A vascular endothelial growth factor receptor inhibitor (VEGFRi) achieves topical efficacy in rat and monkey models of choroidal neovascularization (CNV)

Abstract

Purpose: To explore the topical and oral pharmacokinetics (PK) and efficacy in rats and monkeys of CA-26-UY62 (UY62), a small molecule inhibitor of VEGF receptor-2

Methods: UY62 inhibits VEGFR-2 in a biochemical assay with an IC50 of 8.5 ± 3.3 nM. UY62 or vehicle was dosed topically (4 µL of 0.1 - 3% to both eyes) and q.d. orally (0.1 - 3 mg/kg/day) on day 0 - day 11 in a Brown Norway rat model of laser-induced CNV. Laser was applied on day 0 approximately I hour after the first dose, CNV area measured 12 days later by i.v. injection of a vascular label, flat mounts imaged and analysis of CNV area performed by morphometric analysis. There were 4 laser pulses per eye, 10 rats per group yielding 80 data points per group. In parallel, the ocular PK of oral (1 mg/kg/day q.d.) or topical (1% t.i.d.; 1.2 mg/kg/day) UY62 was determined in rats after the first dose and after a single dose on day 12. To demonstrate efficacy in a larger eye, cynomolgus monkeys were lasered (9 double spots to both eyes) and analyzed by fluorescein angiography (FA) at 2, 3, and 4 weeks. Lesions were graded 1 - 4.The number of Grade 4 lesions (lesions with bright hyperfluorescence and late leakage) were assessed. Monkeys were either dosed topically with 30 µL of 3% UY62 (~ 2 mg/kg/day) or placebo t.i.d. daily or with two IVT doses of 0.5 mg of Lucentis 2 weeks apart. Plasma PK was measured after 33 days of topical dosing.

Results: The oral ED50 and ED90 of UY62 in rats were 0.3 and 0.7 mg/kg respectively and the topical ED50 and ED90 of UY62 were 0.6 and 2.3% (based on 8 or 9 dose-response experiments for each dosing route). CNV fluorescein leakage studies in cynomolgus monkeys dosed with placebo showed 42, 37, and 33% grade 4 lesions at week 2, 3, and 4 respectively. Monkeys dosed topically with UY62 had grade 4 lesions reduced by 64 - 72%, compared to 94 - 100% with IVT Lucentis.<br /> Rat ocular and plasma PK were similar on day 1 and day 12 with no evidence of drug accumulation. However, the plasma AUC of UY62 on day 12 was 3 fold lower in topically dosed rats compared to orally dosed rats (12.7 vs 3.5 µM.h). In monkeys, the plasma AUC on day 37 with 3% t.i.d. formulation was lower than the plasma AUC in rats dosed with 1% t.i.d. (1.1 vs 3.5 µM.h).<br />

Conclusions: Topical UY62 is efficacious in both rat and monkey CNV models.