(3α,5β,6α,7α)-6-Ethyl-3,7-dihydroxycholan-24-oic acid OR (4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
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.[5] FXR-dependent processes in liver and intestine were proposed as therapeutic targets in human diseases.[6] Obeticholic acid is the first FXR agonist to be used in human drug studies.[medical citation needed]
Clinical studies
Obeticholic acid is undergoing[when?] development in phase II and III studies for specific liver and gastrointestinal conditions.[7] 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.[8] 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.[9] Additional studies are being required to prove its clinical benefit.[10]
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.[11] 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.[12] Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC.[13] OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses.[14][15] 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.[16]
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.[17] 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.[18]
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.[19] 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.[20]
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.[21][22]
Portal hypertension
Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in
portal hypertension.[23] An open label phase IIa clinical study is under way.[when?][citation needed]
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.[24] FGF19 is potently stimulated by bile acids and especially by OCA.[25] A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit.[26]
FDA label update
In February 2018, the FDA updated label warnings for obeticholic acid to better explain recommended dosing. According to the agency, a misunderstanding led some health care professionals to improperly dose the drug on a daily basis rather than weekly, which can increase the risk of liver damage.[27]
^Gioiello A, Macchiarulo A, Carotti A, Filipponi P, Costantino G, Rizzo G, et al. (April 2011). "Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine". Bioorganic & Medicinal Chemistry. 19 (8): 2650–2658.
doi:
10.1016/j.bmc.2011.03.004.
PMID21459580.
^Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, et al. (August 2002). "6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity". Journal of Medicinal Chemistry. 45 (17): 3569–3572.
doi:
10.1021/jm025529g.
PMID12166927.
^Rizzo G, Renga B, Mencarelli A, Pellicciari R, Fiorucci S (September 2005). "Role of FXR in regulating bile acid homeostasis and relevance for human diseases". Current Drug Targets. Immune, Endocrine and Metabolic Disorders. 5 (3): 289–303.
doi:
10.2174/1568008054863781.
PMID16178789.
^"Cirrhosis". The Lecturio Medical Concept Library. 28 September 2020. Retrieved 9 July 2021.
^Hirschfield GM, Gershwin ME (January 2013). "The immunobiology and pathophysiology of primary biliary cirrhosis". Annual Review of Pathology. 8: 303–330.
doi:
10.1146/annurev-pathol-020712-164014.
PMID23347352.
^Fiorucci S, Cipriani S, Mencarelli A, Baldelli F, Bifulco G, Zampella A (August 2011). "Farnesoid X receptor agonist for the treatment of liver and metabolic disorders: focus on 6-ethyl-CDCA". Mini Reviews in Medicinal Chemistry. 11 (9): 753–762.
doi:
10.2174/138955711796355258.
PMID21707532.
^Adorini L, Pruzanski M, Shapiro D (September 2012). "Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis". Drug Discovery Today. 17 (17–18): 988–997.
doi:
10.1016/j.drudis.2012.05.012.
PMID22652341.