First‐in‐class fatty acid synthase inhibitor TVB‐2640 reduces hepatic de novo lipogenesis in males with metabolic abnormalities

: Elevated hepatic de novo lipogenesis (DNL) is a key distinguishing characteristic of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In rodent models of NAFLD, treatment with a surrogate of TVB-2640, a pharmacological inhibitor of FAS (FASi), has been shown to reduce hepatic fat and other biomarkers of DNL. The purpose of this Phase I clinical study was to test the effect of the TVB-2640 in obese men with certain metabolic abnormalities that put them at risk for NAFLD. Twelve subjects (mean±SE, 42±2y, BMI 37.4±1.2 kg/m2 , glucose 103±2 mg/dL, TG 196±27 mg/dL, and elevated liver enzymes) underwent 10 days of treatment with TVB-2640 at doses ranging from 50-150 mg/d. Food intake was controlled throughout the study. Hepatic DNL was measured before and after an oral fructose/glucose (F/G) bolus using isotopic labeling with 1-13 C1 -acetate IV infusion, followed by measurement of labeled VLDL-palmitate via GC/MS. Substrate oxidation was measured by indirect calorimetry. Across the range of doses, fasting DNL was reduced by up to 90% (P=0.003). Increasing plasma concentrations of TVB-2640 were associated with progressive reductions in the percent of fructose-stimulated peak fractional DNL (R2 = - 0.749, P=0.0003) and absolute DNL AUC 6h post F/G bolus (R2 = - 0.409, P=0.025). For all subjects combined, ALT was reduced by 15.8±8.4% (P=0.05). Substrate oxidation was unchanged and safety monitoring revealed that the drug was well tolerated, without an increase in plasma triglycerides. Alopecia occurred in two subjects (reversed after stopping the drug), but otherwise no changes were observed in fasting glucose, insulin, ketones, and renal function. These data support the therapeutic potential of FASi, TVB-2640 in particular, in patients with NAFLD and NASH.