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B. D. Kuppermann, S. Patel; Beyond Anti-VEGF in Wet AMD: Interference of Cell Survival Signals by Targeting a5b1 Integrin (Volociximab) in Subjects with Wet AMD. Invest. Ophthalmol. Vis. Sci. 2009;50(13):964.
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Alpha5 Beta1 (a5b1) integrins are transmembrane receptors that bind to extracellular matrix, specifically fibronectin. This leads to intracellular signal transduction controlling critical events involved in angiogenesis such as cell proliferation, survival and migration. These a5b1 integrin mediated activities are downstream to VEGF and other activators of angiogenesis. a5b1 integrin antagonism has resulted in potent anti-angiogenesis in ocular and oncology preclinical models. The current study tests the safety of intravitreal Volociximab, an a5b1 integrin antagonist, on subjects with wet AMD.
A phase 1 safety study of a5b1 integrin antagonist with an anti-a5b1monoclonal antibody (Volociximab) in combination with Lucentis® is in progress (clinical trial registration number NCT00782093). This is a two-part Phase 1 open-label study. In Part 1 (ascending part) up to 18 subjects total receive 3 monthly intravitreal administrations of volociximab in treatment-naïve eyes at one of 3 doses (up to 6 subjects per group receiving 0.5, 1.25 or 2.5 mg in ascending order) in combination with monthly ranibizumab 0.5 mg. In Part 2, the (parallel group) 14 subjects are to be enrolled in each of the following treatment groups: 1) Anti-VEGF Experienced Eyes - volociximab monotherapy for 3 monthly administrations, or 2) Treatment-Naïve Eyes - volociximab given in combination with ranibizumab 0.5 mg for 3 monthly doses. Two volociximab dose levels will be chosen for Part 2, based on the results of Part 1 of the study.
12 sites in the USA are participating in the study, and study recruitment is actively underway. Results to date of the initial patients at the 0.5mg dose in this phase 1 safety study of a5b1 integrin antagonism in combination with Lucentis® for wet AMD suggest that Volociximab appears to be safe. Dose escalation is in progress in this first ever study of a monoclonal antibody approach for a5b1 integrin antagonism in AMD. Study design and results to date are to be presented.
a5b1 integrin antagonism inhibits neovascularization via a pathway distinct to VEGF with pre-clinical evidence that these two pathways may complement each other.
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