Abstract 18435: RVX-208: An Orally Administrated Small Molecule Reduces Atherosclerosis in ApoE Null Mouse and Raises ApoA-I/HDL in Humans
RVX-208 increases apoA-I production in vitro and in vivo. In preclinical animal models RVX-208 raises; plasma apoA-I, HDL, pre-beta HDL, large alpha HDL while promoting SR-B1-, ABCA1-, and ABCG1-mediated cholesterol efflux ex vivo. These changes in biomarkers of reverse cholesterol transport suggest that RVX-208 may be antiatherogenic. To test this possibility, apoE null mice were given a high-fat diet and 150 mg/kg of RVX-208 or vehicle b.i.d. for 12 weeks. In RVX-208 treated mice the plasma HDL-c levels were 2-fold (p<0.01) higher vs. vehicle. Additionally, biomarkers of inflammation; VCAM-1, IL-18 and MIP-1α were 17, 15 and 21% lower in treated vs. vehicle, respectively. Numbers of atherosclerotic lesions in the aortic sinus and thoracic aorta were 28% (p<0.01) and 17% (p<0.05) lower in treated mice, respectively. A phase 1b/2a human trial of RVX-208 included a low (2 mg/kg/d) and a high dose (6 mg/kg/d) of RVX-208 given to 18 subjects and 6 placebos per arm for 28d. Plasma apoA-I levels rose significantly by 5.1 and 8.2% above placebo given 8d of low- and high-doses of RVX-208, respectively. At 28d, the levels rose further by 6.5 and 10.4%, respectively. Similarly, HDL in the same subjects was higher by 6.2% and 9.2%, respectively at 8d and 7.4% and 15.1%, respectively at 28d. In subjects given a low dose of RVX-208, there was a shift in the profile towards alpha1-particles, a subfraction of HDL believed to be associated with atheroprotection. Interestingly, when subjects were grouped into tertiles according to their apoA-I at baseline, the RVX-208 induction of this parameter was most pronounced in those with the lowest level of apoA-I followed by lesser rises in the other tertiles. In summary, RVX-208 raises plasma HDL-c in apoE null mice, reducing the atherosclerotic plaque number in the aorta and in selected biomarkers of inflammation. The human 1b/2a data show the ability of RVX-208 to increase plasma levels of apoA-I/HDL in humans and identify a therapeutic range of RVX-208 that is safe and well tolerated through 28d of treatment. The finding of apoA-I and HDL being higher at 28 vs 8d points to a time dependent rise in these parameters. In subjects with low HDL, the enhanced actions of RVX-208 to raise apoA-I points to the use of this compound in such individuals.
- © 2010 by American Heart Association, Inc.