Future directions in development of VEGF antagonists

Ranibizumab (Lucentis, Genentech) has revolutionized the treatment of age-related macular degeneration, but the impressive results from clinical trials lead to new questions. Is long-term suppression of vascular endothelial growth factor (VEGF) in the eye safe? Do other members of the VEGF gene family contribute to retinal vascular diseases? Are other cytokines or growth factors involved in disease pathogenesis? Are there safe and effective delivery methods other than monthly injections?

Peter A. Campochiaro, MD, professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins Hospital School of Medicine, Baltimore, addressed these issues in a symposium on the use of VEGF inhibitors. He noted that results of a study in a transgenic mouse model in which VEGF signaling was blocked found that there was no effect on the vasculature or ERG function and no decrease in retinal ganglion cells or axons in the optic nerve over a 7-month period.

"Therefore, it appears that blockage of VEGF-A for long periods of time is safe," Dr. Campochiaro said.

He also described a study suggesting that other VEGF family members besides VEGF-A play a role in retinal disease. Preclinical and clinical studies of a chimeric protein that binds VEGF-A and B and placental growth factor (VEGF Trap-Eye, Regeneron) show that it causes a substantial reduction in choroidal neovascularization (CNV).

Platelet-derived growth factor-B (PDGF-B) also is likely to be involved in development of retinal disease. According to Dr. Campochiaro, kinase inhibitors that block both VEGF and PDGF were highly effective in preclinical studies, using a synergistic effect to completely eliminate CNV. A prodrug for a kinase inhibitor was tested in a small clinical trial; it was administered topically b.i.d. for 30 days and substantially reduced thickening and subretinal fluid. It was a pigmented agent that produced colored deposits on the cornea in many patients, however, and the trial was stopped.

"It does provide proof of concept for topical delivery of kinase inhibitors," Dr. Campochiaro said.

"VEGF antagonists provide a benefit for [CNV] and other disease indications as well, such as retinal neovascularization and ischemia due to macular edema," he continued. "They're certainly here to stay and will be the baseline on which other things are added. Improvements are likely, and certainly it's very likely that the newer antagonists will have greater potency and less specificity. In addition, there will be new modes of delivery, including topical delivery and sustained delivery."

Dr. Campochiaro said that sustained delivery of proteins is difficult, but possible, and that studies of this technology are underway. Sustained delivery of small kinase inhibitors is very feasible and is likely to be achieved in the near future.