Talk:Obeticholic acid

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Synthesis[edit]

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)[reply]

It starts from chenodeoxycholic acid, please look here: https://newdrugapprovals.org/tag/459789-99-2/

Untitled[edit]

My name is Jason Le Cocq, MD, and I work at Intercept Pharmaceuticals. I'm here to contribute information that will improve the quality of Intercept-related articles. I am aware of Wikipedia's policies and guidelines, including those on WP:COI, WP:RS, WP:V and WP:NPOV, and I will abide by them. My edit suggestions will be restricted to Talk pages, and I will not engage in directly editing any Intercept-related article. On any pages where I may suggest changes, I will be sure to disclose my relationship to Intercept in the interest of transparency. If you have any questions about my editing activities, please leave me a message on my User Talk page.

Revisions to Obeticholic acid page[edit]

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:

  • Adds additional information on OCA, including its recent approval by the U.S. Food and Drug Administration to treat PBC

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.[1]

Invention and development[edit]

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:

  • Adds additional information on primary bile acids and farnesoid X receptor (FXR)

Primary bile acids are the endogenous ligands for the farnesoid X receptor (FXR) [2] 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.[3] Specifically, the compound displayed 100x greater affinity for FXR than naturally occurring chenodeoxycholic acid. [4] FXR-dependent processes in the liver and intestine were proposed as therapeutic targets in human diseases.[5] Obeticholic acid is the first FXR agonist for PBC to be used in human drug studies.

Clinical studies[edit]

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[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.[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)[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.[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[edit]

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[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.[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:

  • 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

Obeticholic acid is currently undergoing development in phase 2, 3 and 4 studies for specific chronic, non-viral liver conditions.[6] 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.[7]

Primary biliary cholangitis[edit]

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. [8] PBC can cause fatigue, pruritus and jaundice. [9] 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. [10] Animal studies suggested that treatment with FXR agonists should be beneficial in cholestatic diseases such as PBC.[11] OCA at doses between 10 mg and 50 mg was shown to provide significant biochemical benefit, but pruritus was more frequent with higher doses.[12] [13] 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. [14] 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.[15]

Nonalcoholic steatohepatitis (NASH)[edit]

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. [16] [17] [18] Developing NAFLD is associated with abnormal cholesterol, high blood pressure, insulin resistance, central obesity and Type 2 Diabetes Mellitus (T2DM). [19] [20] In time, NASH may progress to cirrhosis and is increasing in global prevalence as well as becoming an increasing indication for liver transplantation. [21]Mccullough, A. J. (2006), Thiazolidinediones for Nonalcoholic Steatohepatitis — Promising but Not Ready for Prime Time., New England Journal of Medicine, 355(22), 2361-2363. doi:10.1056/nejme068232. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 54 (help)</ref> OCA is proposed to treat NASH. [22] 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.[23]

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.[24] 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. [25]

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[edit]

  • No changes

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[edit]

  • No changes

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]

Primary sclerosing cholangitis[edit]

  • New section

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). [26]

Biliary Atresia[edit]

  • New section

A multicenter, randomized, open-label clinical trial of OCA in subjects with biliary atresia is ongoing. [27]

References[edit]

  1. ^ "A $4 Billion Surprise for 45-Person Biotech - Wsj.com". wsj.com. Retrieved 2014-01-10.
  2. ^ Makishima, M. (1999), Identification of a Nuclear Receptor for Bile Acids, Science, 284(5418), 1362-1365. doi:10.1126/science.284.5418.1362. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 32 (help)
  3. ^ Pellicciari, R (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. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 33 (help)
  4. ^ Fiorucci, S., Mencarelli, A., Cipriani, S., Renga, B., Palladino, G., Santucci, L., & Distrutti, E. (2011-12-21), Activation of the farnesoid-X receptor protects against gastrointestinal injury caused by non-steroidal anti-inflammatory drugs in mice., British Journal of Pharmacology, 164(8), 1929-1938. doi:10.1111/j.1476-5381.2011.01481.x. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 53 (help)CS1 maint: multiple names: authors list (link)
  5. ^ Rizzo, G (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. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 68 (help)
  6. ^ "ClinicalTrials.gov". ClinicalTrials.gov. Retrieved 2016-10-04.
  7. ^ "FDA Approves Ocaliva". drugs.com. Retrieved 2016-05-27.
  8. ^ Selmi, C., Bowlus, C. L., Gershwin, M. E., & Coppel, R. L. (2011), Primary biliary cirrhosis, The Lancet, 377(9777), 1600-1609. doi:10.1016/s0140-6736(10)61965-4. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 35 (help)CS1 maint: multiple names: authors list (link)
  9. ^ Lindor, K. D., Gershwin, M. E., Poupon, R., Kaplan, M., Bergasa, N. V., & Heathcote, E. J. (2009-06-26), Primary biliary cirrhosis, Hepatology, 50(1), 291-308. doi:10.1002/hep.22906. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 29 (help)CS1 maint: multiple names: authors list (link)
  10. ^ Hirschfield, GM (January 2013), The immunobiology and pathophysiology of primary biliary cirrhosis, Annu Rev Pathol. 8: 303–30. doi:10.1146/annurev-pathol-020712-164014. PMID 23347352. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 29 (help)
  11. ^ 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. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 52 (help)
  12. ^ 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. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 36 (help)CS1 maint: multiple names: authors list (link)
  13. ^ 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. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 38 (help)CS1 maint: multiple names: authors list (link)
  14. ^ Nevens, F., Andreone, P., Mazzella, G., Strasser, S. I., Bowlus, C., Invernizzi, P., . . . Shapiro, D. (2016), A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis, New England Journal of Medicine N Engl J Med, 375(7), 631-643. doi:10.1056/nejmoa1509840. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 64 (help)CS1 maint: multiple names: authors list (link)
  15. ^ "Phase 3 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cirrhosis (COBALT)". clincialtrials.gov. Retrieved 2016-10-04.
  16. ^ Bhala, N., Jouness, R., & Bugianesi, E. (2013), Epidemiology and Natural History of Patients with NAFLD, CPD Current Pharmaceutical Design, 19(29), 5169-5176. doi:10.2174/13816128113199990336. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 55 (help)CS1 maint: multiple names: authors list (link)
  17. ^ Sumida, Y., Niki, E., Naito, Y., & Yoshikawa, T. (2013), Involvement of free radicals and oxidative stress in NAFLD/NASH, Involvement of free radicals and oxidative stress in NAFLD/NASH. Free Radical Research, 47(11), 869-880. doi:10.3109/10715762.2013.837577. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 106 (help)CS1 maint: multiple names: authors list (link)
  18. ^ Ekstedt, M., Hagström, H., Nasr, P., Fredrikson, M., Stål, P., Kechagias, S., & Hultcrantz, R. (2015), Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up., Hepatology, 61(5), 1547-1554. doi:10.1002/hep.27368. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 31 (help)CS1 maint: multiple names: authors list (link)
  19. ^ Bhala, N., Jouness, R., & Bugianesi, E. (2013), Epidemiology and Natural History of Patients with NAFLD, CPD Current Pharmaceutical Design, 19(29), 5169-5176. doi:10.2174/13816128113199990336. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 55 (help)CS1 maint: multiple names: authors list (link)
  20. ^ Williams, C. D., Stengel, J., Asike, M. I., Torres, D. M., Shaw, J., Contreras, M., . . . Harrison, S. A. (2011), Prevalence of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among a Largely Middle-Aged Population Utilizing Ultrasound and Liver Biopsy: A Prospective Study., Gastroenterology, 140(1), 124-131. doi:10.1053/j.gastro.2010.09.038. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 36 (help)CS1 maint: multiple names: authors list (link)
  21. ^ Charlton, M. R., Burns, J. M., Pedersen, R. A., Watt, K. D., Heimbach, J. K., & Dierkhising, R. A. (2011), Frequency and Outcomes of Liver Transplantation for Nonalcoholic Steatohepatitis in the United States., Gastroenterology, 141(4), 1249-1253. doi:10.1053/j.gastro.2011.06.061. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 38 (help)CS1 maint: multiple names: authors list (link)
  22. ^ 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. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 41 (help)CS1 maint: multiple names: authors list (link)
  23. ^ 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. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 39 (help)CS1 maint: multiple names: authors list (link)
  24. ^ 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. PMID 25468160. {{citation}}: External link in |publisher= (help); templatestyles stripmarker in |publisher= at position 28 (help)CS1 maint: multiple names: authors list (link)
  25. ^ "Intercept Pharma, Government Scientists Spar Over Negative Safety of Liver Drug, Emails Show". TheStreet. Retrieved 2014-05-20.
  26. ^ "Obeticholic Acid (OCA) in Primary Sclerosing Cholangitis (PSC) (AESOP)". clincialtrials.gov. Retrieved 2014-01-10.
  27. ^ "Clinical trials for biliary atresia 2014-004693-42". clinicaltrialsregister.eu. Retrieved 2014-01-10.

Jason.lecocqMD (talk) 17:51, 13 October 2016 (UTC)[reply]

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