Product Candidates

Ophthotech 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.

α5ß1 Antagonist

Pathological angiogenesis is characterized by endothelial cell activation, proliferation, invasion and migration. Our knowledge of biochemical events inducing and regulating this process is evolving at a great pace. Growth factors such as Vascular Endothelial Growth Factor (VEGF), bFGF, IL-8 etc. play a key role in the initial upstream stages of this process. However, there exist redundancies in growth factor mediated angiogenesis. In experimental models, each growth factor can independently induce angiogenesis. Therefore, targeting a downstream, growth factor independent pathway of angiogenesis may result in a potent and enhanced anti-angiogenic effect.

Interaction between activated and proliferating endothelial cells with extracellular matrix (ECM) proteins has been shown to mediate endothelial cell survival, proliferation and migration. Specifically, interaction between endothelial transmembrane protein, α5ß1, with its natural ligand, Fibronectin (an ECM protein), has been shown to regulate all major endothelial cellular processes involved in angiogenesis. Over twenty years of scientific studies from independent labs have demonstrated the key role of α5β1-Fibronectin interaction in angiogenesis. Therefore, interruption of this α5ß1-Fibronectin signal offers an attractive opportunity for an anti-angiogenic attack independent of growth factor stimulation.

Volociximab is a high affinity anti-angiogenic α5β1 integrin inhibitor that blocks the binding of α5β1 to Fibronectin. It is a chimeric (82% human/18% murine) IgG4 monoclonal antibody (Mab) and has been shown in preclinical studies to induce apoptosis in proliferating endothelial cells. In addition, its potent anti-angiogenic effect has been demonstrated to be independent of the upstream growth factor (i.e. VEGF, bFGF, IL-2 etc.) stimulation.

Volociximab administration has resulted in strong inhibition of rabbit and primate retinal neovascularization. In cynomologous monkeys with laser-induced choroidal neovascularization (CNV), volociximab significantly inhibited CNV proliferation and reduced the degree of lesion formation. In a rabbit model, volociximab administered either intravenously or intravitreally prior to the onset of neovascularization significantly reduced angiogenesis as compared to control. Similar anti-angiogenic efficacy with volociximab has also been shown in multiple preclinical models of tumor angiogenesis. α5β1 antagonism with volociximab holds great promise for the treatment of dry and wet forms of age-related macular degeneration. Ophthotech’s phase 1 study with volociximab in age-related macular degeneration will commence shortly.