Abstract
Purpose :
As a potent, selective tyrosine kinase inhibitor, axitinib inhibits VEGF receptors 1, 2, and 3. Pan-VEGF inhibition may be more effective versus current anti-VEGF-A monotherapy, which upregulate other angiogenic factors, including VEGF-C. In animal models, it inhibits corneal, retinal, and choroidal angiogenesis. Thus, the potential of CLS-AX as long-acting therapy for nAMD was assessed.
Methods :
Ocular distribution and PK of CLS-AX were assessed in Dutch-Belted pigmented rabbits. A single bilateral suprachoroidal (SC) injection (100µL) of CLS-AX was administered to each eye as 0.03 mg/eye (group 1) or 0.1 mg/eye (group 2). Efficacy was evaluated in laser-induced choroidal neovascularization (CNV) models in rats and pigs. Brown Norway rats (n=10) were dosed once weekly for two weeks (0.2 mg/ 5µLs/ eye), Weanling pigs (n=8) were treated with 4 mg of CLS-AX in the right eye (OD) and with saline in the left (OS). Retinal lesions were evaluated on fundus photography, fluorescein angiography (FA) and on retinal flat mount tissue (n=16 eyes) by measuring the isolectin IB4 signal.
Results :
CLS-AX was generally well tolerated with no overt signs of toxicity. No axitinib was detected in either plasma or aqueous humor; sustained, high exposure was observed through the 10-week study, highest in the sclera/choroid/RPE>retina> vitreous; preliminary estimation of human ocular levels suggests that SC CLS-AX may provide levels in choroid-retina that are >1000X higher than the in-vitro IC50 value through 6 months. In rats, CLS-AX decreased the incidence of clinically important lesions (scores of 3 or 4) where 8/20 eyes (40%) showed a general improvement (scores of 0 to 2) by Day 21 compared to the control group. In pigs, CLS-AX significantly reduced fluorescein leakage at weeks 1 and 2 (p<0.009 for both) compared to the control. IB4 quantification indicated significantly reduced growth of new blood vessels (p=0.03) at the site of the retinal laser lesion compared to saline treatment.
Conclusions :
CLS-AX was well tolerated with durability in the SC space. Results from the laser CNV studies corroborate others, showing inhibition of neovascularization in animal models. Given this PD effect, ability to directly target affected tissues, and intrinsic highly potent pan-VEGF inhibition through receptor blockade, CLS-AX has potential as long-acting therapy for nAMD.
This is a 2020 ARVO Annual Meeting abstract.