Ashvattha Therapeutics Presents Phase 1 Safety Data in Healthy Subjects for Subcutaneous Anti-VEGF Wet AMD and DME Candidate
Ashvattha Therapeutics announced the presentation of safety data from a phase 1 study of its lead candidate D-4517.2, a VEGFR/PDGFR tyrosine kinase inhibitor conjugated to a hydroxyl dendrimer, at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, taking place in Denver, CO, May 2-4, 2022.
The data were presented in a poster titled, “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),” accessible here. The data showed that single subcutaneous doses of D-4517.2 were safe and well tolerated in healthy subjects at dose levels of 0.25 mg/kg, 0.50 mg/kg and 1.0 mg/kg.
“We are encouraged by the safety and tolerability data on D-4517.2 from the three cohorts and are currently recruiting the fourth cohort at a dose level of 2.0 mg/kg, and plan on initiating a phase 2 study in wet AMD and DME patients in the coming weeks,” Jeffrey Cleland, PhD, Chairman, CEO & President of Ashvattha Therapeutics, said in a company news release. “Current treatments for wet AMD and DME, degenerative retinal diseases, require invasive, intravitreal injections into the eye, which can be a treatment burden on patients and doctors. We are advancing this first-in-class therapy to enable patients the convenience of self administration with an autoinjector up to once a month in the comfort of their home.”
The doses selected for clinical trials were based on preclinical efficacy studies and allometric scaling to humans. In animal toxicology studies, D-4517.2 demonstrated no evidence of genotoxicity and showed local reversible changes at the injection site when administered at dosages several times higher than the effective dose range determined for humans. These animal studies indicated a D-4517.2 dose range of 0.25 mg/kg to 1.0 mg/kg in humans may provide comparable effects to that observed in a choroidal neovascular (CNV) mouse model.
The phase 1 study of healthy human volunteers was conducted in three cohorts of 0.25 mg/kg, 0.50 mg/kg and 1.0 mg/kg subcutaneous doses. The results also showed good tolerability, with adverse events limited to mild transient injection site reactions to be addressed with injection method changes. There were no significant changes in safety labs or other adverse reactions to the treatment.
Hydroxyl dendrimers (HDs) selectively target CNV lesions that underlie wet AMD and DME pathology. HDs are selectively taken up by macrophages, microglia and hypertrophic retinal pigment epithelial (RPE) cells and are retained in the lesion for at least 1 month after a single systemic dose. Similar VEGFR/PDGFR tyrosine kinase inhibitors have been shown to suppress neovascularization in animals and humans but have significant off target toxicity when administered systemically. Covalently linking the tyrosine kinase inhibitor to Ashvattha’s hydroxyl dendrimer creates a new chemical entity that could potentially solve the toxicity issues while retaining potency. In-vitro studies in a retinal pigment cell line with D-4517.2 demonstrated restoration of VEGF mRNA to normal, healthy levels. The lack of toxicity is the result of D-4517.2’s renal clearance with no significant exposure to the liver or detectable metabolism as observed with other clinical stage HDTs.