degradation after laser photocoagulation [60, 61]. These promising preclinical findings are supported by outcomes from a number of smallscale clinical studies in patients with exudative AMD [44]. Importantly, the only large-scale (n = 151), randomized, controlled, doublemasked study of IVTA 4 mg found that although IVTA significantly reduced the growth of neovascular lesions in eyes with CNV with a classic component, there was no significant reduction in the risk of developing severe vision loss (loss of ³30 letters) between the IVTA and placebo recipients [62]. Although this study showed that IVTA was generally well tolerated, there was an increased incidence of mild or moderate elevation of intraocular pressure, which responded well to treatment, and significant progression of cataract [63]. Other studies have also revealed increases in intraocular pressure as well as an increased risk of endophthalmitis [64–66]. In a retrospective, case series, post-injection endophthalmitis was identified in eight eyes following a total of 922 IVTA treatments [65]. Both bacterial and sterile cases of endophthalmitis have been reported following IVTA treatment [65, 66]. Additional large-scale studies are required to further characterize the safety profile of IVTA. In part due to safety concerns, the current balance of evidence suggests that IVTA cannot be recommended for monotherapy of CNV due to AMD [44]. However, the biological effects warrant further investigation, particularly in combination with other treatment modalities.

Verteporfin Angioocclusive Therapy

Verteporfin photodynamic therapy (VPDT) has a selective mechanism of action based on accumulation of the drug in the target tissue followed by activation with laser light [67]. The vascular component of CNV consists of pericytes, endothelial cell precursors, and vascular endothelial cells, which provide the target for verteporfin. Verteporfin is infused intravenously, accumulates preferentially in proliferating cells such as the endothelium in CNV, and generates short-lived reactive oxygen species when activated by laser

light at a wavelength of 689 nm. The standardfluence (SF) rate utilized in clinical trials used a treatment of 50 J/cm [2] delivered over 83 s at 600 mW/cm2 [67, 68]. The reactive oxygen species generated by this photochemical reaction causes highly localized endothelial cell damage leading to rapid and selective occlusion of the CNV without damaging the overlying retina [69, 70]. Specifically, photoactivation of verteporfin generates a reactive oxygen species that causes localized endothelial cell changes. This triggers platelet binding and aggregation, leading to the formation of a stabilized plug and occlusion of the CNV [67, 71]. Although the primary mechanism of action of VPDT involves occlusion of the new vessels, the treatment is also likely to have secondary effects. For example, it has been shown that VPDT induces a response involving increased expression of VEGF, VEGFR-3, and PEDF [45]. However, it is also possible that occlusion of new vessels could directly alter cytokine release or modify angiogenic signals [6].

Verteporfin therapy is currently recommended for patients with subfoveal lesions composed of predominantly classic CNV (regardless of lesion size) and for those with small lesions (£4 disc areas) containing occult with no classic or minimally classic CNV and having evidence of recent disease progression, based on the results of the phase III treatment of age-related macular degeneration with Photodynamic therapy (TAP) Investigation, the phase III Verteporfin In Photodynamic Therapy (VIP) Trial, and the phase II Verteporfin In Minimally Classic CNV (VIM) Trial [72–75]. The ocular and systemic safety of verteporfin was confirmed in phase III studies, and combined safety data have been reported in detail [76]. Acute severe visual acuity decrease (defined as a loss of at least 20 letters of visual acuity within seven days of verteporfin) was a relatively uncommon event, occurring in 0.7% of 402 patients in the TAP Investigation and 4.9% of 225 patients in the VIP Trial [77]. Published data from an extension to the two-year TAP Investigation showed that visual acuity remained stable through five years and that there were no new safety concerns during this period [78].

Rationale for Combination Therapy in the Treatment of Exudative AMD

Despite significant advancements made in the understanding and treatment of exudative AMD over the past decade, the need for therapeutic improvement exists. For example, of all the treatments investigated to date, the intravitreal antiVEGF therapies have been the most clinically successful. However, anti-VEGF monotherapy does not improve vision in all patients, and it appears that frequent treatments are necessary to maintain efficacy [85, 86, 102]. For example, in ANCHOR and MARINA, approximately twothirds of patients did not gain at least 15 letters at 12 months after treatment with ranibizumab [85, 86]. The extension study of MARINA and ANCHOR, the HORIZON study, reported that when monthly treatments were changed to as needed dosing, visual acuity declined over the next two years. This indicates that long-term and frequent dosing are required to maintain the visual gains with anti-VEGF monotherapy. Furthermore, the PIER Study revealed suboptimal efficacy when quarterly dosing of ranibizumab was compared with monthly treatment regimens in patients with subfoveal CNV due to AMD. In the PIER Study, IVR 0.3 or 0.5 mg (or sham) was administered monthly for three months and quarterly thereafter. Patients receiving 0.5 mg IVR demonstrated vision improvement during the initial monthly dosing with a decline to baseline with subsequent mandated quarterly dosing [103]. This loss was accompanied by an average increase in vascular leakage and mean retinal thickness after initiation of the quarterly dosing regimen, suggesting that some patients need IVR injections more frequently to control the neovascular leakage [103]. And it is important to note that each intravitreal treatment of anti-VEGF therapy carries a risk of endophthalmitis, uveitis, cataract formation, and retinal detachment, not to mention physical, emotional, and financial stress. IVR was associated with a presumed endophthalmitis rate of 0.8–.4% of patients and uveitis in 0.7–1.3% of patients in ANCHOR and MARINA [85, 86, 102].

Evidence suggests that anti-VEGF agents become less effective as neovascularization matures, especially as the vessels become enveloped by pericytes. These pericytes may serve to buffer the neovascularization from the anti-VEGF agents and even secrete VEGF themselves. Thus, anti-VEGF therapy may have a limited effect on the more established vasculature observed in the later stages of exudative AMD [104–106]. Since verteporfin targets the vascular component of CNV by occluding vessels within the CNV lesion, combining the angio-occlusive effect of VPDT with anti-VEGF therapies that inhibit growth and decrease the permeability of new vessels might lead to prolonged reduction of leakage, thus necessitating fewer retreatments. Conversely, studies have demonstrated that VPDT may affect the physiological choriocapillary bed surrounding the pathological CNV lesion, indirectly resulting in upregulation of VEGF that may then further stimulate CNV growth [107, 108]. By combining anti-VEGF agents that target the angiogenic component with VPDT that targets the vascular component, the vicious cycle of VPDT-induced VEGF upregulation may be broken and provide subsequent improvements in visual outcomes and perhaps lead to a less frequent dosing schedule of antiVEGF agents. In addition, many clinicians also opt for reduced-fluence (RF) VPDT in an attempt to optimize the efficacy by increasing the selectivity of VPDT’s angio-occlusive effects (300 mW/cm2 for 83 s to deliver 25 J/cm2) [109]. The two-year results of Visudyne in Minimally Classic CNV (VIM) phase II trial have indicated a trend toward better visual acuity (VA) outcomes and a lower incidence of visual disturbance in the RF group compared with the standard-fluence (SF) group at 12 and 24 months [107]. Thus, while evaluating the combination therapies, it would be logical to assess both RF and SF VPDT to help define the most appropriate VPDT combination treatment [109].

The current treatment regimens with intravitreal anti-VEGF injection therapies have no defined endpoint; thus, it is unknown how long these therapies must be continued. Furthermore, the enduring effect on vision is unknown once