|Other names||6α-ethyl-chenodeoxycholic acid; INT-747|
|Drug class||Modified bile acid|
|Main uses||Primary biliary cholangitis|
|Side effects||Itching, tiredness, liver problems|
|Typical dose||5 mg/wk to 10 mg/day|
|US NLM||Obeticholic acid|
|Chemical and physical data|
|Molar mass||420.634 g·mol−1|
|3D model (JSmol)|
|Melting point||108–110 °C (226–230 °F) |
Obeticholic acid (OCA), sold under the brand name Ocaliva, is a medication used to treat primary biliary cholangitis. It is generally used in addition to ursodeoxycholic acid when this is insufficiently effective. It is taken by mouth.
Common side effects include itching and tiredness. Other side effects may include liver problems. It is a modified form of bile acid and works by attaching to farnesoid X receptors and decreasing bile production by the liver.
Obeticholic acid was approved for medical use in the United States and Europe in 2016. In the United Kingdom it costs the NHS about £2,400 per month as of 2021. In the United States this amount costs about 8,000 USD.
Primary biliary cholangitis
Primary biliary cholangitis (PBC), also known as primary biliary cirrhosis, is an auto-immune, inflammatory liver disease which produces bile duct injury, fibrosis, cholestasis and eventual cirrhosis. It is much more common in women than men and can cause jaundice, itching (pruritus) and fatigue. Ursodeoxycholic acid therapy is beneficial, but the disease often progresses and may require liver transplantation. Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC. OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses. The results of a randomized, double-blind phase III study of OCA, 5 mg or 10 mg, compared to placebo (POISE) were presented in April 2014, and showed that the drug met the trial's primary endpoint of a significant reduction in serum alkaline phosphatase, a biomarker predictive of disease progression, liver transplantation or death.
The natural bile acid chenodeoxycholic acid was identified in 1999 as the most active physiological ligand for the farnesoid X receptor (FXR), which is involved in many physiological and pathological processes. A series of alkylated bile acid analogues were designed, studied and patented by Roberto Pellicciari and colleagues at the University of Perugia, with 6α-ethyl-chenodeoxycholic acid emerging as the most highly potent FXR agonist. FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases. Obeticholic acid is the first FXR agonist to be used in human drug studies.
The U.S. Food and Drug Administration (FDA) approved obeticholic acid on May 27, 2016, for the treatment of primary biliary cholangitis. It was approved as an orphan drug based on its reduction in the level of the biomarker alkaline phosphatase as a surrogate endpoint for clinical benefit. It is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. Additional studies are being required to prove its clinical benefit.
Society and culture
Obeticholic acid is being studied for a number of liver and gastrointestinal conditions.
Non-alcoholic steatohepatitis (NASH) OCA is proposed treatment. A trial was halted early in January 2014, after about half of the 283 subjects had completed the study, when a planned interim analysis showed that a) the primary endpoint had been met and b) lipid abnormalities were detected and arose safety concerns. Treatment with OCA (25 mg/day for 72 weeks) resulted in a highly statistically significant improvement in the primary histological endpoint, defined as a decrease in the NAFLD Activity Score of at least two points, with no worsening of fibrosis. 45% (50 of 110) of the treated group had this improvement compared with 21% (23 of 109) of the placebo-treated controls. However concerns about longterm safety issues such as increased cholesterol and adverse cardiovascular events may warrant the concomitant use of statins in OCA-treated patients.
Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in portal hypertension. An open label phase IIa clinical study is under way.[when?]
Bile acid diarrhea
Bile acid diarrhea (also called bile acid malabsorption) can be secondary to Crohn's disease or be a primary condition. Reduced median levels of FGF19, an ileal hormone that regulates increased hepatic bile acid synthesis, have been found in this condition. FGF19 is potently stimulated by bile acids and especially by OCA. A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit.
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