VEGF-Trap Eye is a soluble decoy receptor created through the fusion of key receptor domains of vascular endothelial growth factor (VEGF) receptors 1 and 2 (VEGFR1 and VEGFR2, respectively) to the Fc domain from human IgG1. This unique design imparts several theoretical advantages over existing anti-VEGF agents. First, VEGF-Trap binds to all isoforms of VEGF, as opposed to pegaptanib which specifically binds VEGF isoform 165. VEGF-Trap has a much stronger affinity to circulating VEGF than either anti-VEGF monoclonal antibodies or native VEGF receptors, translating into smaller effective doses and potentially a more protracted biologic effect. VEGF-Trap also binds placental growth factor (PlGF), a member of the VEGF family implicated in the pathogenesis of choroidal neovascularization (CNV). PlGF is found in human neovascular membranes and is upregulated in experimental mouse models of CNV. PlGF deficient mice fail to form CNV following a laser-induced injury.1 Thus, on paper, VEGF-Trap Eye has several advantages over current anti-VEGF agents. The practical relevance of these theoretical advantages awaits confirmation in ongoing clinical trials.
VEGF-Trap Eye is currently being studied head-to-head versus ranibizumab in a phase 3 clinical trial. A brief look at recently reported phase 2 data may give us an idea of what to expect. The CLEAR-IT 2 was a multi-center, randomized, double-masked phase 2 trial evaluating VEGF-Trap Eye in patients with wet age-related macular degeneration (AMD). This 52-week study consisted of a fixed dosing period until week 12 followed by an as needed dosing period until the end of the study. 159 patients were randomized to 5 groups: 0.5 and 2 mg every 4 weeks, and 0.5, 2, and 4 mg every 12 weeks. Results were presented at the 2007 Retina Society meeting.
All groups experienced an improvement in visual acuity. However, it was apparent from the fixed dosing phase that a single injection without a loading dose may be insufficient. Visual acuity in the q4 week dosing groups improved more than in the q12 groups at 12 weeks. Similar differences in improvement were also seen in central retinal/lesion thickness, and in angiographic size of the CNV lesion. In the second part of the phase 2 study, patients were dosed as needed in all groups. On average, only 2 additional doses of VEGF-Trap were required until 52 weeks. The visual gains reported in the fixed-dosing phase persisted to 52 weeks.
An important concern regarding anti-angiogenic treatment in general is the potential risk for systemic ischemic toxicity. One vascular ischemic event (out of 159 patients) was recorded in the CLEAR-IT 2 study—a hemorrhagic stroke in a patient with a previous history of stroke. As with the available anti-VEGF therapies, current data are insufficient to exclude an association. A post-marketing surveillance program is in place to monitor for similar adverse events with ranibizumab.
With all this in mind, the limited available data suggest that VEGF-Trap Eye probably has comparable efficacy to ranibizumab. However, this cannot be known for sure without the results from VIEW 1, a randomized, masked, head-to-head phase 3 study comparing VEGF-Trap Eye to ranibizumab. The potential upside for VEGF-Trap Eye may be in more permissive dosing schedules, as is suggested in CLEAR-IT 2. A confounding factor is that the jury is still out on variable dosing schedules for ranibizumab as well. The CATT trial currently is evaluating whether variable dosing schedules can be used with ranibizumab as well as bevacizumab. Informed judgments on the role of VEGF-Trap Eye in our armamentarium of treatments for wet AMD can only be made after a critical review of the results of the clinical trials that are still underway.
1. Rakic JM, Lambert V, Devy L, et al. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci 2003; 44:3186-3193.
About our author(s):
Ahmad B. Tarabishy, MD
Cole Eye Institute
Peter K. Kaiser, MD
Director, Digital OCT Reading Center
Cole Eye Institute