Abstract
Purpose :
Neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) are associated with abnormalities in the retina, retinal pigment epithelium (RPE) and choroid. AR-13503, a Rho kinase and protein kinase C inhibitor, has therapeutic potential in nAMD and DME based on testing in in vitro and in vivo models. We have developed a biodegradable AR-13503 Implant that provides linear in vitro drug release for more than 100 days. Here, we investigated the distribution of AR-13503 in ocular tissues for up to 6 months following administration of AR-13503 Implants in Dutch-belted rabbits and YucatanTM minipigs.
Methods :
AR-13503 Implant was administered via bilateral intravitreal injections in rabbits and minipigs. Animals were sacrificed at predetermined timepoints for pharmacokinetic analysis. The levels of AR-13503 in aqueous humor (AH), cornea, lens, iris/ciliary body (ICB), vitreous, retina, RPE/choroid, conjunctiva, plasma, and recovered implants were determined by LC/MS/MS.
Results :
In rabbits, AR-13503 concentrations in retina and RPE/choroid reached levels that demonstrated therapeutic effects in in vitro RPE barrier function assays and in a mouse model of proliferative diabetic retinopathy. AR-13503 concentrations were at or above this target for 5 months, followed by a gradual decline through Month 6. The concentrations of AR-13503 in AH, cornea, lens, ICB, vitreous humor and conjunctiva never exceeded 20% of the drug concentration in the retina and RPE/choroid. In addition, AR-13503 levels in plasma were below the limit of quantitation (<0.1 ng/mL) at all timepoints, suggesting minimal systemic exposure. The amount of AR-13503 in the recovered implants decreased with time in a linear fashion with <0.1% remained at Month 6. Fundus examination revealed no morphological abnormalities during the 6-month study period. A similar ocular tissue distribution pattern was observed in minipigs after intravitreal injection of AR-13503 Implant, with the exception of the ICB, where AR-13503 levels were similar to those in the retina and RPE/choroid.
Conclusions :
These results demonstrated that single intravitreal administration of AR-13503 Implant was well tolerated and has the potential to deliver effective levels of AR-13503 to the retina and RPE/choroid for a period of 5-6 months for the treatment of nAMD and DME.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.