Abstract
Purpose :
Age-related macular degeneration (AMD) remains the most significant cause of vision loss in patients over the age of 65. One of the late-stage complications of AMD involves a slow degeneration of the photoreceptors and RPE in the retina leading to geographic atrophy and severe loss of central vision. AVD104, sialic acid coated nanoparticle (NP) has shown promising therapeutic potential in vitro and in vivo mouse models of macular degeneration that are currently in Phase 2 human clinical trials. In these studies, we assess the ocular and systemic toxicity safety pharmacology parameters of AVD-104 following intravenous-IV and intravitreal-IVT administration
Methods :
Battery of systemic safety pharmacology, genotoxicity studies in (rabbit and NHP), dosing (IV, weekly, IVT monthly low dose and bimonthly higher doses, and assessments (Ames, micronuclear, organ weight, structural abnormalities, hERG, respiratory safety, CNS safety, systemic exposure, and histopathology) were conducted to support AVD-104 safety profile
Results :
In the pivotal toxicity studies, a single bilateral dose of AVD-104 was well tolerated in both rabbits and monkeys, with no gross findings, organ weight changes, or systemic microscopic findings observed post-IVT administration of AVD-104. Genotoxicity studies and chronic repeat-dose studies did not reveal any structural abnormalities in systemic or ocular tissues, or any inflammation or adverse effects. Safety pharmacology studies including hERG in vitro assay, a respiratory study in rats, central nervous system study in mice was well tolerated and did not exhibit any safety concerns, post 5 IV injections of AVD-104. No significant elevation or accumulation of sialic acid was observed above endogenous levels in predose group when compared to AVD-104 treated groups. Repeat dose ocular histopathology in rabbits showed no structural abnormalities, inflammation, or retinal degeneration post 2 intravitreal injections of AVD-104. Single and multi-dose IVT injections exhibited safety with nonadverse clinical or ocular effects
Conclusions :
The nonclinical safety assessment of AVD-104 for safety pharmacology, genotoxicity, and ocular toxicity studies suggested a well-tolerated, safe drug with no systemic or ocular toxicity. These preclinical studies highlight the safety of AVD104, supporting our ongoing clinical trials as a promising candidate with a great safety profile and efficacy
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.