ARVO 2023: Preclinical data for Ashvattha Therapeutics anti-VEGF nanomedicine D-4517.2 shared at annual meeting

D-4517.2 is a novel precision nanomedicine that inhibits neovascularization by targeting activated microglia and hypertrophic retinal pigment cells, cells responsible for the increased vascularization associated with neovascular age-related macular degeneration (wet AMD) and diabetic macular edema (DME). (Image Credit: Adobe Stock/Eric Hood)

At the 2023 ARVO annuall meeting, Ashvattha Therapeutics presented two preclinical data sets demonstrating the efficacy of its anti-angiogenic precision nanomedicine, D-4517.2. According to the company, this novel precision nanomedicine inhibits neovascularization by targeting activated microglia and hypertrophic retinal pigment cells, cells responsible for the increased vascularization associated with neovascular age-related macular degeneration (wet AMD) and diabetic macular edema (DME).

“Patients suffering from wet AMD and DME often have to endure injections directly into the eye at a specialist’s office in order to find any relief,” said Jeff Cleland, CEO, co-founder, and chairman of Ashvattha.

Cleland also pointed out the data supports the development of an oral formulation of D-4517.2 as an alternative to injections while greatly reducing the treatment burden on patients.

"The preclinical data also builds on previous findings that demonstrate our precision nanomedicines selectively target regions of inflammation at a cellular level and cross biological barriers including the blood-retinal barrier," he said.

Natacha Le Moan, Ph, Head of Translational Sciences at Ashvattha gave an oral presentation titled "Oral Formulation Development of the Anti-Angiogenesis Drug D-4517.2 to Treat Age-related Macular Degeneration (wet AMD) and Diabetic Macular Edema (DME)" in which she discussed the efficacy of the oral formulation of D-4517.2 in a mouse model of wet AMD.

Key highlights from presentation:

• Results indicated that a single subcutaneous dose of D-4517.2 (40 mg) significantly reduces CNV lesion area by~2-fold compared to vehicle control, which is consistent with previous observations and comparable with aflibercept efficacy.
• A single oral dose of D-4517.2 (40 mg) also significantly reduces CNV lesion area and vascular leakage by ~2-fold. A 200 mg oral dose further reduces the CNV lesion area by ~3.5 fold.
• These results suggest that oral administration of D-4517.2 has similar efficacy to aflibercept, and similar bioavailability when given orally or subcutaneously. This study supports the development of D-4517.2 as a potentially safe and effective oral agent for patients suffering from wet AMD or DME.

Elia Duh, a collaborator from Johns Hopkins University presented a poster titled "Suppression of subretinal neovascularization in Vldlr knockout mice by systemic administration of a targeted VEGF-receptor inhibitor," in which he discussed the cellular localization and efficacy of D-4517.2 in a wet AMD mouse model.

Key highlights from poster presentation:

• The study evaluated the localization of D-4517.2 in Vldr -/- knockout mice, an animal model with symptoms of type III wet AMD after birth.
• Results indicated the nanomedicine conjugated with a fluorophore (D-Cy5) colocalized with activated microglia and macrophages within regions of ocular inflammation in Vldr-/- mice.
• Oral and subcutaneous administration of D-4517.2 significantly reduces the number of CNV lesions in Vldlr-/- mice suggesting a benefit of selectively inhibiting VEGFR in activated microglia/macrophages and RPE cells in the retina and choroid. The data further support that systemic administration of D-4517.2 is effective in reducing neovascular lesions associated with AMD and selectively targets activated microglia and macrophages.