Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism

Summary

The purpose of this study is to assess the effects of an investigational drug, PF-05221304 (PF'1304) on the way the liver handles fat. The planned study will identify why the fat in the blood increases at the same time this drug reduces fat in the liver. The study will have two treatment periods of 6 weeks each, separated by a 3 week rest period with no treatment. The subjects will receive the active drug in one of the 6 week treatment periods and a placebo in the other 6 week period. The investigators will know when the subjects are receiving active treatment or placebo, but the subject will not know.

Timeline

Start

2020-12

Primary completion

2021-08-19

Completion

2021-08-19

Publications

• Background Choi SH, Ginsberg HN. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab. 2011 Sep;22(9):353-63. doi: 10.1016/j.tem.2011.04.007. Epub 2011 May 26.
• Background Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005 May;115(5):1343-51. doi: 10.1172/JCI23621.
• Background Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab. 2003 Nov;29(5):478-85. doi: 10.1016/s1262-3636(07)70061-7.
• Background Kim CW, Addy C, Kusunoki J, Anderson NN, Deja S, Fu X, Burgess SC, Li C, Ruddy M, Chakravarthy M, Previs S, Milstein S, Fitzgerald K, Kelley DE, Horton JD. Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. Cell Metab. 2017 Aug 1;26(2):394-406.e6. doi: 10.1016/j.cmet.2017.07.009.
• Background Goedeke L, Bates J, Vatner DF, Perry RJ, Wang T, Ramirez R, Li L, Ellis MW, Zhang D, Wong KE, Beysen C, Cline GW, Ray AS, Shulman GI. Acetyl-CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents. Hepatology. 2018 Dec;68(6):2197-2211. doi: 10.1002/hep.30097.
• Background Reyes-Soffer G, Moon B, Hernandez-Ono A, Dionizovik-Dimanovski M, Jimenez J, Obunike J, Thomas T, Ngai C, Fontanez N, Donovan DS, Karmally W, Holleran S, Ramakrishnan R, Mittleman RS, Ginsberg HN. Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans. Sci Transl Med. 2016 Jan 27;8(323):323ra12. doi: 10.1126/scitranslmed.aad2195.
• Background Ramakrishnan R, Ramakrishnan JD. Using mass measurements in tracer studies--a systematic approach to efficient modeling. Metabolism. 2008 Aug;57(8):1078-87. doi: 10.1016/j.metabol.2008.03.011.
• Background Hellerstein MK, Neese RA. Mass isotopomer distribution analysis at eight years: theoretical, analytic, and experimental considerations. Am J Physiol. 1999 Jun;276(6):E1146-70. doi: 10.1152/ajpendo.1999.276.6.E1146.
• Background Caulfield MP, Li S, Lee G, Blanche PJ, Salameh WA, Benner WH, Reitz RE, Krauss RM. Direct determination of lipoprotein particle sizes and concentrations by ion mobility analysis. Clin Chem. 2008 Aug;54(8):1307-16. doi: 10.1373/clinchem.2007.100586. Epub 2008 May 29.

Drugs

Indications