Rationale for Treating Wet AMD in Human Using an Oral Pill Consisting of a VEGFR/PDGFR Inhibitor X-82

Abstract

Purpose: To analyze the pre-clinical and clinical safety and biologic activity of X-82, a VEGFR/PDGFR inhibitor.

Methods: X-82 was evaluated in vitro and via oral administration in a rat CNV model, focusing on safety and biologic activity. The safety and pharmacokinetic properties of X-82 in cancer patients were analyzed to define the doses that might be safe and effective in AMD patients.

Results: VEGFR and PDGFR inhibition occurred with <50 nM in the HUVEC tube formation model. In the rat CNV model, 10 mg/kg dosed orally once a day showed >80% inhibition of CNV. Oral administration of X-82 in cancer patients was well tolerated with no Grade 2 or higher toxicities at exposures of 5191 ng.hr/ml and Cmax of 942 nM. At 50mg once a day, the mean AUC, Cmax and Ctrough levels were 1282 ng.hr/ml, 268 nM and 41 nM, respectively.

Conclusions: Oral administration of X-82 at 50mg once a day achieved exposures well above the concentration required to inhibit new blood vessel formation; this level was < ¼ of the well tolerated exposure noted in cancer patients, suggesting that the dose should be well tolerated and could be efficacious in treating wet AMD patients. A pilot clinical study of X-82 in patients with wet AMD has started.

Keywords: 412 age-related macular degeneration • 453 choroid: neovascularization • 748 vascular endothelial growth factor