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DRUG RECORD

 

OBETICHOLIC ACID

OVERVIEW
Obeticholic Acid

 

Introduction

Obeticholic acid (OCA) is a synthetically modified bile acid and potent agonist of the farnesoid X nuclear receptor (FXR) that is used to treat liver diseases including primary biliary cholangitis.  Obeticholic acid has not been linked to elevations in serum enzyme levels during therapy, but has been linked to an increased rate of severe liver related adverse events such as ascites, jaundice and liver failure.

 

Background

Obeticholic (oh bet" i koe' lik) acid is a synthetically modified bile acid that is a potent agonist of the farnesoid X nuclear receptor (FXR), a nuclear receptor with major effects on bile acid synthesis and transport as well as lipid metabolism and glucose homeostasis.  Obeticholic acid has been shown to improve serum enzymes in several diseases including nonalcoholic steatohepatitis (NASH) and primary biliary cholangitis (PBC, previously known as primary biliary cirrhosis).  Obeticholic acid was given provisional approval for use in the United States for primary biliary cholangitis in 2016 and is currently under evaluation in other liver diseases including primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH).  Obeticholic acid is available as tablets of 5 and 10 mg under the brand name Ocaliva.  The typical initial dose for primary biliary cholangitis is 5 mg once daily which can then be increased to a maximum of 10 mg daily.  Patients with advanced cirrhosis (Child's Class B or C) are advised to start at a dose of 5 mg once weekly and increase thereafter based upon tolerance and effect to a maximum of 10 mg twice weekly.  Side effects include pruritus, fatigue, nausea and headache.  Symptoms of pruritus appear to be less if therapy is started at a low dose and increased gradually.  Less common but potentially severe adverse reactions include hypersensitivity reactions and depression.

 

Hepatotoxicity

In multiple preregistration clinical trials, obeticholic acid was found to decrease serum enzyme elevations in a high proportion of patients with different liver diseases.  Instances of paradoxical worsening of liver disease or further increases in serum ALT or AST were not reported.  However, the product label for obeticholic acid includes warnings that serious liver related adverse events occurred more commonly with active therapy than with placebo treatment.  In a pooled analysis of 3 placebo controlled trials in patients with primary biliary cholangitis, liver related adverse events were 5.2 per 100 patient exposure years with 10 mg and 2.4 with placebo.  Even higher rates occurred with higher doses of obeticholic acid: 19.8 per 100 patient years for 25 mg daily and 54.5 for 50 mg daily.  The clinical features, timing of onset, pattern of enzyme elevations and course of these events were not described in detail.  Within a little over a year after approval of obeticholic acid as therapy for primary biliary cholangitis, the FDA published a warning letter stating that they had received notification of 19 deaths and 11 cases of severe liver injury in patients taking obeticholic acid, most but not all of whom had preexisting cirrhosis (Case 1).

 

In patients with normal alkaline phosphatase levels, obeticholic therapy is associated with slight elevations in alkaline phosphatase, but without accompanying changes in serum aminotransferase levels, GGT or bilirubin, suggesting that the increases are due to alkaline phosphatase from other sources (bone, gastrointestinal tract).  Therapy with OCA has been associated with development of pruritus in up to one-third of patients, but the appearance or worsening of itching is not usually associated with worsening of the underlying liver disease or increase in bilirubin or bile acid levels (other than OCA).  Thus, obeticholic acid has apparent beneficial effects on liver test abnormalities, but has been linked to rare instances of worsening liver disease which may have clinical significance in patients with preexisting cirrhosis.

Likelihood score: C (based upon FDA reporting, a suspected rare cause of clinically apparent liver injury occurring mostly in patients with preexisting cirrhosis).

 

Mechanism of Liver Injury

The mechanism by which obeticholic acid might cause liver injury is unclear as it is a synthetic bile acid that is concentrated in the liver and interacts with the nuclear receptor FXR.  Agonism of FXR leads to a decrease in bile acid synthesis and increase in bile acid and bilirubin transporters.

 

Outcome and Management

Patients on obeticholic should be monitored with liver tests, including serum bilirubin, ALT, AST and alkaline phosphatase, during the first few months of therapy to assess both its efficacy and safety.  Patients with paradoxical worsening of the liver disease, with persistent worsening of serum enzyme elevations and particularly with evidence of hepatic decompensation, should discontinue obeticholic promptly.  There does not appear to be cross sensitivity to liver injury or adverse events between obeticholic and other bile acid therapies such as ursodiol.


Other bile acids used in digestive diseases include chenodeoxycholic acid (chenodiol), cholic acid and ursodeoxycholic acid (ursodiol).

Drug Class:  Gastrointestinal Agents, Bile Acids

 

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CASE REPORT 
Obeticholic Acid

 

Case 1.  Hepatic decompensation during therapy of primary biliary cholangitis with  obeticholic acid. [Data provided by Dr. A. Modi, Liver Consultants of Texas, Baylor Scott & White Medical Center]

 

A 59 year old Hispanic woman with primary biliary cholangitis (PBC) developed worsening jaundice and fatigue 3 months after starting obeticholic acid.  She was known to have had autoimmune liver disease for at least 9 years and had been treated in the past with prednisone, mycophenolate mofetil, and ursodiol with only a partial response.  Liver histology initially suggested an overlap syndrome of autoimmune hepatitis and PBC, but with time clinical features suggested that she had primary biliary cholangitis alone despite the absence of antimitochondrial antibody.  On ursodiol, she had minimal symptoms, but laboratory tests showed alkaline phosphatase levels of 569 to 712 U/L, ALT 87 to 109 U/L and bilirubin of 2.3 to 2.7 mg/dL.  Liver biopsy histology demonstrated significant fibrosis (stage 3 of 4) and paucity of bile ducts ("ductopenia").  In mid 2016, she was started on obeticholic acid (OCA) in a dose of 5 mg daily while maintaining a dose of ursodiol of 1.2 grams daily.  She developed pruritus which responded minimally to cholestyramine and hydroxyzine.  Nevertheless, liver tests improved slightly, with alkaline phosphatase levels decreasing to 372 U/L, ALT to 53 U/L and bilirubin to 2.2 mg/dL (Table).  Approximately 3 months after starting OCA, she was found to have worsening jaundice with a bilirubin of 7.6 mg/dL, but with little changes in serum enzymes.  Obeticholic acid was stopped while ursodiol was continued.  She had no history of previous drug allergies or exposure to viral hepatitis.  She did not drink alcohol.  She was managed as an outpatient, but serum bilirubin remained elevated and she developed evidence of ascites and mild hepatic encephalopathy.  Upper gastrointestinal endoscopy showed small varices.  She was treated with lactulose, diuretics, salt restriction and was monitored closely.  Over the next six months, her serum bilirubin decreased to pretreatment values, but alkaline phosphatase levels remained high.  Approximtely a year after onset, her itching and ascites resolved and she felt that she had returned to her pretreatment clinical status.


Key Points

Medication: Obeticholic acid (5 mg daily)
Pattern: Worsening jaundice
Severity: 4+ hepatic decompensation
Latency: 82 days
Recovery: Incomplete at 6 months
Other medications: Ursodiol, cholestyramine, hydroxyzine, bacloften, tramadol, alendronate, calcium, vitamin D

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
Pre Pre 109 712 2.3 Ursodiol 1.2 g/d
- 2 mo Pre 91 664 2.7
0 Pre Obeticholic acid started (5 mg daily)
2 weeks Pre 46 431 2.2 Itching
1 month Pre 50 372 2.2
2 months Pre 52 382 2.6
3 months 0 79 519 7.6 OCA stopped
  9 days 53 551 6.4 Ascites noted
4 months 30 days 51 651 6.2 EGD: Varices
5 months 50 days 83 959 4.2 INR 1.1
6 months 80 days 76 865 3.9 Lactulose started
9 months 6 months 89 743 2.7
11 months 8 months 69 445 2.6 Itching resolved
14 months 11 months 52 362 2.4 Ascites resolved
Normal Values <35 <130 <1.2

Comment

A middle aged woman with primary biliary cholangitis with advanced fibrosis and an inadequate response to ursodiol was started on obeticholic acid shortly after its approval for this indication in the United States.  She had an initial slight improvement in liver tests, but then developed jaundice and signs of hepatic decompensation 3 months after having started obeticholic acid.  Despite stopping the medication, recovery was slow, and she returned to her previous status only 8 to 11 months later.  Sudden unexplained decompensation of liver disease has been described in several patients with PBC within a few weeks to several months after starting obeticholic acid.  The cause is unknown, but may be dose related and appears to be most frequent in patients with cirrhosis or advanced fibrosis.  Patients with decompensated cirrhosis should be treated with caution, starting at a dose of 5 mg once weekly and advancing the dose gradually and with regular monitoring.  The clinical presentation or phenotype of this injury resembles that of spontaneous hepatic decompensation or what is called "acute-on-chronic liver failure."


PRODUCT INFORMATION
Obeticholic Acid

 

REPRESENTATIVE TRADE NAMES
Obeticholic Acid – Ocaliva®

 

DRUG CLASS
Gastrointestinal Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Obeticholic Acid 459789-99-2 C26-H44-O4 Bile Acids Chemical Structure
Cholic Acid 81-25-4 C24-H40-O5 Bile Acids Chemical Structure

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ANNOTATED BIBLIOGRAPHY
Obeticholic Acid

 

References updated: 20 November 2017
Abbreviations used: FXR, farnesoid X receptor; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; OCA, obeticholic acid; PBC, primary biliary cirrhosis (cholangitis).

  1. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.  (Review of hepatotoxicity published in 1999 before the availability of obeticholic acid).

  2. Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.  (Textbook of pharmacology and therapeutics).

  3. Chen J, Raymond K. Nuclear receptors, bile-acid detoxification, and cholestasis. Lancet 2006; 367 (9509): 454-6. PubMed Citation  (Commentary on the nuclear receptor FXR, which acts as a bile acid receptor and mediates reduction in bile acid synthesis and increase in update of bile acids from the circulation as well as secretion of bile acids from hepatocytes).

  4. Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker(fa/fa) obese rats. J Lipid Res 2010; 51: 771-84. PubMed Citation  (In an animal model of obesity and fatty liver, FXR activation using a synthetic bile acid agonist led to less weight gain and reductions in fasting glucose, insulin, triglycerides and ALT levels as well as reduced hepatic fat when compared to placebo).

  5. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, Adorini L, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013; 145: 574-82. PubMed Citation  (Among 64 patients with diabetes and fatty liver treated with OCA [25 or 50 mg] or placebo once daily for 6 weeks, OCA led to increases in insulin sensitivity and reductions in GGT [~50%] and ALT [~25%], but increases in Alk P and LDL cholesterol; 1 patient on placebo and one of OCA [50 mg] had ALT elevations above 3 times ULN and were withdrawn from therapy).

  6. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, Chalasani N, et al.; NASH Clinical Research Network. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis(FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015; 385 (9972): 956-65. PubMed Citation  (Among 141 patients with NASH treated with OCA [25 mg] or placebo daily for 72 weeks, OCA was associated with greater improvements in ALT levels and liver histology, but without a significant increased rate of NASH resolution; pruritus arose in 33% vs 9% of patients, but there was no other evidence of hepatotoxicity or unexplained ALT elevations).

  7. Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, Kowdley KV, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015; 148: 751-61. PubMed Citation  (Among 165 patients with PBC and Alk P elevations despite ursodiol therapy who were treated with OCA [10, 25 or 50 mg] daily for 3 months, Alk P levels decreased more with OCA [20-25%] than placebo [<5%] and mean ALT, AST and conjugated bilirubin levels improved; side effects included pruritus, but no other liver related symptom or blood test result).

  8. Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015; 313: 2263-73. PubMed Citation  (Review of the clinical features, epidemiology, risk factors, incidence, natural history, pathogenesis and therapy of NAFLD and NASH; mentions that OCA was found to have beneficial effects on liver histology, but the effect size was small and similar to that of vitamin E).

  9. Fuchs CD, Traussnigg SA, Trauner M. Nuclear receptor modulation for the treatment of nonalcoholic fatty liver disease. Semin Liver Dis 2016; 36: 69-86. PubMed Citation  (Review of the possible role of FXR modulation as therapy of fatty liver disease).

  10. Pencek R, Marmon T, Roth JD, Liberman A, Hooshmand-Rad R, Young M. Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes Metab 2016 Apr 25. [Epub ahead of print] PubMed Citation  (Commentary on OCA from the sponsor focusing on effects of OCA in 68 healthy volunteers in two phase 1 trials that showed transient increases in total and LDL cholesterol and decreases in HDL, all of which reversed rapidly on discontinuation; no mention of ALT elevations or hepatotoxicity).

  11. Parés A. Therapy of primary biliary cirrhosis: novel approaches for patients with suboptimal response to ursodeoxycholic acid. Dig Dis 2015; 33 Suppl 2: 125-33. PubMed Citation  (Review of current and experimental therapies of PBC including use of OCA; no mention of hepatotoxicity).

  12. Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, Drenth JP, et al.; POISE Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016; 375: 631-43. PubMed Citation  (Among 216 patients with PBC treated with OCA [5 to 10 mg daily] or placebo for 12 months, serum Alk P levels decreased by 35% and 41% with OCA but only by 4% with placebo, while symptoms of pruritus worsened and serious adverse event rates were more common with OCA [15% vs 4%]).

  13. Center for Drug Evaluation and Research. Application 207999Orig1s00. Medical Review. pp: 212-26: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207999Orig1s000MedR.pdf (Medical review of clinical trials of obeticholic acid in primary biliary cholangitis; mentions a dose related increased rate of hepatic adverse events with therapy).

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OTHER REFERENCE LINKS
Obeticholic Acid

  1. PubMed logoRecent References on Obeticholic Acid

  2. Clinical Trials logoTrials on Obeticholic Acid

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