Zellweger Spectrum Disorders

Liver dysfunction is almost universal in Zellweger spectrum disorders1,2

Multiorgan disease that presents as a spectrum1-6

  • Caused by autosomal recessive mutations with incidence of ~1/50,000 live births2-4
  • Reduction or absence of functional peroxisomes in cells1,2
    • Final steps of primary bile acid synthesis occur in peroxisomes5
  • Leads to production and accumulation of hepatotoxic atypical bile acids6
  • Loss of synthesis of cholic acid (CA) and chenodeoxycholic acid (CDCA)2,6
  • Liver involvement7-9

The treatment goals for liver involvement in Zellweger spectrum disorders involve adjunctive therapy, which is important for addressing the liver dysfunction that is part of this disorder.

Due to autosomal recessive mutations,7,10 patients with bile acid synthesis disorders are unable to make primary bile acids. This leads to

  • Loss of cholic acid CA and CDCA11
  • Production and accumulation of hepatotoxic atypical bile acids8,12,13
  • Rapid onset of liver failure and high mortality8

Enzyme defects in the bile acid synthesis pathway can lead to liver disease10

  • Cholesterol is converted to bile acids in the liver by a series of enzymatic reactions8,11,14
  • Enzyme defects may occur anywhere along the pathway and in any compartment14
  • An accumulation of hepatotoxic atypical bile acids occurs above the defect in the pathway15
  • Bile acids regulate their own synthesis via the farnesoid X receptor (FXR)12,8
Therapy

Disease severity spectrum

Zellweger Spectrum Disorder

1. Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17:187-196.  2. Bove KE, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004;7:315-334.  3. Steinberg SJ, Raymond GV, Braverman NE, Moser AB. Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. http://www.ncbi.nlm.nih.gov/books/NBK1448. Updated May 10, 2012. Accessed June 4, 2015.  4. Abdel-Hamid HZ, Kao A. Peroxisomal disorders. http://emedicine.medscape.com/article/1177387-overview9. Updated April 10, 2015. Accessed September 9, 2015.  5. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of Disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5(8):456-468.  6. Grayer J. Recognition of Zellweger syndrome in infancy. Adv Neonatal Care. 2005;5(1):5-13.  7. Steinberg SJ, Raymond GV, Braverman NE, Moser AB. Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum. http://www.ncbi.nlm.nih.gov/books/NBK1448. Updated May 10, 2012. Accessed June 4, 2015.  8. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of Disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5(8):456-468.  9. Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17:187-196. 11. Setchell KD, Heubi JE. Defects in bile acid biosynthesis—diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2006;43:S17-S22.  10. Bove KE, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004;7:315-334.  11. Heubi JE, Setchell K, Bove KE. Inborn errors of bile acid metabolism. Semin Liver Dis. 2007;27(3):282-294.  12. Gonzales E, Gerhardt MF, Fabre M, et al. Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy. Gastroenterology. 2009;137(4):1310-1320.  13. Wanders RJ, Ferdinandusse S. Peroxisomes, peroxisomal diseases, and the hepatotoxicity induced by peroxisomal metabolites. Curr Drug Metab. 2012;13:1401-1411.  14. Setchell KD, Heubi JE. Defects in bile acid biosynthesis—diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2006;43:S17-S22.  15. Ferdinandusse S, Houten SM. Peroxisomes and bile acid biosynthesis. Biochim Biophys Acta. 2006;1763:1427-1440.

Indication and Usage
CHOLBAM® is a bile acid indicated for:

  • Treatment of bile acid synthesis disorders due to single enzyme defects
  • Adjunctive treatment of peroxisomal disorders including Zellweger spectrum disorders in patients who show signs and symptoms of liver disease, steatorrhea (fatty stools), or complications from decreased fat soluble vitamins absorption (A, D, E, K)

Limitation of Use:
The safety and effectiveness of CHOLBAM® on extrahepatic manifestations of bile acid synthesis disorders due to single enzyme defects or peroxisomal disorder including Zellweger spectrum disorders have not been established.

Important Safety Information
Warnings and Precautions—Exacerbation of Liver Impairment

  • Monitor liver function and discontinue CHOLBAM® (cholic acid) in patients who develop worsening of liver function while on treatment.
  • Monitor AST, ALT, GGT, alkaline phosphatase, bilirubin, and international normalized ratio (INR) every month for the first 3 months, every 3 months for the next 9 months, every 6 months during the next 3 years and annually thereafter. Administer the lowest dose that effectively maintains liver function.
  • Discontinue CHOLBAM® if liver function does not improve within 3 months of starting treatment, if complete biliary obstruction develops, or if there are persistent clinical or laboratory indicators of worsening liver function or cholestasis; continue to monitor liver function and consider restarting at a lower dose when parameters return to baseline.

Adverse Reactions
In the CHOLBAM® clinical trials, diarrhea was the most common adverse reaction in approximately 2% of the patient population. All other adverse reactions are less than or equal to 1% of the patient population.

Drug Interaction

  • Bile Salt Efflux Pump (BSEP) Inhibitors (eg, cyclosporine): Avoid concomitant use; if concomitant use is necessary, monitor serum transaminases and bilirubin.
  • Bile Acid Resins and Aluminum-Based Antacids: Take CHOLBAM® at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin or aluminum-based antacids.

Pregnancy
No studies in pregnant women or animal reproduction studies have been conducted with CHOLBAM®. Women who become pregnant during CHOLBAM® treatment are encouraged to call 1-844-202-6262.

Lactation
Endogenous cholic acid is present in human milk. Clinical lactation studies have not been conducted to assess the presence of CHOLBAM® in human milk, the effects of CHOLBAM® on the breastfed infant, or the effects of CHOLBAM® on milk production.

There are no animal lactation data and no data from case reports available in the published literature.

Overdosage
In the event of overdose (elevated GGT and ALT), the patient should be monitored and treated symptomatically.

Elevated serum gamma glutamyltransferase (GGT) and serum alanine aminotransferase (ALT) may indicate CHOLBAM® overdose. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline.

Please see full prescribing information for CHOLBAM® (cholic acid) 50 mg and 250 mg capsules.

To report SUSPECTED ADVERSE REACTIONS, contact Travere Therapeutics, Inc. at 1-877-659-5518 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.