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    New molecule enhances effect of anti-VEGF therapy for DME

    Take-home: A subcutaneously administered molecule, AKB-9778, in combination with an anti-vascular endothelial growth factor drug, enhances the effect of the therapy on diabetic macular edema and might be beneficial for treating diabetic eye disease.

    Dr. KhananiActivation of Tie2–as a result of subcutaneous administration of AKB-9778 (Aerpio Therapeutics) in combination with an anti-vascular endothelial growth factor (anti-VEGF) therapy–enhances the effect of an anti-VEGF drug on diabetic macular edema (DME).

    Based on the results of the Time-2 trial, Tie2 appears to be a beneficial approach for treating diabetic eye disease, according to Arshad M. Khanani, MD.

    Tie2 is a transmembrane receptor expressed on vascular endothelial cells. When active, Tie2 plays a role in vascular stability in a number of ways by enhancing endothelial cellular function and viability, maintaining the integrity of the endothelial cellular junctions, inhibiting vascular inflammation, and blocking pathologic vascular leakage and neovascularization.

    “The body of evidence supporting the role active Tie2 in maintaining vascular stability is significant,” said Arshad M. Khanani, MD, managing partner, director of clinical research Sierra Eye Associates; clinical associate professor, University of Nevada Reno.

    In contrast, inactive Tie2 results in vascular destabilization, which results in vascular leakage and neovascularization, is associated with retinopathies.

    In diabetes, angiopoietin (Ang2) and vascular endothelial tyrosine phosphatase (VE-PTP) reduce Tie2 activation in the diabetic vasculature. Alteration of the ratio of Tie2 regulatory mechanisms is a first step in vascular remodeling, which is a common factor in retinopathies, i.e., diabetic retinopathy, DME, wet age-related macular degeneration (AMD), and retinal vein occlusion, Dr. Khanani explained.

    AKB-9778 inhibits VE-PTP, the most critical negative regulator and the most downstream inhibitor of Tie2, Dr. Khanani added.

    Dr. Khanani and colleagues showed in an in vivo murine experiment that pathologic neovasculature expresses high levels of VE-PTP compared to the normal vasculature. When mice with ischemic retinopathy were treated with a subcutaneous injection of AKB-9778, Tie2 activation in the neovasculature was achieved in contrast to the mice that were treated with vehicle.

    Clinical study

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