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P. Hnik, J. G. Clement, S. J. Ono, S. P. Henry; iCo-007, a VEGF "+" Agent for the Potential Treatment of Diabetic Macular Edema and Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3503.
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To describe background and pre-clinical results of iCo-007 - a new agent for potential treatment of ocular angiogenesis and vascular permeability, including diabetic macular edema.
Angiogenesis is a complex process involving multiple growth factors and cellular processes. iCo Therapeutics Inc. is developing iCo-007, a second generation antisense inhibitor targeting C-raf kinase mRNA, for treatment of retinal neovascular diseases such as diabetic retinopathy (including diabetic macular edema) and age-related macular degeneration. The approach is to use an antisense inhibitor to reduce expression of C-raf kinase to block both growth factor and integrin mediated signal transduction, thus inhibiting both vascular permeability and angiogenic processes. C-raf kinase is a component of the mitogen-activated protein (MAP) kinase signaling pathway and this MAP kinase pathway has been shown to be important in growth factor signaling, integrin signaling and vascular permeability. Recent literature indicates that growth factors other than VEGF (such as EPO, HGF, etc.) may be equally important in the etiology of diabetic retinopathy, including diabetic macular edema. Down-regulating the MAP kinase pathway has the potential to block signaling of these multiple growth factors, and to inhibit both cellular activation and differentiation processes, possibly providing a more robust effect. Both, in vivo and in vitro, models were used to determine signs of safety and efficacy of this approach.
Pre-clinical studies revealed that iCo-007 seems to be safe, has a long t ½ in the choroid and retina of 6-8 weeks in rabbits and monkeys and shows signs of efficacy by lowering C-raf kinase expression and anatomical signs of angiogenesis in pig and mouse models.
These results indicate that by targeting multiple growth factors combined with a long half-life, iCo-007 may prove to be a potent and durable anti-angiogenic treatment requiring less frequent treatments then currently available agents. Phase I dose-escalation clinical study is in progress to evaluate safety and pharmacokinetics of a single intravitreal injection of iCo-007 in patients with diffuse diabetic macular edema. It is expected that in Phase II and III clinical studies the doses will be administered every 3 to 6 months.
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