**Author details**

Shani Golan1,2, Michaella Goldstein1,2 and Anat Loewenstein1,2


### **References**


[5] Kinnunen K, Ylä-Herttuala S. Vascular endothelial growth factors in retinal and cho‐ roidal neovascular disease. Ann Med. 2012 Feb;44(1):1-17

[18] VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, Chakravarthy U, Adamis AP, Cunningham ET Jr, Goldbaum M, Guyer DR, Katz B, Patel M. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006

Anti VEGF Agents for Age Related Macular Degeneration

http://dx.doi.org/10.5772/54198

187

[19] N. Feucht, H. Matthias, C. P. Lohmann, and M. Maier "Pegaptanib sodium treatment in neovascular age-related macular degeneration: clinical experience in Germany,"

[20] Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T; ANCHOR Study Group. Ranibizumab versus verteporfin photodynamic therapy for neovascular agerelated macular degeneration: Two-year results of the ANCHOR study.Ophthalmol‐

[21] Regillo CD, Brown DM, Abraham P et al. Randomized, double-masked, sham con‐ trolledtrial of ranibizumab for neovascular age-relatedmacular degeneration: PIER

[22] U. Schmidt-Erfurth, B. Eldem, R. Guymer et al., "Efficacy and safety of monthly ver‐ sus quarterly ranibizumab treatment inneovascular age-related macular degenera‐

[23] Fung AE, Rosenfeld PJ, Reichel E. The international intravitreal bevacizumab safety survey: using the Internet to assess drug safety worldwide. Br J Ophthalmol 2007;

[24] Schmidt-Erfurth UM, Pruente C. Management of neovascularage-related macular de‐

[25] Mordenti J, Cuthbertson RA, Ferrara N et al . Comparisons of the intraocular tissue distribution, pharmacokinetics and safety of 1251-labeled full-length and Fab anti‐ bodies in rhesus monkeys following intravitreal administration. Toxicol Pathol 1999;

[26] Shahar J, Avery RL, Heilweil G et al. Electrophysiologic and retinal penetration stud‐ ies following intravitreal injection of bevacizumab (Avastin). Retina 2006; 26:262-9.

[27] 24. Rosenfeld PJ, Schwartz SD, Blumenkranz MS, et al. Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration. Ophthalmology 2005;112: 1048–53.

[28] 25. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography find‐ ings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-re‐

[29] 26. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363–72.

lated macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331–5.

tion. The EXCITE study," Ophthalmology, vol. 118, pp. 831–839, 2010.

Sep;113(9):1508.e1-25.

ogy. 2009 Jan;116(1):57-65.e5.

90:1344–1349.

27:536-44.

Clinical Ophthalmology, vol. 2, pp. 253–259, 2008.

study year 1. Am J Ophthalmol.2008;145:239 – 48.

generation. Prog Retin Eye Res. 2007;26:437 – 51.


[18] VEGF Inhibition Study in Ocular Neovascularization (V.I.S.I.O.N.) Clinical Trial Group, Chakravarthy U, Adamis AP, Cunningham ET Jr, Goldbaum M, Guyer DR, Katz B, Patel M. Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration. Ophthalmology. 2006 Sep;113(9):1508.e1-25.

[5] Kinnunen K, Ylä-Herttuala S. Vascular endothelial growth factors in retinal and cho‐

[6] Shima DT, Nishijima K, Jo N, Adamis AP. VEGF-mediated neuroprotectionin ische‐

[7] Terman BI, Dougher-Vermazen M, Carrion ME et al. Identification of the KDR tyro‐ sine kinase as a receptor for vascular endothelial growth factor. Biochem Biophys Res

[8] Ciulla TA, Rosenfeld PJ. Antivascular endothelial growth factor therapy for neovas‐ cular age-related macular degeneration. Curr Opin Ophthalmol. 2009 May;20(3):

[9] Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK,hung CY, et al. Ranibizumab for neovascular age-relatedacular degeneration. N Engl J Med. 2006;355:1419 – 31. [10] H. Yonekura, S. Sakurai, X. Liu et al., "Placenta growth factor and vascular endothe‐ lial growth factor B and C expression in microvascular endothelial cells and peri‐ cytes. Implication in autocrine and paracrine regulation of angiogenesis," Journal of

[11] H. Takahashi and M. Shibuya, "The vascular endothelial growth factor (VEGF)/ VEGF receptor system and its role under physiological and pathological conditions,"

[12] X. Yi, N. Ogata, M. Komada et al., "Vascular endothelial growth factor expression in choroidal neovascularization in rats," Graefe's Archive for Clinical and Experimental

[13] B. A. Keyt, L. T. Berleau, H. V. Nguyen et al., "The carboxylterminal domain (111– 165) of vascular endothelial growth factor is critical for its mitogenic potency," Jour‐

[14] S. Ishida, T. Usui, K. Yamashiro et al., "VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization,"

[15] A. Kvanta, P. V. Algvere, L. Berglin, and S. Seregard, "Subfoveal fibrovascular mem‐ branes in age-related macular degeneration express vascular endothelial growth fac‐ tor," Investigative Ophthalmology and Visual Science, vol. 37, no. 9, pp. 1929–1934,

[16] D 'A mico DJ. Pegaptanib sodium for neovascular age related macular degeneration: two-year safety results of the two prospective, multicenter, controlled clinical trials.

[17] Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR; VEGF Inhibi‐ tion Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovas‐ cular age-related macular degeneration. N Engl J Med. 2004 Dec 30;351(27):2805-16.

roidal neovascular disease. Ann Med. 2012 Feb;44(1):1-17

186 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

Biological Chemistry, vol. 274, no. 49, pp. 35172–35178, 1999.

nal of Biological Chemistry, vol. 271, no. 13, pp. 7788–7795, 1996.

Journal of Experimental Medicine, vol. 198, no. 3, pp. 483–489, 2003.

Clinical Science, vol. 109, no. 3, pp. 227–241, 2005.

Ophthalmology, vol. 235, no. 5, pp. 313–319, 1997.

Ophthalmology. 2006;113:992 – 1001.

mic retinal.Invest Ophthalmol Vis Sci. 2004;45:3270

Commun. 1992;187:1579-86.

158-65.

1996.


[30] 27. Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal eovascularization in age-related macular degeneration. Am J Ophthalmol 2006;142:1–9.

[41] O. P. Gupta, G. Shienbaum, A. H. Patel, C. Fecarotta, R. S. Kaiser, and C. D. Regillo, "A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration: clinical and economic impact," Ophthalmology, vol. 117, no. 11, pp.

Anti VEGF Agents for Age Related Macular Degeneration

http://dx.doi.org/10.5772/54198

189

[42] A. Tufail, P. J. Patel, C. Egan et al., "Bevacizumab for neovascular age related macu‐ lar degeneration (ABC Trial): multicenter randomised double masked study," British

[43] K. C. S. Fong, N. Kirkpatrick, Q. Mohamed, and R. L.Johnston, "Intravitreal bevaci‐ zumab (Avastin) for neovascular age-related macular degeneration using a variable frequency regimen in eyes with no previous treatment," Clinical and Experimental

[44] P. J. Mekjavic, A. Kraut, and M. Urbancic, "Efficacy of 12-month treatment of neovas‐ cular age-related macular degeneration with intravitreal bevacizumab based on indi‐ vidually determined injection strategies after three consecutive monthly injections,"

[45] S. T. Luu, T. Gray, S. K. Warrier et al., "Retrospective study of an as required dosing regimen of intravitreal bevacizumab in neovascular age-related macular degenera‐ tion in an Australian population," Clinical and Experimental Ophthalmology, vol.

[46] J. F. Arevalo, J. G. Snchez, L. Wu et al., "Intravitreal bevacizumab for subfoveal cho‐ roidal neovascularization in age related macular degeneration at twenty-four months: the panamerican collaborative retina study," Ophthalmology, vol. 117, no.

[47] Z. F. Bashshur, Z. A. Haddad, A. R. Schakal, R. F. Jaafar, A. Saad, and B. N. Noured‐ din, "Intravitreal bevacizumab for treatment of neovascular age-related macular de‐ generation: the second year of a prospective study," American Journal of

[48] "Treat-and-extend therapy a popular, cost-effective approach to treating neovascular

[49] D. F. Martin, M. G. Maguire, G. -S. Ying, J. E. Grunwald, S. L. Fine, and G. J. Jaffe, "Ranibizumab and bevacizumab for neovascular age-related macular degeneration,"

[50] P. J. Rosenfeld, "Bevacizumab versus ranibizumab—the verdict," New England Jour‐

[51] Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Re‐ search Group, Martin DF, Maguire MG, Fine SL, Ying GS, Jaffe GJ, Grunwald JE, Toth C, Redford M, Ferris FL 3rd. Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results. Ophthalmology.

New England Journal of Medicine, vol. 364, no. 20, pp. 1897–1908, 2011.

Medical Journal, vol. 340, no. 7761, Article ID c2459, p. 1398, 2010.

Ophthalmology, vol. 36, no. 8, pp. 748–755, 2008.

Ophthalmology, vol. 148, no. 1, pp. 59–65, 2009.

nal of Medicine, vol. 364, no. 20, pp. 1966–1967, 2011.

Acta Ophthalmologica, vol. 89, no. 7, pp. 647–653, 2009.

2134–2140, 2010.

38, no. 7, pp. 659–663, 2010.

10, pp. 1974–1981, 2010.

AMD," PCONSuperSite, 2011.

2012 Jul;119(7):1388-98.


[41] O. P. Gupta, G. Shienbaum, A. H. Patel, C. Fecarotta, R. S. Kaiser, and C. D. Regillo, "A treat and extend regimen using ranibizumab for neovascular age-related macular degeneration: clinical and economic impact," Ophthalmology, vol. 117, no. 11, pp. 2134–2140, 2010.

[30] 27. Bashshur ZF, Bazarbachi A, Schakal A, et al. Intravitreal bevacizumab for the management of choroidal eovascularization in age-related macular degeneration.

188 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

[31] Q. D. Nguyen, J. Heier, D. Brown et al., "Randomized, doublemasked, active-control‐ led phase 3 trial of the efficacy and safety of intravitreal VEGF-Trap-Eye in wet AMD: one-year results of the VIEW-1 study," in Proceedings of the Association for Research in Vision and Ophthalmology, no. 3073, Fort Lauderdale, Fla, USA, 2011.

[32] U. Schmidt-Erfurth, V. Chong, B. Kirchhof et al., "Primary results of an international phase III study using intravitreal VEGF Trap-Eye compared to ranibizumab in pa‐ tients with wet AMD (VIEW2)," in Proceedings of the Association for Research in Vi‐

[33] Brown DM, Heier JS, Ciulla T, Benz M, Abraham P, Yancopoulos G, Stahl N, Inger‐ man A, Vitti R, Berliner AJ, Yang K, Nguyen QD; CLEAR-IT 2 Investigators. Primary endpoint results of a phase II study of vascular endothelial growth factor trap-eye in

wet age-related macular degeneration. Ophthalmology. 2011 ;118(6):1089-97.

[34] G. A. Lalwani, P. J. Rosenfeld, A. E. Fung et al., "A variable dosing regimen with in‐ travitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO study," American Journal of Ophthalmology, vol. 148, no. 1, pp.1–3,

[35] F. G. Holz,W. Amoaku, J. Donate et al., "Safety and efficacy of a flexible dosing regi‐ men of ranibizumab in neovascular agerelated macular degeneration: the SUSTAIN

[36] Boyer DS, Heier JS, Brown DM, Francom SF, Ianchulev T, Rubio RG. A Phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related

[37] Singer MA, Awh CC, Sadda S, Freeman WR, Antoszyk AN, Wong P, Tuomi L.HORI‐ ZON: An Open-Label Extension Trial of Ranibizumab for Choroidal Neovasculariza‐ tion Secondary to Age-Related Macular Degeneration. Ophthalmology. 2012 ;119(6):

[38] Tano Y, Ohji M . ; EXTEND-I Study Group. Long-term efficacy and safety of ranibi‐ zumab administered pro re nata in Japanese patients with neovascular age-related macular degeneration in the EXTEND-I study. Acta Ophthalmol. 2011 ;89(3):208-17

[39] M. Engelbert, S. A. Zweifel, and K. B. Freund, ""treat and extend" dosing of intravi‐ treal antivascular endothelial growth factor therapy for type 3 neovascularization/

retinal angiomatous proliferation," Retina, vol. 29, no. 10, pp. 1424–1431, 2009.

ed macular degeneration," Retina, vol. 31, no. 1, pp. 26–30, 2010.

[40] H.Oubraham, S. Y. Cohen, S. Samimi et al., "Inject and extend dosing versus dosing as needed: a comparative retrospective study of ranibizumab in exudative age-relat‐

study," Ophthalmology, vol. 118, no. 4, pp. 663–671, 2011.

macular degeneration. Ophthalmology. 2009 Sep;116(9):1731-9.

sion and Ophthalmology, no. 1650, Fort Lauderdale, Fla, USA, 2011.

Am J Ophthalmol 2006;142:1–9.

2009.

1175-83.


[52] The IVAN Study Investigators(□) Writing Committee:, Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Wordsworth S, Reeves BC Ranibizumabversus‐ Bevacizumab to TreatNeovascularAge-related Macular Degeneration: One-Year Findings from the IVAN Randomized Trial.Ophthalmology. 2012 May 10. [Epub ahead of print]

[64] Rodrigues EB, Grumann A, Jr., Penha FM, et al. Effect of needle type and injection technique on pain level and vitreal reflux in intravitreal injection. Journal of Ocular

Anti VEGF Agents for Age Related Macular Degeneration

http://dx.doi.org/10.5772/54198

191

[65] Ta CN. Minimizing the risk of endophthalmitis following intravitreous injections.

[66] Lauer G, Sollberg S, Cole M, et al. Expression and proteolysis of vascular endothelial growth factor is increased in chronic wounds. J Invest Dermatol 2000;115:12– 8.

[67] Carmeliet P, Ng YS, Nuyens D, et al. Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms

[68] Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 up‐ date: a report from the American Heart Association Statistics Committee and Stroke

[69] S. Barik, "Development of gene-specific double-stranded RNA drugs," Annals of

[70] M. J. Tolentino, A. J. Brucker, J. Fosnot et al., "Intravitreal injection of vascular endo‐ thelial growth factor small interfering RNA inhibits growth and leakage in a nonhu‐ man primate, laser-induced model of choroidal neovascularization," Retina, vol. 24,

[71] M. J. Tolentino, A. J. Brucker, J. Y. Fosnot et al., "Intravitreal injection of vascular en‐ dothelial growth factor small interfering RNA inhibits growth and leakage in the nonhuman primate, laser-induced model of choroidal neovascularization," Retina,

[72] A. O. Garba and S. A. Mousa, "Bevasiranib for the treatment of wet age-related mac‐ ular degeneration," Journal of Ophthalmology and Eye Diseases, vol. 2, pp. 75–83,

[73] J. Perkel, "RNAi therapeutics: a two-year update," Science, vol. 326, pp. 454–456,

[74] Kaiser PK: Antivascular endothelial growth factor agents and their development: therapeutic implications in ocular diseases. Am J Ophthalmol 2006;142:660–668.

[75] Safety and Efficacy of Oral PTK787 in Patients with Subfoveal Choroidal Neovascu‐ larization Secondary to Age-Related Macular Degeneration (AMD) (ADVANCE). http://www.clinicaltrials.gov/ct2/show/NCT00138632?order=1 (accessed October 02,

[76] Sonpavde G, Hutson TE, Sternberg CN: Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Ex‐

Pharmacology and Therapeutics. 2011;27:197–203.

VEGF164 and VEGF188. Nat Med 1999;5:495–502.

Medicine, vol. 36, no. 7, pp. 540–551, 2004.

pert Opin Investig Drugs 2008;17:253–261.

Statistics Subcommittee. Circulation 2007;115:e69 –171.

Retina 2004;24:699 –705.

no. 1, pp. 132–138, 2004.

vol. 24, no. 4, p. 660, 2004.

2010.

2009.

2012).


[64] Rodrigues EB, Grumann A, Jr., Penha FM, et al. Effect of needle type and injection technique on pain level and vitreal reflux in intravitreal injection. Journal of Ocular Pharmacology and Therapeutics. 2011;27:197–203.

[52] The IVAN Study Investigators(□) Writing Committee:, Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Wordsworth S, Reeves BC Ranibizumabversus‐ Bevacizumab to TreatNeovascularAge-related Macular Degeneration: One-Year Findings from the IVAN Randomized Trial.Ophthalmology. 2012 May 10. [Epub

[54] EQUAL studyhttp://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1331

[56] J. S. Slakter, "What to do when anti-VEGF therapy fails," Retinal Physician, 2010.

[57] A. Y. Lee, A. K. Raya, S. M. Kymes, A. Shiels, andM. A. Brantley, "Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular de‐ generation with ranibizumab," British Journal of Ophthalmology, vol. 93, no. 5, pp.

[58] M. A. Brantley, A. M. Fang, J. M. King, A. Tewari, S. M. Kymes, and A. Shiels, "Asso‐ ciation of complement factor H and LOC387715 genotypes with response of exuda‐ tive age related macular degeneration to intravitreal bevacizumab,"Ophthalmology,

[59] Larsen M, Schmidt-Erfurth U, Lanzetta P, Wolf S, Simader C, Tokaji E, Pilz S, Weis‐ berger A; MONT BLANC Study Group. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month MONT

[60] Kaiser PK, Boyer DS, Cruess AF, Slakter JS, Pilz S, Weisberger A; DENALI Study Group. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study. Ophthalmology.

[61] Piermarocchi S, Sartore M, Lo Giudice G, Maritan V, Midena E, and Segato T. Combi‐ nation of photodynamic therapy and intraocular triamcinolone for exudative age-re‐ lated macular degeneration and long-term chorioretinal macular atrophy. Archives

[62] Iwama D, Otani A, Sasahara M, Yodoi Y, Gotoh N, Tamura H, Tsujikawa A, and Yoshimura N. Photodynamic therapy combined with low-dose intravitreal triamci‐ nolone acetonide for age-related macular degeneration refractory to photodynamic

[63] Blaha GR, Wertz IFD, and Marx JL. Profound choroidal hypoperfusion after com‐ bined photodynamic therapy and intravitreal triamcinolone acetonide. Ophthalmic

therapy alone. British Journal of Ophthalmology 2008;92(10): 1352–1356.

BLANC study results. Ophthalmology. 2012 May;119(5):992-1000

ahead of print]

610–613, 2009.

[53] VIBERA Study. www.clinicaltrials.gov. NCT00559715.

190 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

[55] Manta Study. www.clinicaltrials.gov. NCT00710229.

vol. 114, no. 12, pp. 2168–2173, 2007.

of Ophthalmology 2008;126(10): 1367–1374.

Surgery Lasers and Imaging 2008;39(1): 6–11.

2012 May;119(5):1001-10


[77] A Study to Evaluate the Pharmacodynamics, Safety, and Pharmacokinetics of Pazo‐ panib Drops in Adult Subjects with Neovascular AMD. http://www.clinicaltri‐

[78] Wigginton JM, Gruys E, Geiselhart L, Subleski J, Komschlies KL, Park JW, Wiltrout TA, Nagashima K, Back TC, Wiltrout RH: IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy. J Clin Invest

[79] Mochimaru H, Nagai N, Hasegawa G, Kudo-Saito C, Yaguchi T, Usui Y, et al: Sup‐ pression of choroidal neovascularization by dendritic cell vaccination targeting

[80] Anti-VEGFR Vaccine Therapy in Treating Patients with Neovascular Maculopathy. http://www.clinicaltrials.gov/ct2/show/NCT00791570?order=1 (accessed October 02,

[81] Nozaki M, Raisler BJ, Sakuri E, Baffi JZ, Ambati BK, Ambati J: Drusen complement

[82] AMD Patients Treated with POT-4 Demonstrate No Adverse Toxic Effects during Phase I Clinical Trial. http://www.medicalnewstoday.com/articles/128837.php (ac‐

[83] ARC1905 (ANTI-C5 APTAMER) Given either in Combination Therapy with Lucen‐ tis® 0.5 mg/Eye in Subjects with Neovascular Age-Related Macular Degeneration. http://www.clinicaltrials.gov/ct2/show/ NCT00709527?order=1 (accessed October 02,

[84] Treating Wet Form of AMD – Othera Eye Drop Data Shows Synergistic Effect with Lucentis and Avastin. http://www.medicalnewstoday.com/articles/63892.php (ac‐

[85] OT-551 Antioxidant Eye Drops to Treat Geographic Atrophy in Age-Related Macular Degeneration. http://clinicaltrials.gov/ct2/show/NCT00306488 (accessed October 02,

[86] Mori K, Gehlbach P, Ando A, McVey D, Wei L, Campochiaro PA: Regression of ocu‐ lar neovascularization in response to increased expression of pigment epithelium-de‐

[87] Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN, et al: Adeno‐ viral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther 2006;17:167–

rived factor. Invest Ophthalmol Vis Sci 2002;43:2428–2434.\

als.gov/ct2/show/ NCT00612456?order=1 (accessed October 02, 2012).

192 Age-Related Macular Degeneration - Etiology, Diagnosis and Management - A Glance at the Future

VEGFR2. Invest Ophthalmol Vis Sci 2007;48:4795–4801.

components C3. Proc Natl Acad Sci USA 2006;103:2328–2333.

2001;108:51–62.

cessed October 02, 2012).

cessed October 02, 2012).

2012).

2012).

2012).

176
