Trap-Eye in the VIEW 1 study and all dose groups in the VIEW 2 study were not statistically different from ranibizumab in this secondary end point (average of 8Ð9 letters gained for each cohort). A generally favorable safety proÞle was observed for both aßibercept and ranibizumab. The ocular adverse events were balanced across all treatment groups in both studies. There were no notable differences in nonocular adverse events among the study arms.

AAV2-sFLT01 (Genzyme) is an adenoassociated virus (AAV) that codes for VEGFR-1. It is delivered to retinal cells by intravitreal injection, and the goal is to bind free VEGF to interrupt VEGF signaling. The AAV vector is taken up by perifoveal ganglion cells, which then produce the soluble form of the VEGFR-1 receptor (sFLT01), which binds extracellular VEGF. A phase 1 trial is underway (NCT01024998).

KH902 is a fully human fusion protein containing key domains from VEGFR-1 and -2 with human immunoglobulin Fc. In a phase 1 clinical trial, 28 patients with AMD-associated CNVs (lesion size £12 disc areas and best-corrected visual acuity £55 letters) received a single intravitreal injection of KH902 at 1 of 6 escalating doses if no dose-limiting toxicity occurred through postinjection day 14 of the previous dose level [245]. The primary end point was at 42 days, and patients were monitored for an additional 6 weeks (12 weeks total). The primary safety measures were changes from baseline in visual acuity, intraocular pressure, intraocular inßammation, and production of anti-KH902 antibody. Dose-limiting toxicity was deÞned as intraocular inßammation, elevated intraocular pressure, signiÞcantly reduced vision, or retinal hemorrhage within 42 days after injection. Bioactivity measures included mean change from baseline in visual acuity, central retinal thickness, and total macular volume on optical coherence tomography and CNV changes on ßuorescein angiography. All patients completed the study with no dose-limiting toxicity and no serious or drug-related adverse events. Ocular adverse events were mild to moderate in severity. No serum anti-KH902 antibodies were detected. On day 42 after injection, the mean change in visual acuity from baseline was +19.6 letters with no subjects losing ³1 letter and 57% of patients gaining ³15 letters from baseline. The mean change in center point thickness from baseline was −77.2 mm, and the mean decrease in CNV area was 12.6%. No safety concerns were detected after a single, intravitreal injection of KH902 up to 3.0 mg in this phase 1 study.

1.3.6Endothelial Cell Receptor Binding

VEGF-A binds primarily to VEGFR-1 and -2, both of which are tyrosine kinases [246]. AGN211745 (Sirna-027, Allergan) is an siRNA that inhibits VEGFR-1 synthesis. The safety, tolerability, pharmacokinetics, and dose-limiting toxicity of single intravitreal injection of Sirna-027, a small interfering RNA targeting VEGFR-1 were reported from a phase 1 study [247]. Among patients with AMD-associated CNVs (26 eyes of 26 patients) who had previous treatments with other therapies, intravitreal injection of a single dose of Sirna-027 from 100 to 1,600 mg was well tolerated. Adverse events were mild to moderate in severity. Adjusted mean foveal

thickness decreased within 2 weeks after study treatment. The decrease was most pronounced in the 100 and 200 mg doses. Stabilization or improvement in visual acuity was observed. A phase 2 trial (NCT00395057) was terminated.

1.3.7Endothelial Cell Activation

Pazopanib (GlaxoSmithKline) is a tyrosine kinase inhibitor that blocks the action of VEGFR-1, -2, and -3 and is active against platelet-derived growth factor receptor (PDGFR), kit, and FGFR-1. It is effective in preclinical models of CNVs [248]. It is administered topically and has been tested in a phase 1 trial (NCT01154062). A phase 2 study (NCT00612456) demonstrated a mean 4.3-letter increase in visual acuity after treatment with topical pazopanib (5 mg/mL) t.i.d. (Ophthalmology Times, March 1, 2010, p. 34). Patients with the CFH TT genotype (i.e., the alleles least likely to be associated with AMD) exhibited the best response, both from the standpoint of visual acuity as well as reduction in retinal thickness. PTK787 (Vatalanib, Novartis) is an oral protein kinase inhibitor that targets all known VEGFRs, including VEGFR-1, -2, and -3, PDGFR, and kit and has been tested previously as a treatment for CNV in phase 1/2 clinical studies (NCT00138632). TG100801 (TargeGen), another topically administered tyrosine kinase inhibitor, was in phase 2 clinical trial (NCT00509548), but the study was terminated due to safety concerns. AL39324 (Alcon) is an intravitreally administered tyrosine kinase inhibitor that is in phase 2 clinical trials with ranibizumab using ranibizumab alone as the active control group (NCT00992563). ATG003 (mecamylamine, CoMentis) antagonizes the nicotinic cholinergic receptor pathway in vasculature, inhibits endogenous and VEGF-induced angiogenesis in human endothelial cells, is administered topically, and was in a phase 2 clinical trial (NCT00414206) (343 patients) that was terminated by the sponsor. There was no statistically signiÞcant difference in the chance of losing <15 ETDRS letters among the 1% mecamylamine, 0.3% mecamylamine, and placebo cohorts.

1.3.8Endothelial Cell Proliferation

Sonepcizumab (LT1009, Lpath, Inc.) is a humanized monoclonal antibody that binds sphingosine-1 phosphate (S1P) with picomolar afÞnity. S1P is the extracellular ligand for the G protein-coupled lysophospholipid receptor EDG-1 (endothelial differentiation gene-1). Sonepcizumab inhibits CNVs in preclinical models [249], is administered intravitreally, and is in a phase 1 human trial (NCT00767949).