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For adults with primary biliary cholangitis (PBC)1

For adults with primary biliary cholangitis (PBC)1

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RETHINKING PBC MANAGEMENT

The fundamentals of PBC

PBC is a chronic, progressive autoimmune disease of the small bile ducts that is triggered by both genetic and environmental factors.2,3

Some of the most important prognostic markers of PBC include: ALP, GGT, bilirubin, ALT, AST, and fibrosis.4,5 Monitoring overall liver health—including, but not limited to, pathophysiology, disease progression, prognostic biomarkers, fibrosis, and treatment response—can help optimize patient outcomes in PBC.6

ALP alone is not sufficient as an indicator of disease progression4

A primary goal of PBC treatment is to prevent end-stage liver disease, liver transplant, or death. To achieve this goal, the focus should be4,7:

1.

Normalization, or near normalization, of key liver biomarkers6

2.

Prevention of fibrosis progression5

The path of PBC: Disease progression

With PBC, the focus should be on monitoring overall liver health6,8,a

The path of PBC disease progression

aIn PBC, monitoring overall liver health includes, but is not limited to, pathophysiology, disease progression, prognostic biomarkers, fibrosis, and treatment response.6

bElevated bilirubin can also be a sign of severe cholestasis.4

Up to 30% of patients can have a severe, progressive form of PBC, resulting in early development of liver fibrosis and liver failure9

Some of the risk factors for disease progression include:

  • Age at diagnosis (heightened risk for patients below 45 years of age)10
  • Abnormal biomarker levels10
  • Race (heightened risk for African American and Hispanic patients)11
  • Advanced fibrosis5,10

Because experiences with PBC can vary from patient to patient, being aware of these specific risk factors can help you manage disease progression by determining an appropriate treatment plan for your patients.9,12-14

Consider a range of prognostic biomarkers13

Increasing thresholds and time above ULN for ALP, ALT, and AST were associated with increased risk of adverse outcomes13,a

ALP

Prognostic biomarkers - ALP
Prognostic biomarkers - ALT
Prognostic biomarkers - AST

Adapted from Kowdley K, et al. Poster presented at: EASL Congress; June 21-24, 2023; Vienna, Austria.

aData from a cohort of patients was created using the Komodo Health Map database with national laboratory data between January 1, 2014, and April 1, 2022. Patients were ≥18 years old with ≥1 inpatient PBC diagnosis claim or ≥2 outpatient PBC diagnosis claims separated by ≥30 days. Key exclusion criteria included history of hepatic decompensation, concomitant liver diseases (hepatitis C infection, hepatitis B infection, primary sclerosing cholangitis, alcoholic liver disease, Gilbert’s syndrome, hepatocellular carcinoma), liver transplant, comorbidities associated with abnormal biomarker levels, or use of obeticholic acid or fibrates (second-line therapies for PBC). Over the course of the study period, 77.7% of patients used UDCA. Adverse outcomes were defined as hospitalization for hepatic decompensation, transplant, or death.13

bALP ULN defined as 120 U/L.13

cALT ULN defined as 40 U/L.13

dAST ULN defined as 35 U/L for males and 30 U/L for females.13

A separate observational study demonstrated that GGT can also be used to increase the prognostic value of ALP measurement.15

THE IMPORTANCE OF BILIBRUBIN

In 2 studies, bilirubin >0.6x ULN was associated with increased risk for adverse outcomes, including liver transplant or death.16,17

Surpassing the bilirubin 0.6 x ULN threshold significantly increased risk for liver transplant or death15,16,a

Bilirubin threshold graph

Adapted from Murillo Perez CF, et al. Ailment Pharmacol Ther. 2019.

Total bilirubin >0.6 x ULN was associated with an increased risk for adverse outcomes13,b

Total bilirubin graph

Adapted from Kowdley K, et al. Poster presented at: EASL Congress; June 21-24, 2023; Vienna, Austria.

aCalculation based on percent rates of liver transplant or death extrapolated from survival estimate curve at 10 years.17

bData from a cohort of patients were created using the Komodo Health Map database with national laboratory data between January 1, 2014, and April 1, 2022. Patients were ≥18 years old with ≥1 inpatient PBC diagnosis claim or ≥2 outpatient PBC diagnosis claims separated by ≥30 days. Hazard ratio for risk of hospitalization for hepatic decompensation, transplant, or death.13

cTotal bilirubin ULN defined as 1 mg/dL.13

Fibrosis: Assessing the need for second-line therapy5

Advanced fibrosis (stages 3 and 4) was found to be an independent predictor of transplant-free survival in patients with PBC5,a

Any increase in LSM, as measured by TE, was associated with a significant increased risk of serious clinical events independent of prognostic biochemical markers18,b

Increase in LSM over time was correlated with inadequate response to UDCA (P=0.0017) in a subgroup analysis18

Adjusted relative risk of serious clinical event18,c

Adjusted risk of serious clinical event - graph

Adapted from Corpechot, et al. Oral communication presented at: EASL Congress; June 21-24, 2023; Vienna, Austria.

aAnalysis included 1828 patients with baseline liver biopsy that was performed from 1980 to 2014. Fibrosis was assessed histologically via liver biopsy and noninvasively via noninvasive markers of fibrosis.5

bFrom an international retrospective cohort study of 2244 patients with compensated PBC on UDCA therapy. Serious clinical event was defined as death, liver transplant, or liver complications.18

cHR (95% CI) according to annual relative change in LSM.

dFor the same age and gender.

In a separate study, FIB-4 >2.67 and APRI >0.5 were associated with increased risk for adverse outcomes13

Expert guidance on monitoring fibrosis

Per CLDF 2023 guidance, fibrosis staging using noninvasive tests (MRE or TE) is recommended soon after diagnosis. For patients with a more advanced fibrosis stage (VCTE or TE ≥10 kPa), compensated liver disease, and no signs of portal hypertension, the need for second-line treatment should be assessed at 6 months. Fibrosis surveillance is recommended at all stages of PBC.13

UDCA may not be enough for some patients8,19,20

AASLD expert guidance recommends monitoring patients every 3 to 6 months after initiating treatment with UDCA to determine whether they are achieving adequate lowering of ALP—and other key biomarkers of PBC.8

Up to 50% of patients may not achieve their treatment goals with UDCA alone.13

AASLD, American Association for the Study of Liver Diseases; ALP, alkaline phosphatase; ALT, alanine transaminase; APRI, AST to Platelet Ratio Index; AST, aspartate aminotransferase; CI, confidence interval; CLDF, Chronic Liver Disease Foundation; FIB-4, Fibrosis-4; GGT, gamma-glutamyl transferase; kPa, kilopascal; LSM, liver stiffness measurement; MRE, magnetic resonance elastography; TE, transient elastography; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; VCTE, vibration controlled transient elastography.

References

  1. OCALIVA full prescribing information. Morristown, NJ: Intercept Pharmaceuticals, Inc; 2022.
  2. Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52(5):745-758. doi:10.1016/j.jhep.2009.11.027
  3. Cheung AC; Canadian PBC Society. Primary biliary cholangitis. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/primary-biliary-cholangitis/3/. Updated 2020. Accessed March 17, 2023.
  4. European Association for the Study of the Liver. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-172. doi:1016/j.jhep.2017.03.022
  5. Murillo Perez CF, Hirschfield GM, Corpechot C, et al. Fibrosis stage is an independent predictor of outcome in primary biliary cholangitis despite biochemical treatment response. Ailment Pharmacol Ther. 2019;50(10):1127-1136. doi:10.1111/apt.15533
  6. Levy C, Manns M, Hirschfield G. New treatment paradigms in primary biliary cholangitis. Clin Gastro Hepatol. 2023;21:2076-2087. doi:10.1016/j.cgh.2023.02.005
  7. Ritter T, Hanson C, Fernandes C, et al. Duration and degree of alkaline phosphatase elevation is associated with significantly increased risk of death, liver transplant and hepatic compensation in patients with primary biliary cholangitis. Poster presented at: Digestive Disease Week 2022; May 21-24, 2022; San Diego, CA.
  8. Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-419. doi:10.1002/hep.30145
  9. Younossi ZM, Bernstein D, Shiffman ML, et al. Diagnosis and management of primary biliary cholangitis. Am J Gastroenterol. 2019;114(1):48-63. doi: 10.1038/s41395-018-0390-3.
  10. Hirschfield GM, Chazouilleres O, Cortez-Pinto H, et al. A consensus integrated care pathway for patients with primary biliary cholangitis: a guideline-based approach to clinical care of patients. Expert Rev Gastroenterol Hepatol. 2021;15(8):929-939. doi:10.1080/17474124.2021.1945919
  11. Peters MG, Di Bisceglie AM, Kowdley KV, et al. Differences between Caucasian, African American, and Hispanic patients with primary biliary cirrhosis in the United States. Hepatology. 2007;46(3):769-775. doi:10.1002/hep.2175
  12. Onofrio FQ, Hirschfield GM, Gulamhusein AF. A practical review of primary biliary cholangitis for the gastroenterologist. Gastroenterol Hepatol. 2019;15(3):145-154.
  13. Kowdley KV, Mayne T, Ness E, et al. Risk of death, liver transplant, or hepatic decompensation in primary biliary cholangitis increases with increased duration and degree beyond established clinical thresholds for hepatic biomarkers and fibrosis scores. Poster presented at: EASL Congress 2023; June 21-24, 2023; Vienna, Austria.
  14. Pate J, Gutierrez JA, Frenette CT, et al. Practical strategies for pruritus management in the obeticholic acid-treated patient with PBC: proceedings from the 2018 expert panel. BMJ Open Gastroenterol. 2019;6(1):e000256. doi:10.1136/bmjgast-2018-000256
  15. Gerussi A, Bernasconi DP, O’Donnell SE. et al. Measurement of gamma glutamyl transferase to determine risk of liver transplantation or death in patients with primary biliary cholangitis. Clin Gastro Hepatol. 2021;19:1688-1697. doi:10.1016/j.cgh.2020.08.006
  16. Murillo Perez CF, Harms MH, Lindor KD, et al. Goals of treatment for improved survival in primary biliary cholangitis: treatment target should be bilirubin within the normal range and normalization of alkaline phosphatase. Am J Gastroenterol. 2020;00:1-9. doi:10.14309/ajg.0000000000000557
  17. Data on file: US-PB-MED-00492.
  18. Corpechot, et al. Oral communication presented at: EASL Congress; June 21-24, 2023; Vienna, Austria.
  19. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130(3):715 720. doi:10.1053/j.gastro.2005.12.029
  20. Kuiper EMM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology. 2009;136(4):1281-1287. doi:10.1053/j.gastro.2009.01.003

INDICATION AND IMPORTANT SAFETY INFORMATION

WARNING: HEPATIC DECOMPENSATION AND FAILURE IN PRIMARY BILIARY CHOLANGITIS PATIENTS WITH CIRRHOSIS

  • Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in primary biliary cholangitis (PBC) patients with either compensated or decompensated cirrhosis.
  • OCALIVA is contraindicated in PBC patients with decompensated cirrhosis, a prior decompensation event, or with compensated cirrhosis who have evidence of portal hypertension.
  • Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation; have compensated cirrhosis and develop evidence of portal hypertension; or experience clinically significant hepatic adverse reactions while on treatment.

INDICATION

OCALIVA, a farnesoid X receptor (FXR) agonist, is indicated for the treatment of adult patients with primary biliary cholangitis (PBC)

  • without cirrhosis or
  • with compensated cirrhosis who do not have evidence of portal hypertension,

either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.

This indication is approved under accelerated approval based on a reduction in alkaline phosphatase (ALP). An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Contraindications

OCALIVA is contraindicated in patients with:

  • decompensated cirrhosis (e.g., Child-Pugh Class B or C) or a prior decompensation event.
  • compensated cirrhosis who have evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia).
  • complete biliary obstruction.

Warnings and Precautions

Hepatic Decompensation and Failure in PBC Patients with Cirrhosis

Hepatic decompensation and failure, sometimes fatal or resulting in liver transplant, have been reported with OCALIVA treatment in PBC patients with cirrhosis, either compensated or decompensated. Among postmarketing cases reporting it, median time to hepatic decompensation (e.g., new onset ascites) was 4 months for patients with compensated cirrhosis; median time to a new decompensation event (e.g., hepatic encephalopathy) was 2.5 months for patients with decompensated cirrhosis. Some of these cases occurred in patients with decompensated cirrhosis when they were treated with higher than the recommended dosage for that patient population; however, cases of hepatic decompensation and failure have continued to be reported in patients with decompensated cirrhosis even when they received the recommended dosage.

Hepatotoxicity was observed in the OCALIVA clinical trials. A dose-response relationship was observed for the occurrence of hepatic adverse reactions including jaundice, worsening ascites, and primary biliary cholangitis flare with dosages of OCALIVA of 10 mg once daily to 50 mg once daily (up to 5-times the highest recommended dosage), as early as one month after starting treatment with OCALIVA in two 3-month, placebo-controlled clinical trials in patients with primarily early stage PBC.

Routinely monitor patients for progression of PBC, including hepatic adverse reactions, with laboratory and clinical assessments to determine whether drug discontinuation is needed. Closely monitor patients with compensated cirrhosis, concomitant hepatic disease (e.g., autoimmune hepatitis, alcoholic liver disease), and/or with severe intercurrent illness for new evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia) or increases above the upper limit of normal in total bilirubin, direct bilirubin, or prothrombin time to determine whether drug discontinuation is needed. Permanently discontinue OCALIVA in patients who develop laboratory or clinical evidence of hepatic decompensation (e.g., ascites, jaundice, variceal bleeding, hepatic encephalopathy), have compensated cirrhosis and develop evidence of portal hypertension (e.g., ascites, gastroesophageal varices, persistent thrombocytopenia), experience clinically significant hepatic adverse reactions, or develop complete biliary obstruction. If severe intercurrent illness occurs, interrupt treatment with OCALIVA and monitor the patient’s liver function. After resolution of the intercurrent illness, consider the potential risks and benefits of restarting OCALIVA treatment.

Severe Pruritus

Severe pruritus was reported in 23% of patients in the OCALIVA 10 mg arm, 19% of patients in the OCALIVA titration arm, and 7% of patients in the placebo arm in a 12-month double-blind randomized controlled clinical trial of 216 patients. Severe pruritus was defined as intense or widespread itching, interfering with activities of daily living, or causing severe sleep disturbance, or intolerable discomfort, and typically requiring medical interventions. Consider clinical evaluation of patients with new onset or worsening severe pruritus. Management strategies include the addition of bile acid binding resins or antihistamines, OCALIVA dosage reduction, and/or temporary interruption of OCALIVA dosing.

Reduction in HDL-C

Patients with PBC generally exhibit hyperlipidemia characterized by a significant elevation in total cholesterol primarily due to increased levels of high-density lipoprotein-cholesterol (HDL-C). Dose-dependent reductions from baseline in mean HDL-C levels were observed at 2 weeks in OCALIVA-treated patients, 20% and 9% in the 10 mg and titration arms, respectively, compared to 2% in the placebo arm. Monitor patients for changes in serum lipid levels during treatment. For patients who do not respond to OCALIVA after 1 year at the highest recommended dosage that can be tolerated (maximum of 10 mg once daily), and who experience a reduction in HDL-C, weigh the potential risks against the benefits of continuing treatment.

Adverse Reactions

The most common adverse reactions (≥5%) are: pruritus, fatigue, abdominal pain and discomfort, rash, oropharyngeal pain, dizziness, constipation, arthralgia, thyroid function abnormality, and eczema.

Drug Interactions

  • Bile Acid Binding Resins
    Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the absorption, systemic exposure, and efficacy of OCALIVA. If taking a bile acid binding resin, take OCALIVA at least 4 hours before or 4 hours after taking the bile acid binding resin, or at as great an interval as possible.
  • Warfarin
    The International Normalized Ratio (INR) decreased following coadministration of warfarin and OCALIVA. Monitor INR and adjust the dose of warfarin, as needed, to maintain the target INR range when co-administering OCALIVA and warfarin.
  • CYP1A2 Substrates with Narrow Therapeutic Index
    Obeticholic acid may increase the exposure to concomitant drugs that are CYP1A2 substrates. Therapeutic monitoring of CYP1A2 substrates with a narrow therapeutic index (e.g., theophylline and tizanidine) is recommended when co-administered with OCALIVA.
  • Inhibitors of Bile Salt Efflux Pump
    Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts including taurine conjugate of obeticholic acid in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitor serum transaminases and bilirubin.

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