<p>&lt;p&gt;&amp;lt;p&amp;gt;State-of-the-Science: Treatment of Neovascular Age-Related Macular Degeneration (AMD) Ivan J. SuIvan J. Suer, er, MDMD Associate Professor of OphthalmologyAssociate Professor of Ophthalmology Duke UniversityDuke University Medical Center (Duke Eye Center)Medical Center (Duke Eye Center) Chief of Ophthalmology ServiceChief of Ophthalmology Service Durham Veteran Affairs Medical CenterDurham Veteran Affairs Medical Center Durham, NCDurham, NC Presentation Outline lOverview of age-related macular degeneration (AMD) lCurrent therapies in the treatment of neovascular AMD Thermal laser photocoagulation Ocular photodynamic therapy nVerteporfin Vascular endothelial growth factor (VEGF) inhibitors nFDA approved Pegaptanib Ranibizumab nOff label Bevacizumab lSummary Overview of Age-Related Macular Degeneration (AMD) Definition lLate onset (age &amp;amp;gt; 50 years) lSome degree of vision loss lLipid deposits (drusen) under retina Epidemiology l15 million affected in the United States lLeading cause of vision loss age &amp;amp;gt; 50 years lDistribution (age) 5564: 17% 6574: 26% &amp;amp;gt;75: 42% Congdon N, et al. Arch Ophthalmol. 2004;122:477. Projected Prevalence of Advanced AMD* in the United States 0 1 2 3 20002020 Number of CasesNumber of Cases (millions)(millions) YearYear *Defined as neovascular AMD and/or geographic atrophy in at least 1 eye. Prevalence figures were calculated using 2000 US census data. Friedman DS, et al. Arch Ophthalmol. 2004;122:564. 1.75 2.95 Photoreceptors Choroid RPE Genentech, Inc. Data on file. Normal Retina Fovea Macula Normal retina Bruchs membrane thickens and drusen develop Photoreceptors Choroid RPE Fovea Macula Genentech, Inc. Data on file. Progression of AMD Development of Drusen New abnormal blood vessels proliferate and penetrate Bruchs membrane New blood vessels leak blood and fluid Progression of AMD Formation and Leakage from Choroidal Neovascularization (CNV) Genentech, Inc. Data on file. Advanced Wet AMD Fibrovascular Scar Genentech, Inc. Data on file. Current Therapies in the Treatment of Neovascular AMD l l Thermal effects of laser Thermal effects of laser destroys destroys CNVCNV, low , low recurrence raterecurrence rate l l Causes damage to Causes damage to surrounding healthy tissuesurrounding healthy tissue l l Not for use on Not for use on CNV CNV located located beneath fovea (beneath fovea (subfovealsubfoveal) ) Immediate, permanent Immediate, permanent decrease in central decrease in central visionvision Laser beam Laser beam aimed at CNVaimed at CNV Immediate damage to Immediate damage to RPE and photoreceptors RPE and photoreceptors overlying CNVoverlying CNV Thermal Laser Photocoagulation CNV = choroidal neovascularization RPE = retinal pigment epithelium Genentech, Inc. Data on file. Verteporfin lIntravenously administered photosensitizing drug lAttaches to the inner surface of abnormal proliferating blood vessels lActivated by nonthermal laser light at 689 nm lGenerates highly reactive, short-lived oxygen radicals, which damage vessel walls lMinimal effects on the surrounding tissue structures Forms of Subfoveal Neovascular AMD Minimally classicOccult with no classicPredominantly classic 18%24%6%19%60%75% Olsen T, et al. Ophthalmology. 2004;111:250. Zawinka C, et al. Retina. 2005;25:324. Margherio RR, et al. Retina. 2000;20:325. Ng E, Adamis AP. Can J Ophthalmol. 2005;40:352. 67% 56% 49% 39% 55% 45% 0 10 20 30 40 50 60 70 80 90 100 Predominantly Classic 12-Month Results of PDT Trials TAP-VIP Study Populations % Patients Losing &amp;amp;lt;15 Letters PDT = photodynamic therapy. TAP Study Group. Arch Ophthalmol. 1999;117:1329. VIP Study Group. Am J Ophthalmol. 2001;131:541. *Azab M, et al. Arch Ophthalmol. 2005. Minimally ClassicOccult No Classic PDT Placebo lPDT benefit has been demonstrated for small lesions (&amp;amp;lt;4 disc areas) of all compositions* Endothelial cell activation, proliferation, migration4 VEGF-A Is a Key Mediator of Angiogenesis ANGIOGENESIS3 VASCULAR LEAKAGE3 Environmental factors1 (hypoxia,2 pH) Growth factors, hormones1 (EGF, bFGF, PDGF, IGF-1, IL-1?, IL-6, estrogen) VEGF-A binding and activation of VEGF receptor3 Endothelial cell activation3 VEGF-A = vascular endothelial growth factor A; EGF = epidermal growth factor; bFGF = basic fibroblast growth factor; PDGF = platelet-derived growth factor; lGF = insulin-like growth factor; IL= interleukin. 1. Dvorak HF. J Clin Oncol. 2002;20:4368. 2. Aiello LP, et al. Arch Ophthalmol. 1995;113:1538. 3. Ferrara N, et al. Nat Med. 2003;9:669. 4. Griffioen AW and Molema G. Pharmacol Rev. 2000;52:237. Multiple Isoforms of VEGF-A Are Generated from Exon Splicing Adapted from Ferrara N, et al. Nat Med. 2003;9:669. Highly diffusible isoform 1121VEGF-A121 1206 Highest molecular weight isoform bound to extracellular matrix VEGFR-binding domain Heparin-binding domain VEGF-A206 Sequestered in the extracellular matrix 1 189 VEGF-A189 165 1 Most abundant isoform expressed in humans VEGF-A1&amp;lt;/p&amp;gt;&lt;/p&gt;</p>