1. CNV increases PDGF expression
2. Increased PDGF expression leads to enhanced pericyte coverage of CNV
3. Lack of significant regression of new blood vessels with Anti-VEGF therapy alone
4. E10030 therapy results in stripping of neovascular pericytes from the CNV
5. Combination therapy results in CNV regression
Monotherapy with an anti-VEGF agent is the current standard of care for wet AMD. However, significant visual gain (3 lines or more improvement on an ETDRS chart) occurs in only approximately one third of patients. A major limitation of this monotherapy anti-VEGF approach is lack of regression of the new vessels, which are responsible for the visual loss in wet AMD. Therefore, a therapeutic regimen that induces neovascular regression would likely result in enhanced visual acuity for these patients.
Ophthotech’s anti-PDGF aptamer, E10030, targets PDGF, which regulates neovascular pericytes. In pre-clinical models, E10030 successfully induced neovascular regression when administered in combination with anti-VEGF agents. This effect is further supported by published studies in which inhibition of the binding of PDGF to its receptor, PDGFR-β, plus an anti-VEGF agent cause neovascular regression in ocular angiogenesis models, as shown below.
Mural cells (pericytes) provide neovascular endothelial cell survival signals by juxtacrine secretion of growth factors such as VEGF and other pro-angiogenic factors. Therefore, neovascular tissue is resistant to regression during a monotherapy anti-VEGF attack.
PDGF is a molecule which regulates the recruitment and maturation of pericytes. Increased PDGF expression leads to enhanced pericyte coverage of neovascular tissue. Conversely, its inhibition has been shown to cause pericyte stripping.
E10030 strongly binds to PDGF resulting in pericyte stripping in ocular and oncological models of pathologic neovascularization. Co-administration of E10030 and an anti-VEGF agent, thereby targeting pericytes and endothelial cells respectively, has been shown to induce significant neovascular regression in multiple preclinical ocular and tumor models of angiogenesis.
Ophthotech recently completed enrollment of its phase 1 study (REGAIN), an open-label multicenter study of E10030 in combination with an anti-VEGF agent (Lucentis®), in patients with wet AMD. The objectives of this study are to evaluate the safety, tolerability, and pharmacokinetic profile of E10030 (anti-PDGF) intravitreous injection when given in combination with Lucentis®.
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