Oral Formulation Development of the Anti-Angiogenesis Drug D-4517.2 to Treat Age-related Macular Degeneration (wet AMD) and Diabetic Macular Edema (DME)

Abstract

Purpose : D-4517.2 is a new precision nanomedicine technology inhibiting vascular endothelial growth factor receptor tyrosine kinases selectively in reactive microglia and hypertrophic retinal pigment epithelial (RPE) cells. In a Phase I clinical trial, subcutaneous (SC) administration of D-4517.2 in healthy subjects was safe and well tolerated at dose levels up to 2.0 mg/kg. Here, we evaluate the effect of three oral formulations of D-4517.2 on the development of choroidal neovascularization (CNV) in a laser-induced CNV mouse model and compare the efficacy of D-4517.2 with intravitreal Aflibercept.

Methods : Laser-induced rupture of Bruch’s membrane was performed in both eyes of C57BL/6 mice (n=6-8/group) 24 hours prior to administering a single dose of D-4517.2 subcutaneously (40 µg) or by oral gavage at 2 dose levels (40 and 200 µg). Three excipients were examined for oral dosing: salcaprozate sodium (SNAC), disodium EDTA and sucrose laurate. A cohort of mice received aflibercept intravitreally (IVT; 1 µL, 40 µg) as a positive control. The effect of D-4517.2 and aflibercept on the CNV lesion growth were measured 14 days after laser injury using fluorescein angiography and staining of the RPE-choroid-sclera flat mounts with Isolectin.

Results : The CNV lesion area was significantly reduced by ~2-fold (**p<0.01) in mice treated with a single SC dose of D-4517.2 (40 µg) compared to the vehicle control group, consistent with previous observations and comparable with aflibercept¹. A single oral dose of D-4517.2 with the SNAC excipient provided superior efficacy compared to EDTA and sucrose laurate. When administered with the SNAC excipient, D-4517.2 (40 µg) significantly reduced both CNV lesion area and vascular leakage by ~2-fold (**p<0.01), suggesting comparable SC and oral bioavailability. The CNV lesion area was further reduced by ~3.5-fold (****p<0.0001) with a higher dose of D-4517.2 (200 µg) in the SNAC excipient.

Conclusions : A single oral dose of D-4517.2 significantly reduced CNV lesions to a level comparable to SC D-4517.2 and IVT aflibercept at a same mass dose. These preclinical studies support the development of D-4517.2 as a potential safe and effective oral agent that can be administered chronically to wet AMD and DME patients, eliminating the need for frequent IVT injections.

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

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.