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Anti-VEGF therapy is a promising new avenue for the treatment of neovascular diseases of the eye, including exudative macular degeneration and diabetic retinopathy. Preclinical data from studies with EYE001 support clinical evaluation of its efficacy in such diseases. This report is the first to describe administration of anti-VEGF therapy in humans for exudative macular degeneration and shows the safety of such therapy for single injections. Further clinical studies are necessary to determine the safety of multiple intravitreal injections of EYE001 and larger studies are needed to prove the efficacy of this novel, potentially therapeutic agent for neovascular AMD.

The objective of this study was to determine whether genetically induced hypercholesterolemia affects leukocyte-endothelial cell interactions in postcapillary venules of the mouse cremaster muscle. Leukocyte adhesion, emigration, and other microvascular parameters were assessed in venules of normal (wild-type) and low-density lipoprotein receptor-deficient (LDLr-/-) mice maintained on either normal rodent chow or on a high cholesterol diet (HCD). Measurements were obtained under control conditions and after administration of either leukotriene B4 (LTB4), platelet-activating factor (PAF), or tumor necrosis factor-alpha (TNF-alpha). Elevated numbers of adherent and emigrated leukocytes were observed in venules of LDLr-/- (compared with wild-type) mice on HCD, both under baseline conditions and after exposure to either LTB4, PAF, or TNF-alpha. Plasma TNF-alpha levels were also elevated in LDLr-/- versus wild-type mice. Administration of blocking monoclonal antibodies demonstrated that intercellular adhesion molecule-1, but not vascular cell adhesion molecule-1, mediates the exaggerated leukocyte-endothelial cell adhesion observed in LDLr-/- mice. The results of these studies indicate that chronic hypercholesterolemia predisposes the microvasculature to intense leukocyte-endothelial cell adhesion in response to different inflammatory stimuli.

OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.