XL041 (BMS-852927), has a very favorable profile at efficacious doses in cynomolgus monkeys and mice. XL041 pre-treatment of C57BL/6J mice for 7 days results in potent, dose-dependent stimulation of cholesterol efflux in this system, reaching a maximum in the 3 mg/kg/day dose group of 70% above vehicle in the initial efflux rate. Similar results are obtained in LDLR knockout (KO) mice. In a separate study, XL041 inhibits the progression of atherosclerosis in a 12 week study in LDLR KO mice. Importantly, the dose response for inhibition of atherosclerosis (0.1-3 mg/kg/day) is similar to the dose response for macrophage reverse cholesterol transport (RCT) stimulation (0.03-3 mg/kg/day), a major underlying mechanism through which LXR agonists affect the disease[1].
