Platelet-derived Growth Factor Inhibition for the Treatment of Wet AMD
Inhibition of platelet-derived growth factor (PDGF) is currently being evaluated in several clinical trials for the treatment of choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). While blocking vascular endothelial growth factor (VEGF) is the mainstay of treating CNV in the setting of wet AMD, blocking PDGF is a different treatment approach that is based upon a novel mechanism of action. This brief review will highlight how blocking PDGF may be useful in treating wet AMD.
Pericytes have an intimate relationship with vascular endothelial cells and the association of these two cell types is critical in defining the role of PDGF and VEGF. Pericytes are cells that wrap around endothelial cells of capillaries and venules. They are contractile and regulate blood flow, clear cellular debris, play a role in the blood-brain barrier, and stabilize endothelial cells.
In addition to these functions, pericytes produce VEGF to promote survival of endothelial cells. In turn, VEGF causes the growth of new vessels, and new endothelial cells then elaborate PDGF. PDGF is a mitogenic factor that is produced by endothelial cells, fibroblasts, and smooth muscle.
There are four isoforms of PDGF—A, B, C, and D. PDGF-B is critical for vasculogenesis, and it initiates the proliferation and migration of pericytes. Pericyte proliferation, as a result of elevated PDGF, can cause reduced responsiveness of neovascular vessels to anti-VEGF agents. Blocking PDGF-B results in pericyte stripping, which increases the sensitivity of endothelial cells to anti-VEGF agents.
There are three clinical trials evaluating anti-PDGF agents in patients with neovascular AMD. Fovista (Ophthotech, New York) is a pegylated aptamer that inhibits PDGF-B. The drug is not co-formulated with an anti-VEGF drug. In a phase 2b study including 449 patients with wet AMD, there was significant visual improvement in patients who received both Fovista and the anti-VEGF agent ranibizumab (Lucentis, Genentech, South San Francisco, CA) compared to patients treated with ranibizumab alone. Resolution of CNV and reduced fibrosis were observed in the group treated with both the anti-PDGF and anti-VEGF agents. Phase 3 studies are currently in progress.
Regeneron (Tarrytown, NY) is developing a recombinant human antibody to the PDGF receptor-beta. It is co-formulated with aflibercept (Eylea). Phase 1 dose escalation, safety, and tolerability studies have been completed, with phase 2 studies being initiated this year.
In addition, Santen Inc. has developed a dual tyrosine kinase receptor inhibitor (DE-120) that inhibits both VEGF and PDGF signaling. Phase 1 studies are in progress.
In summary, anti-PDGF agents used in conjunction with anti-VEGF agents hold great promise as a synergistic therapy for patients with neovascular AMD. Ophthotech’s phase 2b clinical trial suggests that visual outcomes will improve for our patients with wet AMD when both classes of drug are used in combination.