Abstract
Purpose :
Wet age-related macular degeneration (wAMD) is the leading cause of vision loss in adults over the age of 50. Current first-line therapies include biologics that target vascular endothelial growth factor (VEGF). Research has indicated that platelet-derived growth factor (PDGF) may play an important role in the pathogenesis of the disease with its involvement in both retinal neovascularization and fibrosis formation. AG-67650 was developed to inhibit VEGF (clinically validated target), plus PDGF to improve vision in wAMD patients. Here we describe the characterization of AG-67650 by evaluating its ocular pharmacology and pharmacokinetics.
Methods :
The in vitro potency of AG-67650 (0.01 – 30 nM) was assessed using binding assays against VEGF and PDGF. In addition, cell-based proliferation assays stimulated with either VEGF (in HUVECs) or PDGF (in 3T3 cells) were used to assess AG-67650’s inhibitory effect. AG-67650 (0.1 – 1 mg/eye) was also assessed in a VEGF-induced retinal leakage model in rabbits (N=6 eyes/group). Lastly, the ocular pharmacokinetics were characterized following a single intravitreal dose to rabbit eyes over 28 days (1 mg/eye).
Results :
AG-67650 has in vitro binding EC50s towards VEGF and PDGF ranging from 0.38 – 0.54 nM and 2.2 – 2.9 nM, respectively. In proliferation assays, AG-67650 was able to inhibit VEGF and PDGF stimulation, with an IC50 ranging from 0.11 – 0.38 nM and 0.27 – 0.7 nM, respectively. In a dose-response study using a VEGF-induced retinal leakage model in rabbits, all doses of AG-67650 significantly reduced vascular leakage compared to vehicle (p<0.0001) and were comparable to aflibercept or bevacizumab. Following a single intravitreal dose to rabbits, the vitreal half-life of AG-67650 was 4.3 days, suitable for monthly injections.
Conclusions :
AG-67650, a bi-specific fusion protein, demonstrated efficacy for inhibiting both VEGF and PDGF in vitro and in in vivo efficacy pre-clinical models, and has potential for use in wAMD treatment.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.