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B. D. Kuppermann, on behalf of the Ophthotech Study Group; Inhibition of 5β1 Integrin in Neovascular AMD - A Phase 1 Study. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1252.
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To assess the safety and pharmacokinetic profile of intravitreal volociximab, an α5β1 integrin antagonist, in combination with ranibizumab in wet age-related macular degeneration (AMD). Alpha5 Beta1 (α5β1) integrins are transmembrane receptors which bind to fibronectin in the extracellular matrix. This leads to intracellular signal transduction controlling critical events involved in angiogenesis such as cell proliferation, survival and migration. These α5β1 integrin mediated activities are downstream to VEGF and other activators of angiogenesis. Alpha5 Beta1 integrin antagonism has demonstrated potent anti-angiogenic effects in preclinical oncologic and ophthalmic models.
Phase 1, open label, multicenter, dose escalation study of eyes with all subtypes of choroidal neovascularization secondary to AMD. Patients receive three monthly intravitreal injections of the combination of volociximab, an anti-α5β1 integrin monoclonal antibody (0.5, 1.25 or 2.5 mg) and ranibizumab (0.5 mg). Both anti-VEGF treatment-naïve eyes (n=37) and anti-VEGF experienced eyes (n=11) were treated with the experimental regimen. Treatment-experienced eyes were investigator determined to be unresponsive to previous anti-VEGF monotherapy (lack of visual and anatomic response).
To date, all 37 treatment-naïve eyes received 2 doses of volociximab in combination with ranibizumab for wet AMD. Baseline visual acuity and OCT center point thickness (CPT) were 52.4 letters and 343 µm respectively. After 2 doses of combination therapy (week 8) the mean change in VA was +9.5 letters. Twenty-four percent of patients gained ≥3 lines of vision. The mean change in OCT center point thickness was -108 µm. To date, 11 treatment-experienced eyes received 2 doses of volociximab in combination with ranibizumab for wet AMD. Baseline visual acuity and OCT CPT were 56.5 letters and 333 µm respectively. After 2 doses of combination therapy (week 8) the mean change in VA was +5.3 letters. Eighteen percent of patients gained ≥3 lines of vision. The mean change in OCT CPT was -107 µm. Dose escalation was completed without evidence of dose-limiting toxicity.
Preliminary results of this phase 1 study of volociximab combined with ranibizumab suggest a favorable safety profile.
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