Obeticholic acid used to treat primary biliary cholangitis

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www.aasraw.com 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. 3.Obeticholic acid Clinical studies Obeticholic acid is undergoing development in phase 2 and 3 studies for specific liver and gastrointestinal conditions. The United States Food and Drug Administration granted accelerated approval to Ocaliva 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. 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 3 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. Nonalcoholic steatohepatitis (NASH) Non-alcoholic steatohepatitis is a common cause of abnormal liver function with histological features of fatty liver, inflammation and fibrosis. It may progress to cirrhosis and is becoming an increasing indication for liver transplantation. It is increasing in prevalence. OCA is proposed to treat NASH. A phase 2 trial published in 2013 showed that administration of OCA at 25 mg or 50 mg daily for 6 weeks reduced markers of liver inflammation and fibrosis and increased insulin sensitivity. 2 aas15@aasraw.com
www.aasraw.com The Farnesoid X Receptor Ligand Obeticholic Acid in Nonalcoholic Steatohepatitis Treatment (FLINT) trial, sponsored by NIDDK, 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. Portal hypertension Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in portal hypertension. An open label phase 2a clinical study is under way. 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.[19] 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. 4.The dosage of Obeticholic acid Obeticholic (oh bet" i koe' lik) acid is a synthetically modified bile acid that is a potent agonist of the farnesoid X nuclear receptor (FXR), a nuclear receptor with major effects on bile acid synthesis and transport as well as lipid metabolism and glucose homeostasis. Obeticholic acid has been shown to improve serum enzymes in several diseases including nonalcoholic steatohepatitis (NASH) and primary biliary cholangitis (PBC, previously known as primary biliary cirrhosis). Obeticholic acid was given provisional approval for use in the United States for primary biliary cholangitis in 2016 and is currently under evaluation in other liver diseases including primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH). Obeticholic acid is available as tablets of 5 and 10 mg under the brand name Ocaliva. The typical initial dose for primary biliary cholangitis is 5 mg once daily which can then be increased to a maximum of 10 mg daily. Patients with advanced cirrhosis (Child's Class B or C) are advised to start at a dose of 5 mg once weekly and increase thereafter based upon tolerance and 3 aas15@aasraw.com
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Obeticholic acid used to treat primary biliary cholangitis

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