As researchers and clinicians are beginning to understand that wet age-related macular degeneration (AMD) is more than simply a vascular disease that includes angiogenic, vascular and inflammatory components, they are exploring new agents with different mechanisms of action addressing multiple targets in this complex pathophysiology. Some of them are already available in human trials or even approved vascular epithelial growth factor (VEGF) blockers such as Macugen, Lucentis, Avastin, VEGF Trap-Eye and Cand5; VEGF receptor blockers such as TG100801, vatalanib, pazopanib, Sirna-027 and a vaccine approach; inflammation inhibitors and immunosuppressants such as Retaane, Kenalog, ARC1905, POT-4, OT-551. The last group is mixed, containing agents such as Zybrestat, AdPEGF, Sirolimus, JSM6427, ATG003, E10030. This article reviews these currently emerging agents and briefly discusses the next step for the treatment of wet AMD.

Keywords:
Age-related macular degeneration, Vascular epithelial growth factor, Choroidal neovascularization, Antiangiogenesis, Anti-inflammatory, Target therapy
1.
Klein R, Wang Q, Klein BE, Moss SE, Meuer SM: The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995;36:182–191.
2.
Harvey PT: Common eye diseases of elderly people: identifying and treating causes of vision loss. Gerontology 2003;49:1–11.
3.
Grossniklaus HE, Martinez JA, Brown VB, Lambert HM, Sternberg P, Capone A, et al: Immunohistochemical and histochemical properties of surgically excised subretinal neovascular membranes in age-related macular degeneration. Am J Ophthalmol 1992;114:464–472.
4.
Ferrara N: Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581–611.
5.
Holmes DI, Zachary L: The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol 2005;6:209.
6.
Rakic JM, Lambert V, Devy L, Luttun A, Carmeliet P, Claes C, 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.
7.
Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR: Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–2816.
8.
Eyetech Study Group: Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration. Retina 2002;22:143–152.
9.
FDA, FDA Approves New Drug Treatment for Age-Related Macular Degeneration. http://www.fda.gov/bbs/topics/news/2004/new01146.html (accessed December 20, 2004).
10.
Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al: Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431.
11.
FDA, FDA Approves New Biologic Treatment for Wet Age-Related Macular Degeneration. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01405.html (accessed June 30, 2006).
12.
Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al: Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444.
13.
Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, Shams N: Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008;145:239–248.
14.
Antoszyk AN, Tuomi L, Chung CY, Singh A, and FOCUS Study Group: Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results. Am J Ophthalmol 2008;145:862–874.
15.
Roberts D: SAILOR Study Results Favorable: Los Angeles: Bascom Palmer Eye Institute’s Angiogenesis Meeting, 2008. http://www.mdsupport.org/library/sailor.html (accessed February 23, 2008).
16.
Singh RP: Highlights of the 26th Annual Meeting of the American Society of Retinal Specialists. http://www.medscape.com/viewarticle/582820 (accessed November 6, 2008).
17.
Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS: Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112:1035–1047.
18.
FDA, FDA Approves First Angiogenesis Inhibitor to Treat Colorectal Cancer. http://www.fda.gov/bbs/topics/NEWS/2004/NEW01027.html (accessed February 26, 2004).
19.
Bashshur ZF, Bazarbaachi A, Schakal A, Hassad ZA, El Haibi CP, Noureddin BN: Intravitreal bevacizumab for the management of choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006;142:1–9.
20.
Ehrlich R, Weinberger D: Outcome of bevacizumab (Avastin) injection in patients with age-related macular degeneration and low visual acuity. Retina 2008;28:1302–1307.
21.
Wolf A, Kook D, Strauss R, Kampik A, Haritoglou C: How to treat recurrences after Avastin treatment for neovascular AMD: stick to Avastin or switch to Lucentis? Br J Ophthalmol 2008;92:1297–1298.
22.
MAAM Study: Avastin and Macugen versus Avastin versus Macugen. http://www.clinicaltrials.gov/ct2/show/NCT00531336?order=1 (accessed September 15, 2007).
23.
Comparison of Age-Related Macular Degeneration Treatment Trials: Lucentis-Avastin Trial. http://clinicaltrials.gov/ct2/show/NCT00593450?order=1 (accessed January 3, 2008).
24.
Wulff C, Wilson H, Wiegand SJ, Rudge JS, Fraser HM: Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2. Endocrinology 2002;143:2797–2807.
25.
Nguyen QD, Shah SM, Hafiz G, Quinlan E, Sung J, Chu K, Cedarbaum JM, Campochiaro PA: A phase I trial of an IV-administered vascular endothelial growth factor trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2006;113:1521–1522.
26.
Bayer Health Care and Regeneron Announce VEGF Trap-Eye Achieved Durable Improvement in Vision over 52 Weeks in a Phase 2. http://www.medicalnewstoday.com/articles/119267.php (accessed August 26, 2008).
27.
Double-Masked Study of Efficacy and Safety of IVT VEGF Trap-Eye in Subjects with Wet AMD (VIEW 1). http://www.clinicaltrials.gov/ct2/show/NCT00509795?order=1 (accessed July 31, 2007).
28.
Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration (AMD) (VIEW 2). http://clinicaltrials.gov/ct2/show/NCT00637377?order=1 (accessed March 12, 2008).
29.
Acuity Pharmaceuticals Reports Positive Initial Phase II Results for Bevasiranib (Cand5) in Wet AMD. http://www.medicalnewstoday.com/articles/44387.php (accessed June 2, 2006).
30.
Michels S, Schmidt-Erfurth U, Rosenfeld PJ: Promising new treatments for neovascular age-related macular degeneration. Expert Opin Investig Drugs 2006;15:779–793.
31.
OPKO’s SiRNA Drug for AMD Shows Promise. Accessed January 2008 at: http://www.retinalphysician.com/article.aspx?article=101325
32.
Safety and Efficacy Study Evaluating the Combination of Bevasiranib and Lucentis Therapy in Wet AMD (CARBON). http://www.clinicaltrials.gov/ct2/show/NCT00499590?order=1 (accessed July 10, 2007).
33.
Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 2003;9:669–676.
34.
Zeng H, Dvorak HF, Muchopadhyay D: Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGFR-1) modulates mitogenic activity of VEGFR-2 in endothelial cells. J Biol Chem 2000;159:993–10008.
35.
Hellström M, Gerhardt H, Kalén K, Li X, Eriksson U, Wolburg H, et al: Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 2001;153:543–553.
36.
Benjamin LE, Hemo I, Keshet E: A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998;125:1591–1598.
37.
Jo N, Maihos C, Ju M: Inhibition of platelet-derived growth factor B signalling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 2006;168:2036–2053.
38.
Doukas J, Mahesh S, Umeda N, Kachi S, Akiyama H, Yokoi K, et al: Topical administration of multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol 2008;216:29–37.
39.
Roberts D: Antiangiogenic drugs are stopping neovascularization in wet macular degeneration. http://www.mdsupport.org/library/anti-angio.html (accessed January 2008).
40.
Open-Label, Pilot Study of TG100801 in Patients with Choroidal Neovascularization due to AMD. http://www.clinicaltrials.gov/ct2/show/NCT00509548?order=1 (accessed July 27, 2007).
41.
Kaiser PK: Antivascular endothelial growth factor agents and their development: therapeutic implications in ocular diseases. Am J Ophthalmol 2006;142:660–668.
42.
Safety and Efficacy of Oral PTK787 in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (AMD) (ADVANCE). http://www.clinicaltrials.gov/ct2/show/NCT00138632?order=1 (accessed August 29, 2005).
43.
Sonpavde G, Hutson TE, Sternberg CN: Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Investig Drugs 2008;17:253–261.
44.
A Study to Evaluate the Pharmacodynamics, Safety, and Pharmacokinetics of Pazopanib Drops in Adult Subjects with Neovascular AMD. http://www.clinicaltrials.gov/ct2/show/NCT00612456?order=1 (accessed January 29, 2008).
45.
Shen J, Sarmul R, Silva RL, Akiyama H, Liu H, Saishin Y, et al: Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther 2006;13:225–234.
46.
Sirna Therapeutics Reports Final Results from Phase 1 Study on Its RNAi-Based Therapeutic for Age-Related Macular Degeneration. http://www.medicalnewstoday.com/articles/49334.php (accessed August 11, 2006).
47.
A Study Using Intravitreal Injections of a Small Interfering RNA in Patients with Age-Related Macular Degeneration. http://www.clinicaltrials.gov/ct/show/NCT00395057?order=1 (accessed October 31, 2006).
48.
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 2001;108:51–62.
49.
Mochimaru H, Nagai N, Hasegawa G, Kudo-Saito C, Yaguchi T, Usui Y, et al: Suppression of choroidal neovascularization by dendritic cell vaccination targeting VEGFR2. Invest Ophthalmol Vis Sci 2007;48:4795–4801.
50.
Anti-VEGFR Vaccine Therapy in Treating Patients with Neovascular Maculopathy. http://www.clinicaltrials.gov/ct2/show/NCT00791570?order=1 (accessed October 31, 2008).
51.
Bok D: Evidence for an inflammatory process in age-related macular degeneration gains new support. Proc Natl Acad Sci USA 2005;102:7053–7054.
52.
Grossniklaus HE, Ling JX, Wallace TM, Dithmar S, Lawson DH, Cohen C, et al: Macrophage and retinal pigment epithelium expression of angiogenic cytokines in choroidal neovascularization. Mol Vis 2002;8:119–126.
53.
Van der Schaft TL, Mooy CM, Bruijn WC, Jong PT: Early stages of age-related macular degeneration: an immunofluorescence and electron microscopic study. Br J Ophthalmol 1993;81:38–47.
54.
Yang R, McColm JR, Bingaman DP, Penn JS: The effect of anecortave acetate on VEGF message and protein levels in hypoxic Muller cells and in rat OIR. Invest Ophthalmol Vis Sci 2005;46:E-abstr 4177.
55.
Liu C, Gu X, Wang W, Bingaman DO, Bingaman H: Local delivery of anecortave acetate inhibits the expression of retinal IGF-1/IGF-1 receptor in the rat OIR model. Invest Ophthalmol Vis Sci 2005;46:E-abstr 4135.
56.
Clinical Policy Bulletin: Anecortave acetate (Retaane). http://www.aetna.com/cpb/medical/data/700_799/0706.html (accessed November 2007).
57.
Slakter JS, Bochow T, D’Amico DJ, Marks B, Jerdan J, Sullivan EK, et al: Anecortave acetate (15 milligrams) versus photodynamic therapy for treatment of subfoveal neovascularization in age-related macular degeneration. Ophthalmology 2006;113:3–13.
58.
Gillies MC, Simpson JM, Luo W, Penfold P, Hunyor AB, Chua W, et al: A randomized clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration: one-year results. Arch Ophthalmol 2003;121:667–673.
59.
Uckermann O, Kutzera F, Wolf A, Pannicke T, Reichenbach A, Wiedemann P, et al: The glucocorticoid triamcinolone acetonide inhibits osmotic swelling of retinal glial cells via stimulation of endogenous adenosine signaling. J Pharmacol Exp Ther 2005;315:1036–1045.
60.
Nozaki M, Raisler BJ, Sakuri E, Baffi JZ, Ambati BK, Ambati J: Drusen complement components C3. Proc Natl Acad Sci USA 2006;103:2328–2333.
61.
AMD Patients Treated with POT-4 Demonstrate No Adverse Toxic Effects during Phase I Clinical Trial. http://www.medicalnewstoday.com/articles/128837.php (accessed November 11, 2008).
62.
ARC1905 (ANTI-C5 APTAMER) Given either in Combination Therapy with Lucentis® 0.5 mg/Eye in Subjects with Neovascular Age-Related Macular Degeneration. http://www.clinicaltrials.gov/ct2/show/NCT00709527?order=1 (accessed July 1, 2008).
63.
Treating Wet Form of AMD – Othera Eye Drop Data Shows Synergistic Effect with Lucentis and Avastin. http://www.medicalnewstoday.com/articles/63892.php (accessed February 26, 2007).
64.
Christman JW, Lancaster LH, Blackwell TS: Nuclear factor kappa B: a pivotal role in the systemic inflammatory response syndrome and new target for therapy. Intensive Care Med 1998;24:1131–1138.
65.
OT-551 Antioxidant Eye Drops to Treat Geographic Atrophy in Age-Related Macular Degeneration. http://www.clinicaltrials.gov/ct2/show/NCT00306488?order=1 (accessed March 22, 2006).
66.
The OMEGA Study: Use of Eye Drops to Treat Geographic Atrophy Associated with Age-Related Macular Degeneration (Dry AMD). http://www.clinicaltrials.gov/ct2/show/NCT00485394?order=1 (accessed June 11, 2007).
67.
Pettit GR, Singh SB, Hamel E, Lin CM, Alerts DS, Garcia Kendall D: Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4. Experientia 1989;45:209–211.
68.
Tozer GM, Prise VE, Wilson J: Mechanisms associated with tumor vascular shut-down induced by combretastatin A-4 phosphate: intravital microscopy and measurement of vascular permeability. Cancer Res 2001;61:6413–6422.
69.
Griggs DJ, Skepper JN, Smith GA, Brindle KM, Metcalfe JC, Hesketh R: Inhibition of proliferative retinopathy by the anti-vascular agent combretastatin-A4. Am J Pathol 2002;160:1097–1103.
70.
OXiGENE-Newsrelease. OXiGENE Announces Interim Results of Wet Age-Related Macular Degeneration Trial of Combretastatin A4 Prodrug. http://www.oxigene.com/press/pressreleases.asp (accessed May 18, 2004).
71.
OXiGENE-Newsrelease. OXiGENE Announces Positive Results from its Phase II CA4P Clinical Trial in Myopic Macular Degeneration (MMD-213). http://www.oxigene.com/press/pressreleases.asp (accessed February 15, 2007).
72.
Duh EJ, Yang HS, Suzuma I, Miyagi M, Youngman E, Mori K, et al: Pigment epithelium-derived factor suppresses ischemia-induced retinal neovascularization and VEGF-induced migration and growth. Invest Ophthalmol Vis Sci 2002;43:821–829.
73.
Mori K, Gehlbach P, Ando A, McVey D, Wei L, Campochiaro PA: Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 2002;43:2428–2434.
74.
Campochiaro PA, Nguyen QD, Shah SM, Klein ML, Holz E, Frank RN, et al: Adenoviral vector-delivered pigment epithelium-derived factor for neovascular age-related macular degeneration: results of a phase I clinical trial. Hum Gene Ther 2006;17:167–176.
75.
Rasmussen H, Chu KW, Campochairo P, Gehlbach PL, Haller JA, Handa JT, et al: An open-label, phase I, single administration, dose-escalation study of ADGVPEDF.11D (ADPEDF) in neovascular age-related macular degeneration (AMD). Hum Gene Ther 2001;12:2029–2032.
76.
Maier AK, Kociok N, Zahn G, Vossmeyer D, Stragies R, Muether PS, Joussen AM: Modulation of hypoxia-induced neovascularization by JSM6427, an integrin α5β 1 inhibiting molecule. Curr Eye Res 2007;32:801–812.
77.
Ramakrishnan B, Bhaskar V, Law DA, Wong MH, DuBridge RB, Breinberg D, et al: Preclinical evaluation of an anti-alpha5beta1 integrin antibody as a novel anti-angiogenic agent. J Exp Ther Oncol 2006;5:273–286.
78.
A Phase 1 Safety Study of Single and Repeated Doses of JSM6427 (Intravitreal Injection) to Treat AMD. http://clinicaltrials.gov/ct2/show/NCT00536016?order=1 (accessed September 25, 2007).
79.
Athenagen’s Eye Drop Therapy for AMD Is Safe and Well Tolerated in Phase I Study. http://www.charterls.com/news-013107.html (accessed January 31, 2007).
80.
Athenagen’s Eye Drop Therapy for AMD is Safe and Well Tolerated in Phase I Study. http://www.charterls.com/news-013107.html (accessed January 31, 2007).
81.
Safety and Efficacy of ATG003 in Patients with Wet Age-Related Macular Degeneration (AMD). http://www.clinicaltrials.gov/ct2/show/NCT00414206?order=1 (accessed December 19, 2006).
82.
Safety and Efficacy of ATG003 in Patients with AMD Receiving Anti-VEGF. http://www.clinicaltrials.gov/ct2/show/NCT00607750?order=1 (accessed January 23, 2008).
83.
Guba M, Breitenbuch PV, Geissler E, Koehl G, Steinbauer M, Jauch K: Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002;8:128–135.
84.
Dejneka NS, Kuroki AM, Fosnot J, Tang W, Tolentino MJ, Bennett J: Systemic rapamycin inhibits retinal and choroidal neovascularization in mice. Mol Vis 2004;10:964–972.
85.
MacuSight™ Announces Positive Preliminary Results from Phase 1 Study of Sirolimus in Wet Age-Related Macular Degeneration. http://www.medicalnewstoday.com/articles/98491.php (accessed February 26, 2008).
86.
Phase 2 Study of an Ocular Sirolimus (Rapamycin) Formulation in Combination with Lucentis® in Patients with Age-Related Macular Degeneration (EMERALD). http://www.clinicaltrials.gov/ct2/show/NCT00766337?order=1 (accessed October 1, 2008).
87.
Roberts D: New Anti-PDGF Aptamer Now in Trials. http://www.mdsupport.org/library/E10030.html (accessed February 15, 2008).
88.
Glossary of Clinical Trials Terms. http://clinicaltrials.gov/ct2/info/glossary (accessed March 18, 2008).
89.
Garcia C, Bartsch DU, Rivero ME, Hagedorn M, McDermott CD, Bergeron-Lynn G, et al: Efficacy of Prinomastat (AG3340), a matrix metalloprotease inhibitor, in treatment of retinal neovascularization. Curr Eye Res 2002;24:33–38.
90.
Pharmacological Therapy for Macular Degeneration Study Group: Interferon alfa-2a is ineffective for patients with choroidal neovascularization secondary to age-related macular degeneration: results of a prospective randomized placebo-controlled clinical trial. Arch Ophthalmol 1997;115:865–872.
91.
Maguire MG, Fine SL, Maguire AM, D’Amato RJ, Singerman LJ: Results of the age-related macular degeneration and thalidomide study (AMDATS). Invest Ophthalmol Vis Sci 2001;42:1233–1255.
92.
Genaera Press Room: Genaera Corporation Terminates Evizon Clinical Program and Restructures. http://www.genaera.com/press_room.php?page=133 (accessed January 3, 2007).
93.
Endostatins Inhibiting Neovascularization to Aid Age-Related Macular Degeneration Treatment. http://www.medinewsdirect.com/?p=362 (accessed December 11, 2007).
94.
Age-Related Macular Degeneration – Preclinical Efficacy Data with Retinostat(R). http://www.medicalnewstoday.com/articles/23896.php (accessed May 5, 2005).
95.
Augustin AJ, Puls S, Offermann I: Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina 2007;27:133–140.
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