Abstract
Purpose :
To evaluate the preclinical efficacy of subcutaneously administered D-4517 in a mouse model of laser-induced choroidal neovascularization (CNV) and its toxicity in a repeat dose rat study.
Methods :
D-4517, a novel analog of sunitinib chemically conjugated to a hydroxyl dendrimer, selectively targets inflammation in CNV lesions. D-4517 is not metabolized and is renally excreted. Laser-induced rupture of Bruch’s membrane was performed in both eyes of C57BL/6 mice (n=8/group) 24 hr prior to dose administration. Mice were dosed with a single subcutaneous (SC) administration of D-4517 at a total mass dose of 40, 200 or 1000 µg. As a positive control group, a cohort of mice were administered aflibercept intravitreally (IVT; 1 µL, 40 µg). The CNV area was measured 14 days after laser treatment by both fluorescein angiography and flat-mounts of the sclera-choroid/RPE complexes stained with Isolectin. To assess the toxicity of D-4517, a repeat dose study was conducted in Sprague Dawley rats (10 male/10 female per group). Rats were dosed daily for 14 days with 30 mg/kg sunitinib (PO) or 12 mg/kg D-4517 (IP; matched exposure to sunitinib) or a single dose of 168 mg/kg D-4517 (IP). Toxicokinetics, clinical evaluation, pathology, and histology were performed on all animals.
Results :
A single SC dose of D-4517 (40 µg) resulted in comparable inhibition of CNV to a single IVT aflibercept dose (40 µg). All doses of D-4517 resulted in a significant inhibition of CNV formation compared to the vehicle control with all three dose levels resulting in comparable levels of CNV lesion area suggesting further dose reductions may be feasible. In the toxicology study, free sunitinib was associated with various clinical and pathological changes in addition to mortality in female rats. D-4517 was well-tolerated following single or repeated dosing with no clinical or histologic indications of toxicity.
Conclusions :
After a single SC dose, D-4517 effectively inhibits CNV formation comparable to the same mass dose of aflibercept IVT. Previous studies demonstrated that HDs persist inside cells in the CNV lesion for at least one month after a systemic injection. Repeat dose toxicology in rats support at least an 80-fold safety factor for the effective dose. Taken together, these studies support the development of D-4517 as a potential once per month less invasive SC treatment for wet AMD.
This is a 2021 ARVO Annual Meeting abstract.