Breaking the vicious cycle of PDGF-VEGF

March 24, 2015

The activity in age-related macular degeneration (AMD) involves a close association between endothelial cells and pericytes, the latter of which wraps around endothelial cells of the capillaries and venules.Pericytes regulate blood flow, clear cellular debris, are a key factor in the blood-brain barrier, and stabilize maturation of endothelial cells, explained Elias Reichel, MD, professor of ophthalmology, Tufts University School of Medicine, and vice chairman, New England Eye Center, Boston.

Boston-The activity in age-related macular degeneration (AMD) involves a close association between endothelial cells and pericytes, the latter of which wraps around endothelial cells of the capillaries and venules.

Pericytes regulate blood flow, clear cellular debris, are a key factor in the blood-brain barrier, and stabilize maturation of endothelial cells, explained Elias Reichel, MD, professor of ophthalmology, Tufts University School of Medicine, and vice chairman, New England Eye Center, Boston.

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Platelet-derived growth factor (PDGF), a mitogenic factor that is a product of the endothelial cells, fibroblasts, and smooth muscle cells, comes in a few isoforms: A, B, C, and D and there are two receptors, a and b.

PDGF-b is crucial for vasculogenesis, as it initiates proliferation and migration of pericytes, said Dr. Reichel. He added that PDGF-b also is required in cellular division of fibroblasts, and it has roles in wound healing, cancer, and fibrosis.

“PDGF-vascular endothelial growth factor (VEGF) is a vicious cycle,” Dr. Reichel said. “Anti-PDGF drugs and anti-VEGF drugs have different mechanisms of action. Anti-PDGF drugs increase sensitivity to anti-VEGF drugs and have anti-fibrotic activity. 

NEXT: PDGF in pathologic neovascularization

 

Dr. Reichel discussed the main players in pathologic neovascularization.

“Pericytes produce VEGF to protect the endothelial cells,” he said. “VEGF causes new vessel growth. New endothelial cells in turn elaborate PDGF, and proliferation of pericytes due to elevated levels of PDGF can result in a reduced response of new vessels to anti-VEGF drugs, as reported by Damas et al. [American Journal of Pathology 2006;168:2036-2053].”

When pericytes cover abnormal blood vessels, Dr. Reichel added, the new vessels are protected and their anti-VEGF-induced disruption is slowed, and, therefore, anti-VEGF drugs do not work as well.

Conclusively, PDGF and VEGF constitute a vicious cycle, he said.

“The PDGF concentration goes up and then the VEGF concentration goes up. We cannot fight this interaction,” Dr. Reichel said.

NEXT: Clinical trials

 

The strategy behind clinical trials is identifying a way to inhibit PDGF in neovascular AMD. By blocking PDGF-b, the pericytes are stripped, which increases the sensitivity of the bare endothelial cells to anti-VEGF agents, which results in regression of neovascularization. Blocking PDGF-b also results in anti-fibrotic activity.

Fovista (Ophthotech Corp.) is a pegylated aptamer that inhibits PDGF-b in combination with administration of an anti-VEGF drug. The drug is not coformulated, but a separate injection from an anti-VEGF drug. The completed phase IIb trial included 449 patients.

“The results showed that the patients treated with Fovista had resolution of choroidal neovascularization and reduced fibrosis with significant visual improvement compared with the use of an anti-VEGF therapy alone,” Dr. Reichel reported.

The phase III trial is ongoing.

Another drug in the pipeline is REGN2176-3 (Regeneron Pharmaceuticals), a recombinant human antibody to PDGFRb. This product is coformulated with aflibercept (Eylea, Regeneron Pharmaceuticals). A phase I study of this treatment has been completed, and the phase II study will start in the first half of this year, according to Dr. Reichel.

A third drug, DE-120, is under study by Santen Pharmaceuticals. This drug is a dual tyrosine kinase receptor inhibitor of VEGF and PDGF. The phase I segment of the trial is ongoing.

 “(These) three clinical trials of drugs are currently ongoing,” Dr. Reichel explained. “The phase II Fovista study shows the benefit of anti-PDGF therapy combined with anti-VEGF therapy for treating neovascular AMD.”