**2. Vascular endothelial growth factors**

Vascular endothelial growth factor (VEGF) plays a key role in ocular angiogenesis and vas‐ cular permeability. Several VEGF family members have been discovered (VEGF-A, B, C, D

and PIGF). These isoforms of VEGF have different effects in ocular pathologies and may dif‐ fer in their neuroprotective abilities [5, 6]. RPE and Müller cells are the major sources of VEGF and they exert their effects through multiple receptors that are mostly expressed on endothelial cells and are also found on monocytes and macrophages [7].

trolled trials comparing the two most commonly drugs available were published recently. A summary of the available drugs (table 1), their mechanism of action and results from large

Anti VEGF Agents for Age Related Macular Degeneration

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

165

This intravitreal RNA aptamer drug was the first anti-VEGF drug approved by the FDA in 2004 for use in neovascular AMD (nvAMD). It targets VEGFA-165[11]Its efficacy and safety

Patients with different types of sub foveal CNV secondary to AMD were randomized into four groups. Three groups received an intravitreal injection of pegaptanib sodium at a dose of 0.3mg, 1.0mg, 3.0mg to one eye respectively. The injection was given every 6 weeks for a period of 48 weeks in total. The forth group was the control group and subjects in this group received a sham injection every 6 weeks. Primary outcome was mean change in visual acui‐

Results from a combined analysis showed that for all three doses of pegaptanib (P<0.001 for the comparison of 0.3 mg with sham injection; P<0.001 for the comparison of 1.0 mg with sham injection; and P=0.03 for the comparison of 3.0 mg with sham injection) there was a significant difference between the patients receiving treatment and those receiving a sham injection. In the group dosed with pegaptanib 0.3 mg, 70 percent of patients lost fewer than 15 letters of visual acuity (VA), as compared with 55 percent among the controls (P<0.001). The risk of severe loss of VA (loss of 30 letters or more) was reduced from 22 percent in the sham-injection group to 10 percent in the group receiving 0.3 mg of pegaptanib (P<0.001). More patients receiving pegaptanib (0.3 mg), as compared with sham injection, maintained their VA or gained acuity (33 % vs. 23%; P=0.003). As early as six weeks after beginning ther‐ apy with the study drug, and at all subsequent points, the mean visual acuity among pa‐ tients receiving 0.3 mg of pegaptanib was better than in those receiving sham injections (P<0.002). During the second year, patients initially assigned to pegaptanib were re-random‐ ized (1:1) to continue or discontinue therapy for 48 additional weeks (8 injections). Those ini‐ tially assigned to sham were re-randomized to continue sham, discontinue sham, or receive 1 of 3 pegaptanib doses. The proportion of patients who lost more than 15 letters or more in vision between week 52 to week 96 was double (14 *vs* 7%), if treatment was discontinued compared to those who continued to receive pegaptanib injections. This suggests that there is a more favorable outcome when continuing treatment for at least two years [18].The Pe‐ gaptanib was found safe and there was no significant difference in serious systemic adverse events or severe ocular inflammation, cataract or glaucoma between the pegaptanib treated

The VA results of the VISION study are clearly inferior to those of the MARINA and AN‐ CHOR studies evaluating the efficacy of intravitreal ranibizumab for nvAMD (detailed lat‐

multicenter trials evaluating their efficacy and safety is presented below.

**3. Anti VEGF drugs**

ty from baseline.

**3.1. Pegaptanib sodium (Macugen) – OSI/Eyetech**

were evaluated in the large VISION trial [16, 17].

groups and the sham treated groups [16, 17].

VEGF-A, has been most strongly associated with angiogenesis and thus consists the target of most anti-VEGF treatments [8, 9]. VEGF-A signals through two receptor tyrosine kinases, VEGFR1 and VEGFR2, and is induced by hypoxia, unlike other VEGF isoforms [7, 10].

Alternative exon splicing of the human VEGF-A gene results in at least four major biologi‐ cally active isoforms, containing 121, 165, 189, and 208 aminoacids (five more are VEG‐ FA-145, VEGFA-162, VEGFA-165b, VEGFA-183, and VEGFA-206) [11].

Different VEGF-A isoforms may have different functions in ocular diseases.

VEGF 121 appears to be essential for normal retinal vascular function [12-13], and VEG‐ FA-165 is the predominant isoform in the human eye. It isa heparin-binding, homodimeric, 45-kDa glycoprotein that is predominantly secreted, although a substantial fraction is bound to the cell surface and to the extracellular matrix[13-14].It appears to be the isoform respon‐ sible for pathological ocular neovascularization.

Both isoforms are found in CNV tissue excised from patients with AMD.

In autopsy studies, VEGF levels were found to be elevated in the retinal pigment epithelium (RPE) and choroidal blood vessels within the macular area of eyes with AMD [15].

In summary VEGF-A acts through various pathways which result in promoting pathologic neovascularization:


Several anti-VEGF drugs have been studied and have been shown to be effective. However, effective, long-term drug-delivery remains a challenge. Two multi-center, randomized con‐ trolled trials comparing the two most commonly drugs available were published recently. A summary of the available drugs (table 1), their mechanism of action and results from large multicenter trials evaluating their efficacy and safety is presented below.
