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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-C5
There is mounting evidence that both the wet and dry forms of AMD are primarily the result of an inflammatory process. Patients with AMD are known to have elevated systemic inflammatory biomarkers such as CRP, IL-6 and homocysteine [1, 2]. Furthermore, surgically excised choroidal neovascular tissue in patients with AMD contain inflammatory cells. Drusen are crystalline deposits under the retina and are the hallmark of AMD. Recent studies have implicated local inflammation and activation of the complement cascade in their formation [3]. Preclinical laser-induced choroidal neovascular models have implicated complement activation as well. Evidence for complement-mediated inflammation in AMD is further reinforced by genetic linkage and association studies which suggest that approximately 50 to 75% of AMD cases have polymorphism in complement regulatory proteins compared to age-matched controls [4, 5, 6, 7]. These findings have been confirmed by multiple independent labs and published in leading peer-reviewed journals such as Science, The New England Journal of Medicine, JAMA and PNAS. The complement pathway is part of the innate immune system and is a complex system of serum proteins which interact in a cascade. This complement cascade is activated via the classical (antibody-dependent), the alternative (antibody-independent) and the lectin pathways. By reducing or abating the increased complement activation occurring in macular degeneration, it may be possible to slow down or arrest the disease process. Thus, molecules involved in inhibition of complement activation and in complement regulation become prime targets for therapeutic intervention in AMD. Anti-C5 aptamer ARC1905 is a potent and specific inhibitor of complement activation. ARC1905 is a pegylated RNA aptamer. ARC1905 inhibits C5, a central component of the complement cascade, which plays multiple roles in innate immunity and inflammatory diseases. Inhibition of this key step in the complement cascade at the level of C5 prevents the formation of key terminal fragments (C5a and C5b-9) regardless of which pathway (alternate, classical or lectin) induced their generation. The C5a fragment is an important inflammatory activator inducing vascular permeability, recruitment and activation of phagocytes. C5b-9 is involved in the formation of membrane attack complex (MAC: C5b-9) which initiates cells lysis. By inhibiting these C5-mediated inflammatory and MAC activities, therapeutic benefit may be achieved in both dry as well as wet AMD.
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