Results suggest favorable safety for combination strategy targeting AMD

Volociximab is a chimeric monoclonal antibody targeting α5β1 integrin, which is a transmembrane receptor expressed on activated vascular endothelial cells. Binding between α5β1 integrin and its natural ligand, fibronectin, is a step in the angiogenesis cascade that results in proliferation and migration of vascular endothelial cells and ultimately new blood vessel formation. Volociximab interferes with angiogenesis by blocking binding of α5β1 integrin with fibronectin, said Dr. Kuppermann, professor of ophthalmology and biomedical engineering, University of California at Irvine.

The patients enrolled in the phase I study of volociximab plus ranibizumab had treatment-naïve subfoveal neovascular AMD of any angiographic subtype, lesion size up to 5 disc areas, and ETDRS visual acuity ranging from 20/63 to 20/200. They received a series of three combination treatments at monthly intervals composed of ranibizumab 0.5 mg plus volociximab 0.5, 1.25, or 2.5 mg.

The gains in vision were accompanied by anatomic benefit. Optical coherence tomography (OCT) evaluations using spectral-domain (eight patients) or time-domain (29 patients) technology showed central subfield thickness was reduced about 30% by week 4 and was relatively stable thereafter. The only adverse event judged to be related to volociximab was worsening of central macular edema at week 1 in a single eye, but visual acuity was not affected and the issue resolved within 1 week.

"Anti-vascular endothelial growth factor (VEGF) therapy with ranibizumab has been a major step forward in the treatment of neovascular AMD, but there is continued excitement about the prospect of developing combination regimens using modalities with a different mechanism of action that may have additive or synergistic effects with anti-VEGF agents," Dr. Kuppermann said. "Upregulation of α5β1 integrin receptors is pathologic in neovascular tissue and occurs as a downstream event to VEGF upregulation in the angiogenic cascade so that there is great interest in the potential of using volociximab in a combination strategy.

"Based on the scientific rationale for using volociximab together with anti-VEGF therapy and the results obtained in this phase I study, further investigation in a randomized controlled trial is warranted," he said.