Talk:Obeticholic acid

Synthesis
If it is semi-synthetic, where does the starter compound come from? — Preceding unsigned comment added by 66.210.101.146 (talk) 13:08, 30 June 2016 (UTC)
 * It starts from chenodeoxycholic acid, please look here: https://newdrugapprovals.org/tag/459789-99-2/

Untitled
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Revisions to Obeticholic acid page
Current: Obeticholic acid (abbreviated to OCA), is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It has also been known as INT-747. It is undergoing development as a pharmaceutical agent for several liver diseases and related disorders. Intercept Pharmaceuticals Inc. (NASDAQ symbol ICPT) hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.[2]

Revised: Obeticholic acid (abbreviated to OCA), also known as 6 α-ethyl-chenodeoxycholic acid or INT-747 and branded as Ocaliva® within the United States, is a semi-synthetic bile acid analogue. OCA is a selective and potent agonist of the farnesoid X receptor (FXR). Chemically, OCA is 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid. OCA has been granted approval by the FDA as a treatment for patients with primary biliary cholangitis (PBC) and is also undergoing development as a potential therapeutic, pharmaceutical agent for several other liver diseases and related disorders. Intercept Pharmaceuticals Inc. (NASDAQ symbol ICPT) holds the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.
 * Adds additional information on OCA, including its recent approval by the U.S. Food and Drug Administration to treat PBC

Invention and development
Current: 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.[3] FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases.[4] Obeticholic acid is the first FXR agonist to be used in human drug studies.

Revised: Primary bile acids are the endogenous ligands for the farnesoid X receptor (FXR) which is involved in the regulation of many physiological and pathological processes. The naturally occurring bile acid, chenodeoxycholic acid, was identified in 1999 as the most active physiological ligand for the FXR. 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. Specifically, the compound displayed 100x greater affinity for FXR than naturally occurring chenodeoxycholic acid. FXR-dependent processes in the liver and intestine were proposed as therapeutic targets in human diseases. Obeticholic acid is the first FXR agonist for PBC to be used in human drug studies.
 * Adds additional information on primary bile acids and farnesoid X receptor (FXR)

Clinical studies
Current: Obeticholic acid is undergoing development in phase 2 and 3 studies for specific liver and gastrointestinal conditions.[5] The FDA granted accelerated approval to Ocaliva (obeticholic acid) on 27 May 2016 for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as a single therapy in adults unable to tolerate UDCA.[6]

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.[7] Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC.[8] OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses.[9][10] 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.[11]

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.[12] 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.[13] 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.[14] 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.[15]

Portal hypertension
Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in portal hypertension.[16] 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.[17] FGF19 is potently stimulated by bile acids and especially by OCA.[18] A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit.[19]

Revised: Obeticholic acid is currently undergoing development in phase 2, 3 and 4 studies for specific chronic, non-viral liver conditions. The FDA granted accelerated approval to OCALIVA (obeticholic acid) on 27 May 2016 indicated for the treatment of primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as a single therapy in adults unable to tolerate UDCA.
 * Adds updated information on ongoing clinical studies/developments
 * Adds updated information on OCA in PBC, new research/findings and new trials
 * Adds new information on NASH including comorbidities
 * Adds information on OCA clinical trial in NASH
 * Adds new sections on the study of OCA in PSC and biliary atresia

Primary biliary cholangitis
Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an auto-immune, inflammatory liver disease which produces bile duct injury resulting in [cholestasis], fibrosis, and eventual cirrhosis. It is much more common in women than men and usually presents around the 5th decade. PBC can cause fatigue, pruritus and jaundice. Ursodeoxycholic acid therapy has been shown to be beneficial when administered early and in responsive patients 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 in PBC of OCA, 5 mg or 10 mg, compared to placebo (POISE) were published in 2016. The POISE trial found that the drug met the trial's primary composite endpoint of a significant reduction from baseline as well as measurement level in serum alkaline phosphatase (ALP), and also maintain a normal total bilirubin level.

The currently on-going COBALT Phase 3b trial is a double-blind, randomized, placebo-controlled study to evaluate the long term clinical outcomes in patients with OCA PBC treatment.

Nonalcoholic steatohepatitis (NASH)
Non-alcoholic steatohepatitis is an advanced form of the condition known as non-alcoholic fatty liver disease (NAFLD) and is a common cause of abnormal liver function with histological features of fatty liver, inflammation and fibrosis. Developing NAFLD is associated with abnormal cholesterol, high blood pressure, insulin resistance, central obesity and Type 2 Diabetes Mellitus (T2DM). In time, NASH may progress to cirrhosis and is increasing in global prevalence as well as becoming an increasing indication for liver transplantation. OCA is proposed to treat NASH. A phase 2 trial in patients with T2DM and presumed NAFLD was published in 2013 and showed that administration of OCA at 25 mg or 50 mg daily for 6 weeks reduced markers of liver inflammation and fibrosis and as well as increased insulin sensitivity.

A Phase 2b trial, 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 long-term safety issues such as increased cholesterol and adverse cardiovascular events may warrant the concomitant use of statins in OCA-treated patients.

OCA is currently being investigated in on-going Phase 2 and Phase 3 clinical trials assessing the long-term safety and efficacy of its use for the treatment of NASH.

Portal hypertension
Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in portal hypertension.[16] An open label Phase 2a clinical study is under way.
 * No changes

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.[17]FGF19 is potently stimulated by bile acids and especially by OCA.[18] A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit.[19]
 * No changes

Primary sclerosing cholangitis
A Phase 2, randomized, double-blind, placebo-controlled, dose-finding, clinical trial is currently on-going evaluating the efficacy and safety of OCA in subjects with primary sclerosing cholangitis (PSC).
 * New section

Biliary Atresia
A multicenter, randomized, open-label clinical trial of OCA in subjects with biliary atresia is ongoing.
 * New section