Pharmacokinetics and Ocular Tolerability of Suprachoroidal CLS-AX (axitinib injectable suspension) in rabbits

Abstract

Purpose : Axitinib is a potent and selective tyrosine kinase inhibitor that achieves pan-VEGF inhibition through receptor blockade (VEGFR-1, -2, and -3). In neovascular age-related macular degeneration (nAMD), such pan-inhibtion of VEGFRs may have efficacy advantages over existing anti-VEGF-A monotherapy. Topical and systemic axitinib have been shown to inhibit corneal, retinal and choroidal neovascularization in animal models. Given the durability potential of small molecule suspensions in the suprachoroidal space, the pharmacokinetics (PK) and ocular tolerability of suprachoroidal axitinib suspension (CLS-AX) was assessed in rabbits.

Methods : Male Dutch-Belted (DB) pigmented rabbits (age: 4-6 months; N=2 rabbits/ timepoint) were utilized to assess ocular tolerability and PK of CLS-AX. A single bilateral suprachoroidal injection (100 µL) of CLS-AX was administered at 0.03 mg/eye (group 1) or 0.1 mg/eye (group 2). Retinal pigment epithelium-choroid-sclera (RCS), neural retina, vitreous humor, aqueous humor and blood were collected, at pre-determined timepoints for up to 10 weeks, and analyzed for drug content via LC-MS-MS. PK parameters were estimated using Phoenix WinNonLin, version 6.2.1.

Results : Suprachoroidal CLS-AX was generally well tolerated in DB rabbits. No overt signs of toxicity were observed in this study. Sustained and high exposure of Axitinib was observed in RCS throughout the 10-week study. Mean RCS levels at week 10 (C_last) were 138 ng/g and 4400 ng/g for Groups 1 and 2, respectively, that are 1153X and 36667X higher than the in-vitro (VEGFR autophosphorylation inhibition) IC₅₀ value. Mean retina levels reached maximum values (C_max) of 4480 and 6260 ng/g, at 24 hours postdose (T_max) for Groups 1 and 2, respectively. The vitreous levels were 4 to 5 orders of magnitude lower than in retina. No quantifiable axitinib was detected in either aqueous humor or plasma throughout the study. Preliminary estimation of human ocular levels suggests that suprachoroidal CLS-AX (0.1 mg/eye) may provide axitinib levels in choroid-retina that are >1000X higher than the in-vitro IC50 value, through 6 months.

Conclusions : Suprachoroidal CLS-AX provides sustained, safe and targeted delivery of axtinib to the back of the eye. Given the durability, intrinsic high potency and pan-VEGF inhibition, suprachoroidal CLS-AX has potential to be a bi-annual therapy for nAMD.

This is a 2020 ARVO Annual Meeting abstract.