Safety and Tolerability of a Single Subcutaneous Dose of Anti-Angiogenesis Drug to Treat Neovascular Age-related Macular Degeneration (wet AMD) and Diabetic Macular Edema (DME)

Abstract

Purpose : To evaluate the toxicology, safety, and tolerability of D-4517.2 in rats, dogs and humans at doses anticipated to be efficacious in the treatment of wet AMD and DME.

Methods : D-4517.2 is comprised of a hydroxyl dendrimer covalently linked to a potent inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. A single subcutaneous (SC) or oral dose of D-4517.2 inhibited choroidal neovascularization (CNV) comparable or better than a single intravitreal injection of aflibercept in laser-induced CNV mice¹. Single-dose GLP toxicology, safety pharmacology studies (rat neurobehavioral and pulmonary studies, dog cardiovascular study, in vitro hERG ionic conductance study) and genotoxicology studies were conducted. A healthy volunteer Phase 1 study has been initiated with regulatory approval to enroll single ascending SC cohorts (n=4/cohort) from 0.25 to 2 mg/kg D-4517.2.

Results : A single SC dose of D-4517.2 was generally well tolerated in rats at levels up to 1000 mg/kg and at levels up to 200 mg/kg in dogs with a no-observed-adverse-effect level of 200 mg/kg. In vitro and rat genotoxicity tests conducted up to limit doses were negative. No findings of toxicologic importance were obtained in safety pharmacology evaluations in rats or dogs treated with D-4517.2 up to doses of 1000 mg/kg and 200 mg/kg, respectively. Analysis of the pharmacokinetics in mice, rats and dogs enabled allometric scaling to determine that the potential efficacious human doses are 0.25 to 2 mg/kg. A Phase 1 study is ongoing and the safety, tolerability, and pharmacokinetics of a single SC dose of D-4517.2 in healthy volunteers will be presented.

Conclusions : The GLP toxicology and safety pharmacology studies conducted in rats and dogs indicated a 100-fold safety margin above the maximum proposed human single SC dose (2.0 mg/kg D-4517.2). Allometric scaling of the D-4517.2 efficacious SC doses in the laser-induced CNV mouse model indicated that a SC dose of D-4517.2 of 0.25 to 2 mg/kg may be effective in treating patients with wet AMD or DME. Although D-4517.2 is renally cleared within 24 hours in animals, CNV lesion formation was suppressed for 2 weeks after a single SC in the CNV mouse model¹. D-4517.2 may provide a safe SC administered chronic anti-angiogenesis treatment.

¹Cleland et al, 2021, IOVS vol 62, 205

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