Abstract
Purpose :
Many factors are involved in retinal diseases such as diabetic macular edema (DME). Current anti-vascular endothelial growth factor (VEGF) therapies alone are not enough to improve vision in DME patients. Integrins have been shown to affect inflammation, fibrosis and neurodegeneration, and have become important new targets for the potential treatment of retinal diseases. We have developed AG-73305 as a next generation biologic for the treatment of various retinal diseases including DME by targeting both VEGF and integrins simultaneously. Here we profiled the ocular pharmacology, pharmacokinetics, and safety of AG-73305 to support its advancement to full development.
Methods :
The in vitro binding potency of AG-73305 (0.01 – 1.5 nM) was assessed using ELISAs for αvβ3 and α5β1. Potency was also assessed in a VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation assay in the absence or presence of AG-73305 (0.01 – 10 nM). The in vivo efficacy was examined in a VEGF-induced retinal leakage model in rabbits (N=6 eyes/group) following intravitreal doses of up to 1 mg/eye. In addition, the ocular pharmacokinetics were determined in rabbits over 28 days following a single 1 mg intravitreal dose, and the ocular safety was evaluated following 2-monthly intravitreal injections of purified AG-73305 to nonhuman primates (NHPs) at doses up to 2 mg/eye.
Results :
AG-73305 showed in vitro binding potencies (EC50) of 0.056 ± 0.004 nM and 0.278 ± 0.016 nM for αvβ3 and α5β1, respectively. AG-73305 inhibited VEGF-induced HUVEC proliferation with an IC50 of 0.083 nM. AG-73305 (0.03 – 1 mg/eye) showed a robust dose-dependent reduction in VEGF-induced vascular leakage compared to vehicle (p<0.0001). AG-73305 showed equal or better response compared to aflibercept or bevacizumab. Ocular pharmacokinetic studies in rabbits showed a half-life of 3.2 days in the vitreous compartment. Lastly, AG-73305 showed a good ocular safety profile in NHPs.
Conclusions :
AG-73305 is being developed for the treatment of DME and other retinal diseases.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.