The ability of vascular endothelial growth factor (VEGF) inhibitors to improve visual acuity in most patients with neovascular age-related macular degeneration (AMD) has been well established in clinical trials and clinical practice. In most of these patients, however, choroidal neovascularization (CNV) is stabilized but does not regress. Anti-VEGF drugs control angiogenesis and leakage, but they do not effect vascular remodeling.
Platelet-derived growth factor (PDGF) is a protein that regulates cell growth and is involved in angiogenesis. An anti-PDGF pegylated aptamer (E10030, Ophthotech) has been shown in experimental models of neovascularization to "strip away" pericytes from neovascular tissue.1,2
A phase 1 clinical trial was conducted to evaluate intravitreal combination therapy of the PDGF inhibitor E10030 plus the VEGF inhibitor ranibizumab (Lucentis, Genentech).3 This dose-escalation study included 22 patients at multiple sites, with 0.03-, 0.3-, 1.5-, and 3.0-mg doses of E10030 given in combination with ranibizumab once monthly for 3 months. All eyes in the study had subfoveal CNV with some classic component and a total lesion size of five disc areas or less. Pre- and post-treatment fluorescein angiography were analyzed for CNV vascular area and qualitative patterns.
Results of this phase 1 study were compared with a retrospective group of 24 patients treated with ranibizumab or bevacizumab (Avastin, Genentech) induction therapy, once a month for 3 to 5 months, from 2007 to 2009.3 These patients had mostly predominantly classic CNV lesions secondary to AMD with total lesion size of five disc areas or less.
With anti-PDGF/anti-VEGF combination therapy, partial regression of CNV lesions occurred in 91% of patients. Vascular regression of CNV was observed to leave a hypofluorescent plaque. No patients receiving combination therapy experienced progression of CNV in the trial. In contrast, in patients treated with anti-VEGF monotherapy, CNV regressed in 16% of patients, but most remained stable and some progressed. Stable inactivity was observed in 9% of eyes treated with combination therapy, compared with 68% of eyes treated with anti-VEGF monotherapy.
These preliminary data suggest that combination therapy with an anti-PDGF aptamer plus a VEGF inhibitor produces regression of CNV lesions. Fluorescein and indocyanine green angiography is useful in evaluating the regression of CNV lesions in response to treatment.
Scott W. Cousins, MD, is Director of the Center for Macular Diseases at Duke University Eye Center. Dr. Cousins reports that he is a consultant to Ophthotech. He may be reached via email at scott.cousins@duke.edu; phone: 919-684-3090; fax: 919-681-6474.
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