E10030 - Anti-PDGF Aptamer

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 enrolled its first patient in a randomized, controlled, Phase II study of E10030 in combination with Lucentis®, an anti-VEGF agent, for the treatment of wet age-related macular degeneration (AMD). This Phase II trial will assess the efficacy and safety of the combination treatment regimen. In an open-label Phase I clinical study, E10030 was well tolerated with no evidence of drug-related adverse events. In this Phase I clinical study, 59 percent of patients treated with E10030 and Lucentis® gained significant vision (3-line gain or better) 12 weeks after the start of therapy. Notably, there was a mean decrease of 86% in the area of choroidal neovascularization (CNV) at 12 weeks.

References:

1.  Jo N, Mailhos C, Ju M, Cheung E, Nishijima K, Robinson GS, Adamis AP, and Shima DT. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol (2006); 168(6):2036-2053.

2.  Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 1998; 125(9):1591-8.

3.  Enge M, Bjarnegard M, Gerhardt H, Gustafsson E, Kalen M, Asker N et al. Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy. EMBO J 2002; 21(16):4307-16.

4.  Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003; 111(9):1287-95.

5.  Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 2004; 18(2):338-40.