Obeticholic acid (OCA), sold under the brand name Ocaliva, is a

semi-synthetic Semisynthesis, or partial chemical synthesis, is a type of chemical synthesis that uses chemical compounds isolated from natural sources (such as microbial cell cultures or plant material) as the starting materials to produce novel compounds wit ...

bile acid Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile ...

analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used to treat

primary biliary cholangitis Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to buil ...

Intercept Pharmaceuticals Intercept Pharmaceuticals, Inc. is an American biopharmaceutical company incorporated in 2002, focusing on the development of novel synthetic bile acid analogs to treat chronic liver diseases, such as primary biliary cirrhosis (PBC) now called p ...

Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to

Dainippon Sumitomo Pharma is a Japanese multinational pharmaceutical company. The company is focused on oncology, psychiatry, neurology, women's health issues, urological diseases among other areas. Its headquarters are located in Chuo-ku, Osaka. History The original ...

Invention and development

The natural bile acid

chenodeoxycholic acid Chenodeoxycholic acid (CDCA; also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the ...

was identified in 1999 as the most active physiological

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

for the

farnesoid X receptor The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a nuclear receptor that is encoded by the ''NR1H4'' gene in humans. Function FXR is expressed at high level ...

(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 The University of Perugia ( Italian ''Università degli Studi di Perugia'') is a public university in Perugia, Italy. It was founded in 1308, as attested by the Bull issued by Pope Clement V certifying the birth of the Studium Generale. The offi ...

, 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

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

has flagged cases of serious liver injury associated with the use of obeticholic acid. The agency stated that

’ liver disease medication, Ocaliva (obeticholic acid), is under scrutiny for causing liver damage in patients without advanced scarring. This follows the FDA’s 2021 decision to restrict the drug’s use in patients with advanced

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

. On Thursday, the FDA revealed its findings of severe liver injury in individuals treated for

based on post-market clinical trial data.

Clinical studies

Obeticholic acid is undergoing development in phase II and III studies for specific liver and gastrointestinal conditions. The U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) approved obeticholic acid on 27 May 2016, for the treatment of primary biliary cholangitis. It was approved as an

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

based on its reduction in the level of the biomarker

alkaline phosphatase The enzyme alkaline phosphatase (ALP, alkaline phenyl phosphatase, also abbreviated PhoA) is a phosphatase with the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryo ...

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 Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is an autoimmune disease of the liver. It results from a slow, progressive destruction of the small bile ducts of the liver, causing bile and other toxins to buil ...

(PBC), also known as primary biliary cirrhosis, is an auto-immune, inflammatory liver disease which produces

bile duct A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. The bile duct is separated into three main parts: the fundus (superior), the body (middle), and the neck (inferior). Bile is requ ...

injury,

fibrosis Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries, ch ...

cholestasis Cholestasis is a condition where the flow of bile from the liver to the duodenum is impaired. The two basic distinctions are: * obstructive type of cholestasis, where there is a mechanical blockage in the duct system that can occur from a gallston ...

and eventual

. It is much more common in women than men and can cause

jaundice Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...

, itching (

pruritus An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

) and fatigue.

Ursodeoxycholic acid Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile o ...

therapy is beneficial, but the disease often progresses and may require

liver transplantation Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, al ...

. 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

, a

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

predictive of disease progression, liver transplantation or death.

Nonalcoholic steatohepatitis (NASH)

Non-alcoholic steatohepatitis An alcohol-free or non-alcoholic drink, also known as a temperance drink, is a version of an alcoholic drink made without alcohol, or with the alcohol removed or reduced to almost zero. These may take the form of a non-alcoholic mixed drink or n ...

is a common cause of abnormal liver function with

histological Histology, also known as microscopic anatomy or microanatomy, is the branch of biology that studies the microscopic anatomy of biological tissue (biology), tissues. Histology is the microscopic counterpart to gross anatomy, which looks at large ...

features of

fatty liver Fatty liver disease (FLD), also known as hepatic steatosis and steatotic liver disease (SLD), is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper r ...

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

and

. It may progress to

and is becoming an increasing indication for

. It is increasing in prevalence. OCA is proposed to treat NASH. A phase II trial published in 2013, showed that administration of OCA at 25 mg or 50 mg daily for six weeks reduced markers of liver inflammation and fibrosis and increased insulin sensitivity. 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. In 2023, a FDA panel voted against approval of obeticholic acid for NASH, citing a lack of evidence that the benefits of the drug outweighed the risks.

Portal hypertension

Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in

portal hypertension Portal hypertension is defined as increased portal venous pressure, with a hepatic venous pressure gradient greater than 5 mmHg. Normal portal pressure is 1–4 mmHg; clinically insignificant portal hypertension is present at portal pressures 5� ...

. An open label phase IIa clinical study is under way.

Bile acid diarrhea

Bile acid diarrhea Bile acid malabsorption (BAM), known also as bile acid diarrhea, is a cause of several gut-related problems, the main one being chronic diarrhea. It has also been called bile acid-induced diarrhea, cholerheic or choleretic enteropathy, bile salt di ...

(also called

bile acid malabsorption Bile acid malabsorption (BAM), known also as bile acid diarrhea, is a cause of several gut-related problems, the main one being chronic diarrhea. It has also been called bile acid-induced diarrhea, cholerheic or choleretic enteropathy, bile salt di ...

) can be secondary to

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...

or be a primary condition. Reduced median levels of

FGF19 Fibroblast growth factor 19 is a protein that in humans is encoded by the ''FGF19'' gene. It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a fact ...

, 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.

Society and culture

Legal status

In June 2024, the

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

of the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

concluded its review of the medicine Ocaliva (obeticholic acid) and recommended that the medicine's marketing authorization be revoked, because its benefits are no longer considered to outweigh its risks. Ocaliva is used to treat adults with primary biliary cholangitis, an autoimmune condition that causes gradual destruction of the bile ducts in the liver, which can lead to liver failure and increase the risk of liver cancer.

Research

A systematic review and meta-analysis of obeticholic acid, published in 2024, found that its effects on lipid parameters and its other adverse effects warrant further investigation.

References

{{Authority control Bile acids Cholanes Drugs acting on the gastrointestinal system and metabolism Farnesoid X receptor agonists Orphan drugs Hepatotoxins Experimental drugs developed for non-alcoholic fatty liver disease Diols