Obeticholic acid (OCA), 6α-ethyl-3α,7α-dihydroxy-5-cholan-24-oic acid, is a semisynthetic derivative of the chenodeoxycholic acid (CDCA, 3α,7α-dihydroxy-5-cholan-24-oic acid), a relatively hydrophobic primary bile acid synthesized in the liver from cholesterol. OCA, also known as 6-ethyl-CDCA or INT-747, was originally described by investigators at the Perugia University in 2002 as a selective ligand for the bile acid sensor, farnesoid-X-receptor (FXR). In addition to FXR and similarly to CDCA, OCA also activates GPBAR1/TGR5, a cell membrane G protein-coupled receptor for secondary bile acids. In 2016, based on the results of phase II studies showing efficacy in reducing the plasma levels of alkaline phosphatase, a surrogate biomarker for disease progression in primary biliary cholangitis (PBC), OCA has gained approval as a second-line treatment for PBC patients nonresponsive to UDCA. The use of OCA in PBC patients associates with several side effects, the most common of which is pruritus, whose incidence is dose-dependent and is extremely high when this agent is used as a monotherapy. Additionally, the use of OCA associates with the increased risk for the development of liver failure in cirrhotic PBC patients. Currently, OCA is investigated for its potential in the treatment of nonalcoholic steatohepatitis (NASH). Phase II and III trials have shown that OCA might attenuate the severity of liver fibrosis in patients with NASH, but it has no efficacy in reversing the steatotic component of the disease, while reduces the circulating levels of HDL-C and increases LDL-C. In summary, OCA has been the first-in-class of FXR ligands advanced to a clinical stage and is now entering its third decade of life, highlighting the potential benefits and risk linked to FXR-targeted therapies.
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