NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Abstract

Non-alcoholic fatty liver disease is highly prevalent in overweight and obese children and adults. It progresses to steatohepatitis (with raised liver transaminase levels) and fibrosis, and eventually to cirrhosis. Detecting this, excluding other causes of liver disease, and monitoring its progress takes up much resource in the obesity clinic. But, frustratingly, there are currently no effective treatments, other than weight loss. The hormone fibroblast growth factor 19 (FGF19) is produced by the gut in response to absorption of bile acids and it acts on hepatocytes via the receptor functional growth factor receptor 4 (FGFR4). Here, it is shown to markedly reduce liver fat content, steatohepatitis, and non-invasive serum biomarkers of fibrosis, probably by acting on multiple pathogenic pathways. FGF19 is a potent inhibitor of bile acid synthesis and inhibits fatty acid synthesis and de novo lipogenesis. Recent data show that FGF19 also decreases markers of hepatic inflammation, and improves markers of fibrosis in patients with primary sclerosing cholangitis. There were concerns that endogenous FGF19 also confers hepatocellular carcinoma, but so far the engineered FGF19 analogue, NGM282, appears to be non-tumorigenic.