Obeticholic acid

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Obeticholic acid
Obeticholic acid.svg
Clinical data
Trade namesOcaliva
Other names6α-ethyl-chenodeoxycholic acid; INT-747
License data
Routes of
By mouth
ATC code
Legal status
Legal status
CAS Number
PubChem CID
CompTox Dashboard (EPA)
ECHA InfoCard100.238.318 Edit this at Wikidata
Chemical and physical data
Molar mass420.634 g·mol−1
3D model (JSmol)
Melting point108–110 °C (226–230 °F) [1]

Obeticholic acid (abbreviated to OCA, trade name Ocaliva), is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a drug to treat primary biliary cholangitis, and is undergoing development for several other liver diseases and related disorders. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.[2]

Invention and development[edit]

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.

Clinical studies[edit]

Obeticholic acid is undergoing development in phase 2 and 3 studies for specific liver and gastrointestinal conditions.[5] 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.[6] 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.[7] Additional studies are being required to prove its clinical benefit.[8]

Primary biliary cholangitis[edit]

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.[9] Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC.[10] OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses.[11][12] 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.[13]

Nonalcoholic steatohepatitis (NASH)[edit]

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.[14] 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.[15]

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.[16] 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.[17]

Portal hypertension[edit]

Animal studies suggest that OCA improves intrahepatic vascular resistance and so may be of therapeutic benefit in portal hypertension.[18] An open label phase 2a clinical study is under way.

Bile acid diarrhea[edit]

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.[20] A proof of concept study of OCA (25 mg/d) has shown clinical and biochemical benefit.[21]

FDA Label Update[edit]

On February 1, 2018, the FDA updated label warnings for Obeticholic acid to better explain recommended dosing. According to the agency, 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.[22]


  1. ^ Gioiello, Antimo; Macchiarulo, Antonio; Carotti, Andrea; Filipponi, Paolo; Costantino, Gabriele; Rizzo, Giovanni; Adorini, Luciano; Pellicciari, Roberto (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. PMID 21459580.
  2. ^ Wall Street Journal. "A $4 Billion Surprise for 45-Person Biotech". Retrieved 10 January 2014.
  3. ^ Pellicciari R, Fiorucci S, Camaioni E, Clerici C, Costantino G, Maloney PR, Morelli A, Parks DJ, Willson TM (August 2002). "6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity". J. Med. Chem. 45 (17): 3569–72. doi:10.1021/jm025529g. PMID 12166927.
  4. ^ 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". Curr. Drug Targets Immune Endocr. Metabol. Disord. 5 (3): 289–303. doi:10.2174/1568008054863781. PMID 16178789.
  5. ^ "ClinicalTrials.gov".
  6. ^ "Press Release - FDA Approves Ocaliva for Rare, Chronic Liver Disease". United States Food and Drug Administration. May 31, 2016. Retrieved 15 November 2016.
  7. ^ "Package Insert for Ocaliva" (PDF). fda.gov. Intercept Pharmaceuticals. Retrieved 15 November 2016.
  8. ^ Egan, Amy G.(Deputy Director, Center for Drug Evaluation and Research). "Letter from Food and Drug Administration to Intercept Pharmaceuticals" (PDF). fda.gov. Food and Drug Administration. Retrieved 15 November 2016.
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  10. ^ Lindor, KD (May 2011). "Farnesoid X receptor agonists for primary biliary cirrhosis". Current Opinion in Gastroenterology. 27 (3): 285–8. doi:10.1097/MOG.0b013e32834452c8. PMID 21297469.
  11. ^ 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 Rev Med Chem. 11 (9): 753–62. doi:10.2174/138955711796355258. PMID 21707532.
  12. ^ Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, Kowdley KV, Vincent C, Bodhenheimer HC, Parés A, Trauner M, Marschall HU, Adorini L, Sciacca C, Beecher-Jones T, Castelloe E, Böhm O, Shapiro D (2015). "Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid". Gastroenterology. 148 (4): 751–61.e8. doi:10.1053/j.gastro.2014.12.005. PMID 25500425.
  13. ^ Intercept Pharma. "Press release: Intercept Announces Positive Pivotal Phase 3 POISE Trial Results". Archived from the original on March 26, 2014. Retrieved March 27, 2014.
  14. ^ Adorini L, Pruzanski M, Shapiro D (September 2012). "Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis". Drug Discov. Today. 17 (17–18): 988–97. doi:10.1016/j.drudis.2012.05.012. PMID 22652341.
  15. ^ Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, Sciacca CI, Clopton P, Castelloe E, Dillon P, Pruzanski M, Shapiro D (September 2013). "Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease". Gastroenterology. 145 (3): 574–82.e1. doi:10.1053/j.gastro.2013.05.042. PMID 23727264.
  16. ^ Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, Dasarathy S, Diehl AM, Hameed B, Kowdley KV, McCullough A, Terrault N, Clark JM, Tonascia J, Brunt EM, Kleiner DE, Doo E (2015). "Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial". Lancet. 385 (9972): 956–65. doi:10.1016/S0140-6736(14)61933-4. PMC 4447192. PMID 25468160.
  17. ^ "Intercept Pharma, Government Scientists Spar over Negative Safety of Liver Drug, Emails Show". 2014-05-20.
  18. ^ Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S, Vander Elst I, Windmolders P, Vanuytsel T, Nevens F, Laleman W (November 2013). "Obeticholic acid, a farnesoid-X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats". Hepatology. 59 (6): :2286–98. doi:10.1002/hep.26939. PMID 24259407.
  19. ^ Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW (November 2009). "A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis". Clin. Gastroenterol. Hepatol. 7 (11): 1189–94. doi:10.1016/j.cgh.2009.04.024. PMID 19426836.
  20. ^ Zhang JH, Nolan JD, Kennie SL, Johnston IM, Dew T, Dixon PH, Williamson C, Walters JR (May 2013). "Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids". Am. J. Physiol. Gastrointest. Liver Physiol. 304 (10): G940–8. doi:10.1152/ajpgi.00398.2012. PMC 3652069. PMID 23518683.
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  22. ^ Schroeder, C. "FDA Warns of Liver Injury from Improper Ocaliva Dosing". DrugNews. Retrieved 20 February 2018.

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