A Safety and Pharmacokinetic Study of a Novel Hydrogel-based Axitinib Intravitreal Implant (OTX-TKI) in Non-Human Primates

Abstract

Purpose : Current anti-VEGF therapy for wet age-related macular degeneration (wet AMD) is rapidly cleared from the vitreous and requires injections every 1-2 months. OTX-TKI is a novel, hydrogel-based intravitreal implant designed to deliver a tyrosine kinase inhibitor, axitinib, for up to 6-9 months for the treatment of neovascular retinal diseases. Here we characterize the ocular distribution of axitinib from OTX-TKI implant following a single intravitreal injection in non-human primates.

Methods : Cynomolgus monkeys received intravitreal injections of either three 200 µg- (group 1, n=8), one 300 µg- (group 2, n=8) or one 600 µg- (group 3, n=8) OTX-TKI implant(s) bilaterally on Day 0. Experimental doses were selected to study the effects of dose and number of implants on distribution of axitinib. Ocular exams with slit lamp, intraocular pressure (IOP), confocal scanning laser ophthalmoscopy (cSLO) images and plasma samples were collected throughout the 9-month study. Subsets of eyes were enucleated at 3, 6 and 9 months to collect retina, choroid/retinal pigment epithelium (RPE), vitreous and aqueous humor tissue samples and analyzed for axitinib levels.

Results : OTX-TKI was well tolerated in all groups. No significant inflammatory response to OTX-TKI or clinically significant changes in IOP were observed. High axitinib levels in retina tissue were measured at Month 3 (>900 IC₅₀) and Month 6 (>16,000 IC₅₀) for all groups (Figure 1). Drug distribution in retina and choroid/RPE was higher in group 1 at Month 3, but comparable across all groups at Month 6. By Month 6, groups 1 and 2 implants released ~50% and group 3 implants released 35% of the dose in the vitreous. Daily release rates in group 1 implants were higher than groups 2 and 3 likely due to the larger surface area with the three implants used in group 1 only. Implant degradation was observed around Month 6 and released axitinib particles were visible in the vitreous at Month 9 (Figure 2). Plasma samples at Month 3 from all groups were below the level of quantification of axitinib (0.1 ng/mL) indicating minimal systemic exposure.

Conclusions : OTX-TKI delivered high levels of axitinib to retinal tissue and was generally well tolerated in non-human primates with no signs of significant inflammation. OTX-TKI is currently being investigated in humans for the treatment of wet AMD in a U.S.-based Phase 1b clinical trial.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.