Vascular endothelial growth factor antagonists will have greater potency, less specificity, ophthalmologist predicts

Key Points

Atlanta-Antagonists of vascular endothelial growth factor (VEGF) provide a benefit for choroidal neovascularization (CNV) and are promising for other retinal diseases, but they represent only the beginning of a transformation in the treatment of certain eye diseases, according to Peter A. Campochiaro, MD.

"It's very likely that the newer antagonists will have greater potency and less specificity, as opposed to what you may hear, which is essentially hype, that we should be using less-potent and isoform-specific antagonists," he said. "There's no indication that that's the case, and it's going to go in the other direction." Dr. Campochiaro is the George S. and Dolores Doré Eccles Professor of Ophthalmology and Neurosciences, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore.

Two new modes of delivery, topical application and sustained delivery, will arise, he predicted. Although it is difficult to achieve sustained delivery of proteins, it is possible, Dr. Campochiaro said, and studies attempting to use this technology are under way. Delivery of small kinase inhibitors is very feasible and highly likely in the future, he said.

Dr. Campochiaro noted that large, randomized phase III clinical trials of the VEGF inhibitor ranibizumab (Lucentis, Genentech) have shown that improvements in visual acuity that last at least 2 years can be achieved in many patients with age-related macular degeneration (AMD).

Questions remain

"These are very impressive results considering all the past failures in treating neovascular AMD. But the question arises: is this the best we can do, or is there potential for improvement?" he asked rhetorically. "Some related questions are: is long-term suppression of VEGF in the eye safe, do other VEGF family members contribute to retinal vascular diseases, are there other cytokines and growth factors that contribute in addition to the VEGF family members, and are there ways other than frequent intraocular injections that we can deliver VEGF antagonists?"

To address the first question, Dr. Campochiaro cited the creation with colleagues of transgenic mice that express a soluble VEGF receptor. The mice do not express this potent binding protein unless they have been treated with doxycycline. Intraocular injection of VEGF in the mice induces severe vascular permeability, whereas if they are treated with doxycycline, all VEGF signaling is blocked.

The investigators have studied these transgenic mice for periods of up to 7 months and have found that the blockade does not appear to affect the vasculature or electroretinogram response function, nor does it decrease the number of retinal ganglion cells or the number of axons in the optic nerve.

"It appears that blockade of VEGF-A for even long periods of time is safe," Dr. Campochiaro said.

Moving to the question of whether other members of the VEGF family play a role in retinal vascular diseases, he observed that studies of a chimeric protein (VEGF Trap-Eye, Regeneron Pharmaceuticals) have proven that this is the case. The protein binds not only VEGF-A but also VEGF-B and placental growth factor (PlGF). In a murine model, the protein produced substantial reductions in CNV.

Results of a phase II trial of the protein (CLEAR-IT 2), reported last fall, showed significant improvements in visual acuity among patients to whom various doses of the drug had been administered either every 4 weeks or every 12 weeks during a 12-week fixed dosing period that was followed by as-needed dosing out to 52 weeks.

"The improvement in visual acuity was quite dramatic in patients who received three injections a month apart-very comparable to what happens with [ranibizumab]," Dr. Campochiaro said. "There was not as much improvement in patients who received a single injection over 12 weeks. After the 12-week fixed dosage period, there was a PRN period, and many of the patients who had received three injections of [the protein] in the first phase only required one or two additional injections to maintain this visual improvement.

"There is a phase III trial that may provide a definitive answer to the question, but based on early phase studies and studies in animal models that have implicated PlGF, it appears likely that other VEGF family members are involved," he continued.