increased VEGF expression is associated with pathologic CNV.7 CNV, a form of abnormal blood vessel growth which emerges from choroidal vessels, penetrates Bruch’s membrane and grows below the retinal pigment epithelium (RPE) space and into the subretinal space.10 Figure 1 shows the different stages of growth of a subretinal choroidal membrane in response to VEGF stimulation. The increased production of VEGF and subsequent CNV formation can occur in degenerative, inflammatory, neoplastic, traumatic, hereditary, and idiopathic diseases of the retina and choroid. The most commonly encountered conditions associated with CNV are AMD and pathologic myopia. AMD is the leading cause of irreversible vision loss among the elderly population in the Western world.11

To view the full article in PDF or eBook formats, please click on the icons above.

Article Information:
Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Shlomit Schaal, MD, PhD, 301 E Muhammad Ali Boulevard, Louisville, KY 40202, US. E: s.schaal@louisville.edu

Received

2011-10-29T00:00:00

References

  1. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al., Pegaptanib for neovascular age-related macular degeneration, N Engl J Med, 2004;351:2805–16.
  2. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Macular Photocoagulation Study Group, Arch Ophthalmol, 1991;109:1109–14.
  3. Bressler NM, Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2, Arch Ophthalmol, 2001;119:198–207.
  4. Brown DM, Michels M, Kaiser PK, et al., Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study, Ophthalmology, 2009;116:57–65.
  5. Heier JS, Boyer D, Nguyen QD, et al., The 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor trap-eye dosed as-needed after 12-week fixed dosing, Ophthalmology, 2011;118:1098–106.
  6. Rosenfeld PJ, Brown DM, Heier JS, et al., Ranibizumab for neovascular age-related macular degeneration, N Engl J Med, 2006;355:1419–31.
  7. Penn JS, Madan A, Caldwell RB, et al., Vascular endothelial growth factor in eye disease, Prog Retin Eye Res, 2008;27:331–71.
  8. Ferrara N, Gerber HP, LeCouter J, The biology of VEGF and its receptors, Nat Med, 2003;9:669–76.
  9. Kliffen M, Sharma HS, Mooy CM, et al., Increased expression of angiogenic growth factors in age-related maculopathy, Br J Ophthalmol, 1997;81:154–62.
  10. Campochiaro PA, Retinal and choroidal neovascularization, J Cell Physiol, 2000;184:301–10.
  11. West SK, Looking forward to 20/20: a focus on the epidemiology of eye diseases, Epidemiol Rev, 2000;22:64–70.
  12. Schaal S, Tezel T, Differences in the Biological Responses of Subretinal Choroidal Neovascularization Subtypes to Intravitreal Anti-VEGF Pharmacotherapy, Presented at: 28th Annual Meeting of the American Society of Retina Specialists, Vancouver, Canada, 30 August 2010.
  13. Iacono P, Parodi MB, Papayannis A, et al., Intravitreal Bevacizumab Therapy on an As-per-needed Basis in Subfoveal Choroidal Neovascularization Secondary to Pathological Myopia: 2-Year Outcomes of a Prospective Case Series, Retina, 2011;31:1841–7.
  14. Gulati N, Forooghian F, Lieberman R, Jabs DA, Vascular endothelial growth factor inhibition in uveitis: a systematic review, Br J Ophthalmol, 2011;95:162–5.
  15. Artunay O, Yuzbasioglu E, Rasier R, et al., Combination Treatment with Intravitreal Injection of Ranibizumab and Reduced Fluence Photodynamic Therapy for Choroidal Neovascularization Secondary to Angioid Streaks: Preliminary Clinical Results of 12-Month Follow-Up, Retina, 2011;31:1279–86.
  16. Schaal S, Barr C, Kaplan H, Tezel T, Intravitreal Bevacizumab is Superior to Laser Photocoagulation in the Treatment of Juxtafoveal Choroidal Neovascularization Secondary to POHS, Presented at: Retina Congress, a combined meeting of the American Society of Retina Specialists, The Macula Society, and The Retina Society, New York, NY, 4 October 2009.
  17. Bressler NM, Arnold J, Benchaboune M, et al., Verteporfin therapy of subfoveal choroidal neovascularization in patients with age-related macular degeneration: additional information regarding baseline lesion composition’s impact on vision outcomes-TAP report No. 3, Arch Ophthalmol, 2002;120:1443–54.
  18. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Macular Photocoagulation Study Group, Arch Ophthalmol, 1991;109:1109–14.
  19. Bressler NM, Bressler SB, Hawkins BS, et al., Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: I. Ophthalmic outcomes submacular surgery trials pilot study report number 1, Am J Ophthalmol, 2000;130:387–407.
  20. Battaglia PM, Iacono P, Verbraak FD, Bandello F, Antivascular endothelial growth factors for inflammatory chorioretinal disorders, Dev Ophthalmol, 2010;46:84–95.
  21. Nielsen JS, Fick TA, Saggau DD, Barnes CH, Intravitreal anti-vascular endothelial growth factor therapy for choroidal neovascularization secondary to ocular histoplasmosis syndrome, Retina, 2011;32(3):468–72.
  22. Gragoudas ES, Adamis AP, Cunningham ET Jr, Pegaptanib for neovascular age-related macular degeneration, N Engl J Med, 2004;351:2805–16.
  23. Brown DM, Michels M, Kaiser PK, et al., Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study, Ophthalmology, 2009;116:57–65.
  24. Rosenfeld PJ, Brown DM, Heier JS, et al., Ranibizumab for neovascular age-related macular degeneration, N Engl J Med, 2006;355:1419–31.
  25. Arevalo JF, Sanchez JG, Wu L, et al., Intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration at twenty-four months: the Pan-American Collaborative Retina Study, Ophthalmology, 2010;117:1974–81.
  26. Arevalo JF, Adan A, Berrocal MH, et al., Intravitreal bevacizumab for inflammatory choroidal neovascularization: results from the Pan-American Collaborative Retina Study Group at 24 months, Retina, 2011;31:353–63.
  27. Bashshur ZF, Haddad ZA, Schakal AR, et al., Intravitreal bevacizumab for treatment of neovascular age-related macular degeneration: the second year of a prospective study, Am J Ophthalmol, 2009;148:59–65.
  28. Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S, Pharmacotherapy for neovascular age-related macular degeneration: an analysis of the 100% 2008 medicare fee-forservice part B claims file, Am J Ophthalmol, 2011;151:887–95.
  29. Martin DF, Maguire MG, Ying GS, et al., Ranibizumab and bevacizumab for neovascular age-related macular degeneration, N Engl J Med, 2011;364:1897–908.
  30. 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;44:3186–93.
  31. FDA, VEGF Trap-Eye (aflibercept ophthalmic solution) Briefing Document. Available at: www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/ DermatologicandOphthalmicDrugsAdvisoryCommittee/ UCM259143.pdf (accessed September 3, 2012).
  32. Regeneron Announces EYLEAâ„¢, 2011. Available at: http://investor.regeneron.com/releasedetail.cfm?ReleaseID= 585837 (accessed September 3, 2012).
  33. Patel JJ, Mendes MA, Bounthavong M, et al., Cost-utility analysis of bevacizumab versus ranibizumab in neovascular age-related macular degeneration using a Markov model, J Eval Clin Pract, 2010;18(2):247–55.
  34. van der Reis MI, La Heij EC, De Jong-Hesse Y, et al., A systematic review of the adverse events of intravitreal anti-vascular endothelial growth factor injections, Retina, 2011;31:1449–69.
  35. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1, Am J Ophthalmol, 2008;145:239–48.
  36. Lalwani GA, Rosenfeld PJ, Fung AE, et al., A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study, Am J Ophthalmol, 2009;148:43–58.
  37. Gupta OP, Shienbaum G, Patel AH, et al., A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact, Ophthalmology, 2010;117:2134–40.
  38. Chen C, Double-dose Ranibizumab For Choroidal Neovascularization Association With Age-related Macular Degeneration Minimally Responsive To Prior antiα-VEGF Treatment, Presented at: American Society of Retina Specialists 29th Annual Meeting, Boston, MA, US, August 2011.
  39. Chan CK, Management of Vascularized Pigment Epithelial Detachments Due to AMD with High (2.0 MG) vs. Conventionaldose (0.5 MG), Ranibizumab, Presented at: American Society of Retina Specialists 29th Annual Meeting, Boston, MA, US, August 2011.
  40. Nielsen JS, Increased Dose Ranibizumab for Persistent Choroidal Neovascular Activity in Neovascular Age-related Macular Degeneration, Presented at: American Society of Retina Specialists 29th Annual Meeting, Boston, MA, US, August 2011.
  41. Gaudric A, Cohen SY, When should anti-vascular endothelial growth factor treatment be stopped in age-related macular degeneration?, Am J Ophthalmol, 2010;149:4–6.
  42. Couch SM, Bakri SJ, Review of combination therapies for neovascular age-related macular degeneration, Semin Ophthalmol, 2011;26:114–20.
  43. Avila MP, Farah ME, Santos A, et al., Three-year safety and visual acuity results of epimacular 90strontium/90yttrium brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularization secondary to age-related macualr degeneration, Retina, 2011;32(1):10–8.
  44. Schaal S, Kaplan HJ, Tezel TH, Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology, 2008;115:2199–205.

Further Resources

Share this Article
Related Content In Retina/Vitreous
Imaging, Retina/Vitreous
Foreword: touchREVIEWS in Ophthalmology, Volume 17, Issue 2, 2023
Read Time: 2 mins

Welcome to the latest edition of touchREVIEWS in Ophthalmology, and my first as the journal’s Editor-in-Chief. In this issue, we are delighted to present a series of compelling articles providing insights into some of the cutting-edge developments in this diverse and ever-evolving field. Dhanashree Ratra and Aashna Ratra open the edition with the first in […]

Retina/Vitreous
Review of Suprachoroidal Delivery and its Application in Small Molecule Therapy
Luke G Qin, Venkatkrish M Kasetty, Diego Espinosa-Heidmann Read Time: 10 mins

touchREVIEWS in Ophthalmology. 2023;17(2):4–8 DOI: https://doi.org/10.17925/USOR.2023.17.2.6

Retinal pharmacotherapy encompasses various drug delivery routes that offer potential avenues for effective treatment (Figure 1). Among these, intravitreal injections have emerged as the predominant method employed in clinical practice.1 They have established themselves as the primary approach for administering anti-vascular endothelial growth factor (anti-VEGF) therapy, serving as the frontline treatment for neovascular age-related macular degeneration […]

Artificial Intelligence, Retina/Vitreous
Artificial Intelligence for the Diagnosis and Screening of Retinal Diseases
Alessandro Arrigo, Emanuela Aragona, Francesco Bandello Read Time: 10 mins

touchREVIEWS in Ophthalmology. 2023;17(2):9-14 DOI: https://doi.org/10.17925/USOR.2023.17.2.1

Article highlights Artificial intelligence (AI) represents a powerful way of analysing a large amount of data, extracting those features characterizing a given disease or condition. AI-based models have been largely tested in the main retinopathies, including age-related macular degeneration, diabetic retinopathy and myopia. AI algorithms have been highly effective in screening for retinopathies. The same […]

Trending In Retina/Vitreous:

Foreword: touchREVIEWS in Ophthalmology, Volume 17, Issue 2, 2023
Imaging, Retina/Vitreous
    • Download PDF More Actions
    Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72