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Obeticholic Acid for the Treatment of Nonalcoholic Steatohepatitis

Obeticholic acid (OCA) is a synthetic analogue of chenodeoxycholic acid designed to have a much stronger, nanomolar potency as a farnesoid X receptor agonist than the native bile acid. Because of its biliary structure, OCA is conjugated in the intestine and thus undergoes an enterohepatic cycle. Farnesoid X receptor (FXR) agonism by OCA takes place both in the ileal epithelial cell (where it induces secretion of fibroblast growth factor 19 (FGF19) in the circulation) and in the hepatocyte. The concerted action of FGF19 acting in the hepatocyte through its cognate receptor and of direct hepatocyte agonism of FXR results in a tight control and downregulation of bile acid synthesis from cholesterol. However, FXR agonism in the hepatocytes also has other effects: mostly an inhibition of lipogenesis, inhibition of neoglycogenesis, as well as antiinflammatory actions. The antifibrotic actions of FXR agonism do not seem to be exerted directly on stellate cells but are rather indirect, by reducing inflammatory mediators in macrophages and sinusoidal endothelial cells. OCA, which is approved for patients with primary biliary cholangitis refractory or intolerant to ursodeoxycholic acid, has also been tested successfully in nonalcoholic steatohepatitis (NASH). Remarkably, it is so far the only drug for which a large phase 3 trial, the REGENERATE trial, has confirmed, at an interim analysis, the results of a phase 2b smaller trial with histological endpoints.