Augustin treatment for choroidal neovascularization (CNV). Although effective in ablating CNV and attenuating vision loss over time, laser photocoagulation may be cytodestructive to retinal neurons and can result in an immediate and permanent loss of vision in the treated area, a trade-off unacceptable to many patients considering the procedure. Verteporfin PDT (Visudyne) was approved in 2000 following the demonstration that the procedure was effective in attenuating the rate of vision loss in AMD patients with classic containing lesions. The necessity of retreatments led to the investigation of combination strategies in multiple case series and different lesion types. Those combination approaches are now used by many clinicians on a routine basis (Augustin and Schmidt-Erfurth 2006). During the approval process, various pharmacological agents found to be effective in retarding vessel growth in animal models of ocular neovascularization were subsequently evaluated in AMD patients for inhibiting CNV growth and preservation of vision. In December, 2004, Macugen, an aptamer inhibiting vascular endothelial growth factor (VEGF) became the first pharmacological agent to be approved for treatment of CNV in all lesion subtypes in patients with exudative AMD. At one year, Macugen was demonstrated to be more effective than sham injection at preserving vision. Patients treated with Macugen 0.3 mg had a 10% risk of experiencing severe vision loss (≥6 lines of vision) compared with 22% in the sham-injection group. Also at one year, 70% of patients in the treatment group had preserved vision compared with 55% in the sham-injected group (Gragoudas et al 2004). At the two year endpoint Macugen demonstrated a 45% treatment effect (difference between sham and active groups with less than 3 lines of lost vision). Subsequent approval of Macugen is expected in Europe in early 2006. Other pharmacologic interventions for wet AMD including the VEGF inhibitor Ranibizumab (Lucentis®), and RETAANE, an angiostatic cortisene, are in late stages of clinical development/approval. Additionally, non- pharmacological approaches including transpupillary thermotherapy, radiation therapy, and surgical intervention are still being clinically evaluated. Table 1 summarizes available and potential AMD treatment options. However, the results of those approaches are less promising as compared with drug therapies of this disease entity. Pathophysiology of wet AMD AMD is a complex, multi-faceted disease. While the definitive cause has not been elucidated, epidemiological studies have identified several risk factors. Age is by far the most prominent risk factor for AMD among males and Table 1 CNV therapies currently approved or under clinical development Therapy Active ingredient Company/sponsor Verteporfin Pegaptanib sodium Anecortave acetate Triamcinolone acetonide Bevacizumab Ranibizumab Rostaporfin Squalamine lactate siRNA Fluocinolone acetonide Celecoxib Thalidomide Combretastatin A4 phosphate Vatalanib Talaporfin sodium VEGF Trap Adenovirus vector siRNA Ciliary Neurotrophic factor Novartis Eyetech/Pfizer Alcon Bristol Meyers Squibb Genentech Genentech Miravant Genaera Acuity Pharma Bausch & Lomb NEI Celgene Oxigene Novartis Light Sciences Regeneron GenVec SiRNA Therapeutics Neurotech Type PDT Anti-VEGF Angiostatic cortisene Corticosteroid Anti-VEGF Anti-VEGF PDT Anti-angiogenic small molecule Inhibits VEGF mRNA Corticosteroid Anti-angiogenic & anti-inflammatory Anti-angiogenic small molecule Vascular targeting agent Anti-VEGF and PTK inhibitor PDT VEGF receptor decoy Anti-angiogenic protein Inhibits VEGF receptor mRNA Encapsulated cell therapy Stage Approved Approved Approved in Australia* Used off label Used off label NDA filed Phase III Phase III Phase II/III Phase II Phase II Phase II Phase I/II (for MMD) Phase I/II Phase I Phase I Phase I Phase I Phase I Note: *Global approval process is ongoing. Abbreviations: adPEDF, adenoviral pigment-epithelium-derived factor; CNV, choroidal neovascularization; mRNA, messenger ribonucleic acid; NEI, National Eye Institute; PDT, photodynamic therapy; PTK, protein tyrosine kinases; siRNA, small interfering ribonucleic acid;VEGF, vascular endothelial growth factor. Visudyne Macugen RETAANE Kenalog Avastin Lucentis Photrex Evizon Cand5 Retisert Celebrex with PDT Thalidomide CA4P Vatalanib with PDT Talaporfin with PDT VEGF trap AdPEDF siRNA-027 NT-501 238 Clinical Interventions in Aging 2006:1(3)