5-Year Open-Label Extension Data

POISE Trial

Open-label extension study design

OCALIVA® (obeticholic acid) open-label extension study design chart

aIn the 5 mg→10 mg titration group, 36 patients stayed at 5 mg and 33 were titrated to 10 mg after 6 months.1

bAmong patients who entered the open-label extension, 13 (7%) were intolerant and did not receive concomitant UDCA during double-blind or open-label treatment with OCALIVA.3

cProtocol initially allowed doses up to 25 mg, but was later amended to a maximum daily dose of OCALIVA 10 mg to ensure dosing per the approved label.3

UDCA, ursodeoxycholic acid.

  • Of 198 patients who completed the double-blind phase, 193 (97%) elected to enter the open-label extension.3
  • All patients switched from double-blind medication to OCALIVA 5 mg daily + UDCAb for at least 3 months.3
    • After 3 months, OCALIVA dosage could be increased based on response and tolerability.
  • A maximum dose of OCALIVA 10 mg is represented, excluding data points after a subject titrated to >10 mg daily of OCALIVA, to capture patients within product labeling.3,5
  • Total duration of OCALIVA treatment was 5 years (60 months) or more.3,5

Study limitations: In this open-label extension, no placebo or other comparators were included and therefore no clinical conclusions should be made.

Clinical Data

From the open-label extension study

Mean alkaline phosphatase levels in the open-label extension3,5

Graph showing mean alkaline phosphatase (ALP) levels in the open-label extension study for OCALIVA® (obeticholic acid)

Mean bilirubin levels in the open-label extension3,5

Graph showing mean bilirubin levels in the open-label extension study for OCALIVA® (obeticholic acid)

A maximum dose of OCALIVA 10 mg is presented, excluding data points as subjects titrated to >10 mg daily.3,5

Study limitations: This analysis selectively excluded data as patients titrated above 10 mg. As this was a post hoc analysis, these results are exploratory and no clinical conclusions should be made.3,5

Using the composite endpoint

Composite endpoint in the open-label extension3,5
Graph showing composite endpoint in the open-label extension study for OCALIVA® (obeticholic acid)
  • As in the double-blind phase, response was defined as meeting the following 3 criteria3,5:
    • Alkaline phosphatase <1.6x ULN.
    • Total bilirubin ≤ULN.
    • Alkaline phosphatase decrease ≥15% from baseline.

A maximum dose of OCALIVA 10 mg is presented, excluding data points as subjects titrated to >10 mg daily.3,5

dIncludes only patients who received OCALIVA in the double-blind phase.3

ALP, alkaline phosphatase.

dIncludes only patients who received OCALIVA in the double-blind phase.3

ALP, alkaline phosphatase.

A maximum dose of OCALIVA 10 mg is presented, excluding data points as subjects titrated to >10 mg daily.3,5

  • As in the double-blind phase, response was defined as meeting the following 3 criteria3,5:
    • Alkaline phosphatase <1.6x ULN.
    • Total bilirubin ≤ULN.
    • Alkaline phosphatase decrease ≥15% from baseline.

Study limitations: This analysis selectively excluded data as patients titrated above 10 mg. As this was a post hoc analysis, these results are exploratory and no clinical conclusions should be made.3,5

FIBROSIS DATA FROM THE OPEN-LABEL EXTENSION

Exploratory analysis

Liver stiffness as measured by transient elastography6,e

Categorical changes in liver stiffness based on transient elastography6,e,h

Mean ELF score over time6,i

eFibroScan®. FibroScan is a registered trademark of Echosens SA, Paris.

fOCALIVA baseline: For subjects who received placebo in the double-blind phase, baseline was the last assessment prior to the first OCALIVA dose in the long-term safety extension. For subjects who received OCALIVA in the double-blind phase, baseline was the mean of all available evaluations prior to double-blind treatment.

gData were excluded if: 1) IQR/median exceeded 30%, or 2) transducers between baseline and follow-up did not match, or 3) the number of valid measurements were <10, >20, N/A, or 4) measurements were not actually transient elastography.

hIncreased/decreased/unchanged from baseline were defined as advancement/reduction/unchanged in fibrosis category based on defined cut points in table.

iELF score is a fibrosis marker set consisting of tissue inhibitor of metalloproteinase-1 (TIMP-1), amino-terminal propeptide of type III procollagen (PIIINP), and hyaluronic acid (HA).8

ELF, enhanced liver fibrosis; IQR, interquartile range; kPa, kilopascal; SD, standard deviation; TE, transient elastography.

Study limitations: This analysis selectively excluded data as patients titrated above 10 mg.6 As this was a post hoc analysis, these results are exploratory and no clinical conclusions should be made.

Safety Data

From the open-label extension

Adverse events5

  • The most common adverse events were pruritus (70% of patients), fatigue (28%), and nasopharyngitis (27%).

Discontinuations5

  • Of 34 patients who discontinued during the open-label extension, reasons included:
    • Clinical or laboratory adverse events (n=9); pruritus (n=4); withdrew consent (n=9), lost to follow-up (n=5); death (n=1); major protocol violation/noncompliance (n=1); other (n=5).

Pruritus in the open-label extension3,5

  • 63% of patients who entered the open-label extension had a history of PBC-related pruritus.3
    • At baseline, 56% of patients had pruritus.
  • During the open-label extension, 70% of patients experienced pruritus.5
    • Throughout treatment, more pruritus days were mild than moderate or severe.
Graph showing pruritus duration in the open-label extension study for OCALIVA® (obeticholic acid)

A maximum dose of OCALIVA 10 mg is presented, excluding data points as subjects titrated to >10 mg daily.3,5

PBC, primary biliary cholangitis.

Study limitations: This analysis selectively excluded data as patients titrated above 10 mg. As this was a post hoc analysis, these results are exploratory and no clinical conclusions should be made.3,5

Additional Resources

References

  1. OCALIVA full prescribing information. New York, NY: Intercept Pharmaceuticals, Inc; 2021.
  2. Nevens F, Andreone P, Mazzella G, et al; for the POISE Study Group. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631-643. doi:10.1056/NEJMoa1509840.
  3. Trauner M, Nevens F, Shiffman ML, et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study. Lancet Gastroenterol Hepatol. 2019;4(6):445-453.
  4. Trauner M, Nevens F, Shiffman ML, et al. Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study [supplemental appendix]. Lancet Gastroenterol Hepatol. 2019;4(3):1-11. doi:10.1016/S2468-1253(19)30094-9.
  5. Data on file: INT-PB-MED-00009. New York, NY: Intercept Pharmaceuticals, Inc.; 2019.
  6. Data on file: US-PB-MED-00899.
  7. Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 2012;56(1):198-208.
  8. Day J, Patel P, Parkes J, Rosenberg W. Derivation and performance of standardized enhanced liver fibrosis (ELF) test thresholds for the detection and prognosis of liver fibrosis. J Appl Lab Med. 2019;3(5):815-826.

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 ResinsBile 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.

WarfarinThe 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 IndexObeticholic 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 PumpAvoid 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.

Please click here for Full Prescribing Information, including Boxed WARNING.

To report SUSPECTED ADVERSE REACTIONS, contact Intercept Pharmaceuticals, Inc. at 1-844-782-ICPT or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

If you have questions or would like more information about OCALIVA, contact Intercept Medical Information.

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 ResinsBile 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.

WarfarinThe 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 IndexObeticholic 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 PumpAvoid 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.

Please click here for Full Prescribing Information, including Boxed WARNING.

To report SUSPECTED ADVERSE REACTIONS, contact Intercept Pharmaceuticals, Inc. at 1-844-782-ICPT or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

If you have questions or would like more information about OCALIVA, contact Intercept Medical Information.