Abstract 5458: VIA-3196, a Liver-directed Thyroid Beta Agonist for Treating Cardiometabolic Disease

Abstract

Thyroid hormone has beneficial metabolic benefits such as cholesterol, triglyceride and glucose lowering primarily through its action in the liver. However, in excess, TH causes adverse effects in heart and bone primarily mediated by the THR-alpha receptor. VIA-3196 is a novel THRbeta receptor selective (17/1 relative to TH) thyromimetic with high hepatic uptake and the possibility of providing metabolic benefits and avoiding adverse effects on the thyroid axis, heart and bone. In a rodent hypothyroid model, as compared with TH (T3), VIA-3196 showed no upregulation of a TH regulated gene in the heart even at high doses. In hypercholesterolemic rabbits, VIA- 3196 lowered non-HDL cholesterol alone or in synergy with atorvastatin up to 50% (p<0.001), increased the HDL/LDL ratio, and lowered plasma triglycerides 35% (p<0.05) alone and 50% (p<0.001) in combination with atorvastatin. In hypercholesterolemic rats, VIA-3196 lowered non-HDL cholesterol 73%, (p<0.005) and liver triglycerides 66% (p<0.0001), and did not decrease TSH, whereas T3 had little effect on cholesterol or liver triglycerides at doses that suppressed TSH. Steatosis is a major cause of liver insulin resistance (IR) and non-alcoholic steatohepatitis. In preclinical mouse models of IR, at doses as low as 0.3 mg/kg VIA-3196 reduced plasma cholesterol 40% (p<5×10 −6 ) and liver triglycerides 51% (p<0.05). In mouse models of IR, VIA-3196 at 1 mg/kg improved insulin sensitivity as demonstrated by an insulin tolerance test (p<0.05), lowered glucose to a near normal level (p<0.05) similar to rosiglitazone, and unlike rosiglitazone, did not cause weight gain. Hepatic gene expression studies suggest that VIA-3196 may lower cholesterol through increasing cholesterol metabolism and biliary excretion (upregulation of Cyp7A1, ABCB11), perhaps increasing reverse cholesterol transport. Interestingly, VIA-3196 downregulated hepatic inflammatory genes CRP and Saa2 (serum amyloid a2) that are associated with cardiovascular risk. VIA-3196 demonstrates good pharmaceutical properties predictive of qd dosing in humans. VIA-3196 has the potential to provide benefit to patients with diabetes and dislipidemia and ultimately, reduce their risk from atherosclerotic cardiovascular disease.