The first stage of the study will evaluate the safety and relative pharmacodynamic effect of different doses of subcutaneously administered D-4517.2 compared to intravitreal injection of aflibercept, an approved therapy, in both wet AMD and DME patients up to 12 weeks.
Ashvattha Therapeutics today announced that the first patient has been enrolled in a two-stage Phase 2 clinical study of D-4517.2, an HDT with potent anti-VEGF activity.
According to a company news release, the study aims to evaluate the safety and efficacy of a subcutaneous (SC) injection of D-4517.2 at different dose levels in comparison to intravitreal (IVT) injection of aflibercept, an approved therapy, in patients suffering from wet age-related macular degeneration (wet AMD) or diabetic macular edema (DME).
According to the company, D-4517.2 is a hydroxyl dendrimer therapeutic (HDT) with potent anti-angiogenic activity inhibiting VEGFR/PDGFR that crosses the blood-retinal barrier and selectively targets reactive inflammatory cells. Hydroxyl dendrimers (HDs) selectively target choroidal neovascular lesions that underlie wet AMD and DME pathology.
HDs are selectively taken up by macrophages, microglia and hypertrophic retinal pigment epithelial (hRPE) cells and are retained in the lesion for at least 1 month after a single systemic dose. Current therapies have been shown to suppress neovascularization in animals and humans but have significant off-target toxicity when administered systemically.
Covalently linking an anti-angiogenic small molecule to Ashvattha’s hydroxyl dendrimer creates a new chemical entity that could potentially solve the toxicity issues while retaining potency. In-vitro studies in hRPE cells 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.
Jeffrey Cleland, PhD, chairman and CEO of Ashvattha Therapeutics, pointed out that the company is moving forward with the first stage of its Phase 2 study evaluating its subcutaneous anti-VEGF wet AMD and DME candidate, D-4517.2.
“We believe in its potential to not only treat neovascular retinal diseases but also reduce the burden of treatment often associated with invasive IVT injections into the eye,” he said in the news release. “A subcutaneously administered treatment offers an at-home option that patients can administer themselves.”
Cleland added that the company is proceeding into Phase 2 based on positive results from our Phase 1 study in healthy subjects that we presented at ARVO demonstrating D-4517.2 has an exceptional safety and tolerability profile at varying dose levels and has been efficacious in animal models of choroidal neovascular disease.
“The potential of HDT treatment for wet AMD and DME is in the systemic administration combined with the high degree of selectivity for inflammatory cells in the back of the eye, targeting diseased cells, potentially reducing the VEGF levels to normal while minimizing or eliminating entirely off-target effects,” Jeffrey Heier, MD, the director of Retina Research at Ophthalmic Consultants of Boston, said in the news release. “We look forward to further exploring D-4517.2’s potential to improve the current treatment paradigm for patients.”
The first stage of the Phase 2 study (NCT05105607) will evaluate the safety of a single subcutaneous dose of D-4517.2 in approximately 30 patients with wet AMD or with DME randomized between three dosage cohorts (0.25 mg/kg, 0.50 mg/kg, an optional high dose). Patients will first undergo treatment with an IVT injection of aflibercept, then be given an SC dose of D-4517.2 up to 8 weeks later after the effects of aflibercept are no longer present (wash-out). Patients will be monitored for adverse events for up to 12 weeks following the SC administration of D-4517.2. Stage 1 of the study will also compare the reduction of subretinal fluid after a single IVT injection of aflibercept and a single SC dose of D-4517.2. Best-corrected visual acuity (BCVA) in the study eye will also be measured for each patient during the 12-week treatment period. Monitoring of the fellow eye will also be conducted.
The second stage of the study will measure the relative efficacy of different dose regimens of SC administered D-4517.2 compared to IVT aflibercept as measured by the mean change from baseline in BCVA in the study eye up to 9 months post-administration in wet AMD patients. The second stage is a double masked sham and placebo controlled non-inferiority study.