Those with NAFLD have excessive levels of fat build-up within the liver, despite no obvious direct cause such as high alcohol consumption. The most common risk factors are obesity and type 2 diabetes; those who are overweight or have metabolic syndrome are also at risk.
NAFLD can progress to a much more dangerous form of disease, non-alcoholic steatohepatitis (NASH), which can be a precursor to other life-threatening conditions, including cirrhosis or liver failure, liver cancer or cardiovascular disease. Treatment currently relies on weight loss (diet and exercise), but there is a lot of interest among pharmaceutical companies in developing drugs.
One such treatment is TVB-2640, being developed by Sagimet Biosciences. The compound is a novel first-in-class inhibitor of fatty acid synthase or FASN.
This is a key enzyme in the de novo lipogenesis (DNL) pathway that’s responsible for the synthesis of excess liver fat in NASH patients and the activation of fibrogenic and inflammatory mechanisms in their livers. Preclinical trials showed that not only does blocking FASN reduce liver fat, it also directly reduces fibrosis and inflammation.
A Phase I trial was done in 12 obese men with metabolic abnormalities that put them at risk of developing NAFLD.1 Subjects were given doses ranging from 50–150 mg/day for 10 days; their food intake was controlled throughout the duration of the study.
Hepatic de novo lipogenesis (DNL) was measured both before and after an oral bolus of glucose/fructose with carbon-13 labelling followed by the GCMS measurement of labelled LDL. Fasting DNL was reduced by up to 90% whereas increasing plasma concentrations of the drug were associated with progressive reductions in the percentage of fructose-stimulated peak fractional DNL.
The biomarker alanine aminotransferase (ALT) was also reduced.
A Phase II randomised placebo-controlled trial has also been done in 99 patients with NASH, most of whom had type 2 diabetes.2
Liver fat reduction was measured using an MRI technique and biomarkers including ALT monitored. Subjects were given 25 or 50 mg doses of the drug daily and a clear dose-dependent effect on liver fat reduction was observed: a 9.6% decline with the lower dose and 25% with the higher dose, compared with a 4.5% increase in the placebo group.
Improvements in serum markers of inflammation and fibrosis were also seen, plus decreases in ALT levels. Adverse events were predominantly mild.
A larger Phase IIb clinical trial in NASH patients with stage 2–3 fibrosis, with outcomes monitored using liver biopsy, is now being planned. It is expected to start in the first half of 2021.
References
- M.M. Syed-Abdul, et al., Hepatology 72, 103 (2020).
- R. Loomba, et al., AASLD 2020 (13–16 November 2020), Abst. 0067.
