Non-clinical evaluation of YN001-a promising drug for atherosclerotic therapy by targeted delivery system

Abstract Background Atherosclerosis (AS) is a systemic disease and the common cause of heart attacks, strokes and peripheral vascular disease collectively referred to as cardiovascular diseases (CVD). In AS plaques, CD44 is upregulated and functionally activated on vascular endothelial cells, smooth muscle cells, and macrophages. YN001 is a liposome encapsulated Rosuvastatin calcium which was initially approved for the reduction of cholesterol levels and slowing the progression of atherosclerosis. YN001 is being developed for the treatment of AS by targeted enrichment of Rosuvastatin in the local atherosclerotic plaques by CD44 active targeting ability of HPD, one of the components of liposome. Purpose Investigating pharmacology, PK and toxicity of YN001 to evaluate its clinical use potential for AS patients. Results As expected, YN001 could bind to CD44 with KD as 485.5pm while there’s no binding affinity of non-targeted liposome (encapsulate Rosuvastatin without HPD). In stimulated human macrophages in which CD44 was overexpressed, YN001 showed enhanced uptake and higher cholesterol effluxion ability than Rosuvastatin, meanwhile more MCP-1 reduction was also observed. In ApoE AS mice model, single YN001 administration showed much higher drug concentrations in the plaque of aortas compared to Rosuvastatin (oral or iv) or non-targeted liposome which demonstrated targeted enrichment ability by HPD. With repeat treatment of YN001 at 5mg/kg in AS mice model, atherosclerotic plaque weight decreasing and plaque area reduction were observed, following MCP-1 reduction. YN001 may down-regulate the expression of inflammatory signaling pathways, such as chemokine-related signaling pathway to reduce the inflammatory response of atherosclerotic plaques to decrease plaque levels. In pharmacokinetic studies in rats and dogs, YN001 had much higher exposure in plasma and prolonged existence compared to Rosuvastatin i.v administration. A comprehensive safety evaluation package was performed in rats and dogs including safety pharmacology, general toxicity, genotoxicity, immunotoxicity and local tolerance. Results showed YN001 has promising safety with NOAEL as 40mg/kg in both or rats and dogs. Conclusion YN001 demonstrated excellent efficacy in AS model, a favorable pharmacokinetic and safety profiles in rats and dogs. These support its FDA IND approval and phase I study is ongoing to investigate further character in clinical.Efficacy and pharmacokinetics resultsSafety evaluation