Optimized pharmacokinetic profile of intravitreal axitinib intravitreal implant (Axpaxli™): a comparison of first- and second-generation implants

Abstract

Purpose : Axitinib intravitreal implant (AXPAXLI™) is designed to deliver axitinib for 9-12 months using a bioresorbable hydrogel platform (ELUTYX™). Wet AMD clinical studies using the first-generation (Gen1) 600 µg dose showed evidence of biological activity with no drug-related ocular or systemic serious adverse events. A second-generation (Gen2) axitinib implant was developed to better synchronize release of the total dose with the durability of the hydrogel while maintaining the daily delivered dose. We performed two studies to assess the intraocular pharmacokinetics of the Gen2 axitinib intravitreal implant.

Methods : In the first study, cynomolgus monkeys received a Gen2 300 µg implant via intravitreal injection and were compared to formulations used in clinical trials (three 200 µg or one 600 µg Gen1 implants). In the second study, Dutch-belted rabbits were dosed with a Gen2 300 µg or 600 µg implant and compared to a Gen1 600 µg implant. Axitinib concentrations in the vitreous, retina, choroid/retinal pigment epithelium (RPE), and aqueous humor, were quantified over 6 months in rabbits and 9 months in monkeys.

Results : Data from monkeys showed Gen2 300 µg delivered axitinib at a faster rate to the vitreous in the first 3 months than the Gen1 600 µg and at a comparable rate to three 200 µg Gen1 implants. Both Gen1 groups, exhibited concentration spikes in the retina and choroid/RPE at 6 months correlating with hydrogel bioresorption at ~5-6 months. Gen2 300 µg implants reached steady state earlier than both Gen1 groups and maintained tissue concentrations at the time of hydrogel bioresorption (also at ~5-6 months). Temperature-influenced hydrogel bioresorption in monkeys equates to a longer ~8-9 months duration in humans, after adjusting for vitreal temperature differences. Findings in rabbits were similar, with both Gen2 groups (300µg and 600µg) achieving consistent axitinib levels in the retina and choroid/RPE through 6 months.

Conclusions : Gen2 intravitreal axitinib implants achieved higher initial axitinib concentrations rapidly in the target tissues and maintained steady state concentrations without spikes as observed with the Gen1 implants, indicating improved synchronization of drug release with hydrogel bioresorption. These findings highlight the promising pharmacokinetic profile of Gen2 axitinib implants in treating retinal vascular diseases.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.