 |
||||
Product CandidatesOphthotech is developing three compounds that address major molecular events that contribute to the pathology of AMD. These include an anti-platelet-derived growth factor (anti-PDGF) aptamer, E10030, which is in Phase I clinical studies for wet AMD. Additionally, an aptamer program (ARC 1905) targeting the C5 component of the complement cascade will focus on the treatment of both the wet and dry forms of AMD. The lead compound, ARC1905, will enter Phase I trials in 2008. We are also developing an α5β1 antagonist, volociximab (a monoclonal antibody), for the treatment of dry and wet forms of AMD. Anti-PDGF
While vascular endothelial growth factor (VEGF) is thought to be a key mediator in the process of neovascularization, it is well established that the angiogenic cascade is complex and involves multiple distinct cytokine growth factors. In addition, anti-VEGF therapy alone does not cause regression of the neovascular tissue and hence may limit the potential visual outcome. Combined antagonism of VEGF and PDGF has resulted in regression of neovascular tissues in preclinical ocular and tumor angiogenesis models. Regression of neovascular tissue in AMD may result in enhanced visual acuity. Platelet-derived growth factors (PDGFs) and their receptors are critical targets in anti-angiogenic therapy. PDGF plays a significant role in angiogenesis and has been implicated in ocular neovascularization. The activities of PDGF and VEGF in the initiation of angiogenesis and mediation of blood vessel growth and behavior are independent of each other, suggesting that concurrent inhibition could lead to superior efficacy in treating neovascularization. Platelet-derived growth factor B (PDGF-B) is implicated in vascular stability and function through its role in activating the recruitment of mural cells (pericytes) by endothelial cells to envelop the developing vasculature. Pericyte recruitment is part of the maturation process in blood vessel development and pericytes act as support cells for mature blood vessels. Once the mural cell population is well established, the effectiveness of anti-VEGF agents is greatly reduced. It is possible that disruption and stripping of mural cell recruitment by an anti-PDGF agent could potentiate the efficacy of an anti-VEGF attack by causing neovascular regression. Therefore, combination therapy in wet AMD with anti-VEGF and anti-PDGF agents could represent breakthrough therapy. E10030, an aptamer-based compound directed against PDGF-B, is being developed for the potential treatment of wet AMD. E10030 is a pegylated aptamer containing 32 monomeric units (32-mer) arranged as a linear sequence of three oligonucleotide segments connected by non-nucleotide hexaethylene glycol spacers. The aptamer terminates in a hexylamino linker to which two 20-kilodalton monomethoxy polyethylene glycol units are covalently attached via the two amino groups on a lysine residue. Pharmacology studies indicate that E10030 binds to PDGF-B with high specificity and affinity and inhibits the functions of PDGF-B both in vitro and in vivo. In pre-clinical studies, E10030 demonstrated the potential to regress neovascularization when used in combination with a VEGF-A inhibitor. In experiments involving models of ocular vascularization [1], concurrent inhibition of PDGF-B and VEGF-A signaling was superior to inhibition of the VEGF-A pathway alone. The combined treatment was able to induce the regression of existing vessels, compared to inhibition of VEGF-A alone. Findings from a corneal neovascularization model demonstrated that pericytes were stripped from newly growing vessels, but not from existing limbal vessels. This evidence suggests that combined administration of an anti-PDGF-B agent with an anti-VEGF agent may result in regression of abnormal blood vessels in neovascular AMD while preserving the normal vascular architecture. Therefore, combination therapy with a regimen incorporating an anti-PDGF agent with an anti-VEGF agent holds great promise for enhanced efficacy in wet AMD.
|
||||
|
||||
