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VITAE PHARMACEUTICALS, INC filed this Form S-1 on 08/12/2014
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is approximately a 30-fold dose difference between the dose that increases the expression of ABCA1 and ABCG1 and the dose that causes the induction of plasma and liver TG levels.

Blood ABCA1
(Day 14)

  Blood ABCG1
(Day 14)
  Plasma Triglycerides


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Figure 17: Cynomolgus monkeys were dosed once-a-day for 14 days with VTP-38443. Levels of mRNA for ABCA1 and ABCG1 were measured in blood as well as plasma TG levels.

        We also tested the ability of VTP-38443 to promote RCT and reduce atherosclerosis in mice. For the RCT experiment, VTP-38443 was administered to mice, and the mice were injected with macrophages loaded with labeled cholesterol. The amount of labeled cholesterol in feces was determined over 48 hours after dosing. VTP-38443 treatment significantly increased the excretion of labeled cholesterol at both doses, indicating an increase in RCT in the treated mice.

        Finally, we tested the ability of VTP-38443 to prevent cholesterol accumulation and decrease inflammation in a cholesterol rich plaque in an experimental mouse model of accelerated atherosclerosis. Animals were put on a high fat diet for two weeks. The left common carotid artery, an artery in the neck that supplies blood to the brain, was then surgically ligated and the mice continued the high fat diet for two additional weeks. Under these conditions, atherosclerotic lesions form within the ligated carotid artery characterized by an increase in cholesteryl esters as well as an increase in vascular inflammation, both characteristics of an unstable atherosclerotic plaque. VTP-38443 was orally administered to these mice starting at the time of ligation surgery, and as shown in Figure 18 below, it produced a significant, dose-dependent decrease in cholesteryl esters at all doses, while demonstrating minimal change in TGs. In addition, vascular inflammation was diminished at all doses as evidenced by a decrease in the FDG-6-phosphate, an indirect marker of vascular inflammation. As such, VTP-38443 had a significant and potent anti-atherosclerotic effect in this experimental model of an unstable atherosclerotic plaque.


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Figure 18: VTP-38443 significantly decreased carotid cholesteryl ester content and vascular inflammation in a mouse model of experimental atherosclerosis.

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