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Combination therapy of an anti-platelet-derived growth factor aptamer plus an anti-vascular endothelial lesion regression in 91% of eyes with choroidal neovascularization compared with only 16% of eyes with anti-VEGF monotherapy.
Dr. Cousins, who reported the study results for the Ophthotech Study Group at the annual meeting of the Association for Research in Vision and Ophthalmology, said that the two drugs work on different types of cells within CNV lesions, which explains the higher rate of regression with combination therapy compared with anti-VEGF monotherapy.
"Based on the traditional angiogenesis paradigm for CNV, the retina community would have predicted vascular regression with anti-VEGF monotherapy," said Dr. Cousins. He is the Robert Machemer, MD, professor of ophthalmology, director of the Duke Center for Macular Disease, and professor of ophthalmology and immunology, Duke Center for Macula Disease, Duke University, Raleigh, NC.
He said that in the ranibizumab pivotal trials it was surprising that there was about a 10% enlargement of lesions in the treatment groups in which patients received regularly scheduled anti-VEGF injections.
A look at the histopathology of choroidal new vessels, however, seems to explain why this happens, according to Dr. Cousins.
"Endothelial cells, which are the ones sensitive to VEGF, represent only about 20% of the cells in CNV," he said. "They form the initial capillary tube. Most lesions also contain mesenchymal [cell] types such as pericytes and myofibroblasts. Pericytes are responsive to a different growth factor, PDGF."
In the process of vascular remodeling, pericytes ensheathe the initial endothelial tube, creating a stable vessel that does not respond to anti-VEGF therapy.
"From a scientific perspective, this complexity is attractive because it suggests that there are alternative biologic paradigms for neovascularization in addition to angiogenesis and leakage," he said. "This diversity represents an opportunity for targeted combination therapy."
Comparison with combination therapy
Dr. Cousins and associates conducted a study in which they compared fluorescein images and high-speed indocyanine green angiography images (ICGA) (Spectralis, Heidelberg Engineering) before and after treatment to identify CNV with vascular remodeling and to validate the mechanism of action of anti-VEGF therapy. They evaluated the fluorescein angiograms from 22 patients in a prospective phase I study who received three monthly doses of targeted combotherapy with intravitreal ranibizumab plus intravitreal anti-PDGF aptamer. This group was compared with a retrospective comparison group of 24 patients treated with three to five doses of anti-VEGF monotherapy with ranibizumab or bevacizumab (Avastin, Genentech). All patients had predominantly classic CNV and 22 also underwent high-speed ICGA.
The investigators first sought to determine the rates of regression and progression of CNV. In the anti-VEGF monotherapy group, four eyes (16%) had regression of CNV (two completely and two partially), and four eyes (16%) had enlargement of lesions during induction therapy. In contrast, no eyes in the PDGF aptamer combination therapy group developed enlarged lesions. All but two eyes (91%) showed significant regression of CNV, most of which demonstrated greater than 75% regression.
"This response to anti-PDGF combination therapy was dramatically different from that observed with anti-VEGF monotherapy in our retrospective series." Dr. Cousins said. These data were determined after three doses. It is possible that even greater frequency of regression may be observed after longer observation.
The investigators evaluated the correlation between progression and regression on fluorescein angiography and the qualitative patterns on ICGA in the anti-VEGF monotherapy group, Using high-speed ICGA, the technology captured video angiography of the initial 30 seconds of the ICG angiogram, Dr. Cousins said.
"Classic CNV can demonstrate four components-feeder arteries, branching arterioles, a rim of capillary, and a draining vein," he said. "We can stratify CNV subtypes based on the amount of capillary component relative to the branching arterioles and feeder vessels."
In the series of patients treated with anti-VEGF monotherapy, Dr. Cousins said that imaging showed 18% of eyes had mostly a capillary pattern, 31% a mixed pattern, and 50% mostly branching arteriolar networks with large feeder arteries.
In the patients treated with anti-VEGF monotherapy, three of the four patients with regression of CNV had a capillary pattern that was composed of lesions smaller than half of a disc area. In the four patients with lesions that enlarged over time, all had branching arteriolar networks. The single patient treated with anti-PDGF combination therapy imaged with ICGA, showed dramatic regression of branching arteriolar CNV.
In Dr. Cousins' series of patients, the capillary subtype represented about 20% of the lesions and the remaining 80% demonstrate some form of branching arterioles and vascular remodeling. Furthermore, eyes with capillary lesions were the ones to show regression with anti-VEGF monotherapy. Lesions with branching arterioles demonstrated leakage control without vascular regression, or enlarged during therapy.
"If one extrapolates our retrospective findings to the prospective phase I study of anti-PDGF aptamer, the high frequency of vascular regression observed in the combination therapy study implies that mature vessels with branching arterioles were regressing," he concluded. "This observation suggests that the anti-PDGF drug is working based on the proposed mechanism of action."