1. Academic Validation
  2. Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils

Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils

  • Cell Metab. 2016 Aug 9;24(2):223-33. doi: 10.1016/j.cmet.2016.07.016.
Todd G Kirchgessner 1 Paul Sleph 2 Jacek Ostrowski 2 John Lupisella 2 Carol S Ryan 2 Xiaoqin Liu 2 Gayani Fernando 2 Denise Grimm 2 Petia Shipkova 2 Rongan Zhang 2 Ricardo Garcia 2 Jun Zhu 2 Aiqing He 2 Harold Malone 2 Richard Martin 3 Kamelia Behnia 2 Zhaoqing Wang 2 Yu Chen Barrett 2 Robert J Garmise 2 Long Yuan 2 Jane Zhang 2 Mohit D Gandhi 2 Philip Wastall 2 Tong Li 2 Shuyan Du 2 Lisa Salvador 2 Raju Mohan 3 Glenn H Cantor 2 Ellen Kick 2 John Lee 2 Robert J A Frost 2
Affiliations

Affiliations

  • 1 Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA. Electronic address: [email protected].
  • 2 Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
  • 3 Exelixis, Inc., South San Francisco, CA 94080, USA.
Abstract

The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR Agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRβ-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse Cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR Agonist clinical responses and emphasize the importance of further translational research in this area.

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