Obeticholic Acid for Biliary Atresia

Recruiting at 8 trial locations

Overseen By Scott Birnbaum

Age: < 65

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Intercept Pharmaceuticals

Must not be taking: Anticoagulants

Disqualifiers: Liver transplant, BASM, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

144 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the efficacy, safety and tolerability, as well as PK/PD of OCA in eligible pediatric participants with biliary atresia with successful hepatoportoenterostomy (HPE, also known as a Kasai portoenterostomy). The double-blind period comprises of 2 phases: dose titration phase and age expansion treatment phase.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on anticoagulation therapy, you cannot participate in the trial.

What data supports the effectiveness of the drug Obeticholic Acid for treating biliary atresia?

Obeticholic Acid has been shown to be effective in treating primary biliary cholangitis, a liver disease, especially in patients who do not respond well to the standard treatment, ursodeoxycholic acid. This suggests it may have potential benefits for other liver-related conditions, although specific data for biliary atresia is not provided. ^{1 2 3 4 5}

Is obeticholic acid safe for humans?

Obeticholic acid has been approved for use in adults with primary biliary cholangitis, but it has been associated with serious liver-related side effects, especially in patients with advanced liver disease. It is important to monitor liver function closely when using this medication. ^{1 2 4 6 7}

How is the drug Obeticholic Acid unique for treating biliary atresia?

Obeticholic Acid is unique because it is a farnesoid-X receptor (FXR) agonist, which helps regulate bile acid metabolism in the liver, and is used for liver diseases like primary biliary cholangitis, especially when other treatments are inadequate or not tolerated. ^{1 2 3 8 9}

Research Team

Lynda Szczech, MD

Principal Investigator

Intercept Pharmaceuticals

Eligibility Criteria

This trial is for children under 18 with non-syndromic biliary atresia who've had a successful hepatoportoenterostomy, indicated by bilirubin levels below 2 mg/dL. Children younger than 2 may join later, pending safety reviews.

Inclusion Criteria

I have been diagnosed with non-syndromic biliary atresia.

My bilirubin levels are below 2 mg/dL three months after my HPE procedure.

I am under 18 years old and may be eligible depending on safety reviews for those under 2.

Exclusion Criteria

I am currently on blood thinner medication.

GGT >500 Units per Liter (U/L)

Albumin <3.5 grams per deciliter (g/dL).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Titration

Participants receive OCA or placebo with dose titration every 2 weeks for the first 6 weeks

6 weeks

Age Expansion Treatment

Participants continue at the tolerated dose for approximately 24 months

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Obeticholic Acid

Trial Overview The study tests Obeticholic Acid (OCA) against a placebo in kids with biliary atresia post-hepatoportoenterostomy. It includes dose titration and age expansion phases to assess effectiveness and drug behavior in the body.

Participant Groups

Group I: Participants receiving OCA Active Control 1 Intervention

Participants will be randomized to receive OCA (starting at 1.5 milligrams \[mg\] adult equivalent dose \[AED\]) orally, with water, once daily. Dose will be titrated every 2 weeks in a stepwise manner for the first 6 weeks, starting at 1.5 mg AED and titrating through 3 mg AED to a maximum of 5 mg AED, as tolerated; a discussion with the Medical Monitor is encouraged when determining uptitration if considerable signs or symptoms have arisen. Following the 6-week dose titration phase, participants will continue at the tolerated dose for approximately 24 months in Age Expansion Treatment Phase.

Group II: Participants receiving Matching placebo Placebo Group 1 Intervention

Participants will be randomized to receive matching placebo orally, with water, once daily. Dose will be titrated every 2 weeks in a stepwise manner for the first 6 weeks, starting at 1.5 mg AED and titrating through 3 mg AED to a maximum of 5 mg AED, as tolerated; a discussion with the Medical Monitor is encouraged when determining uptitration if considerable signs or symptoms have arisen. Following the 6-week dose titration phase, participants will continue at the tolerated dose for approximately 24 months in Age Expansion Treatment Phase.

Obeticholic Acid is already approved in United States, European Union for the following indications:

Approved in United States as Ocaliva for:

• Primary biliary cholangitis (PBC) without liver problems or with compensated cirrhosis but without portal hypertension

Approved in European Union as Ocaliva for:

• Primary biliary cholangitis (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA

Who Is Running the Clinical Trial?

Intercept Pharmaceuticals

Lead Sponsor

Trials

29

Recruited

16,600+

Findings from Research

Obeticholic acid (Ocaliva) is an FXR agonist that has received accelerated approval in the USA for treating primary biliary cholangitis, particularly in patients who do not respond adequately to ursodeoxycholic acid or cannot tolerate it.

The drug is currently in preregistration for the same indication in the EU, highlighting its potential as a significant treatment option for liver diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obeticholic Acid: First Global Approval. Markham, A., Keam, SJ.[2018]

In a study of 191 patients with primary biliary cholangitis (PBC), obeticholic acid (OCA) demonstrated effectiveness, with a 42.9% response rate after 12 months, particularly in patients who did not have cirrhosis.

However, patients with cirrhosis experienced lower tolerability and a higher discontinuation rate (30% vs. 12%) due to adverse effects, primarily treatment-induced pruritus, highlighting the need for careful monitoring in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with obeticholic acid in patients with primary biliary cholangitis. D'Amato, D., De Vincentis, A., Malinverno, F., et al.[2022]

In a study of 351 patients with primary biliary cholangitis, treatment with obeticholic acid (OCA) or fibrates significantly improved liver enzyme levels and the GLOBE score, indicating better liver health.

Adverse events occurred in 14.7% of patients, with the most common being pruritus, and treatment discontinuation was more frequent with fenofibrate due to intolerance, highlighting the need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obeticholic Acid and Fibrates in Primary Biliary Cholangitis: Comparative Effects in a Multicentric Observational Study. Reig, A., Álvarez-Navascués, C., Vergara, M., et al.[2021]

In a real-world study of 120 patients with primary biliary cholangitis (PBC) who were not responding to ursodeoxycholic acid (UDCA), obeticholic acid (OCA) significantly improved liver function markers, including a notable decrease in alkaline phosphatase and ALT levels after one year of treatment.

OCA was well-tolerated, with a 35% rate of adverse events, but only 11.67% of patients discontinued treatment, primarily due to pruritus, indicating that it is a viable option for patients with PBC who have not responded to standard therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of obeticholic acid in a Southern European multicentre cohort of patients with primary biliary cholangitis and suboptimal response to ursodeoxycholic acid. Gomez, E., Garcia Buey, L., Molina, E., et al.[2021]

In a study of 457 patients with primary biliary cholangitis, obeticholic acid (OCA) showed a significant reduction in alkaline phosphatase levels by 29.5% after 12 months, while fibric acid derivatives achieved a higher reduction of 56.7%.

Despite the differences in alkaline phosphatase reduction, the overall biochemical response rates were similar between OCA (70.6%) and fibric acid treatments (80%), indicating that both therapies are effective second-line options for patients who do not respond adequately to ursodeoxycholic acid.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis. Abbas, N., Culver, EL., Thorburn, D., et al.[2023]

In a study of 100 cirrhotic patients with primary biliary cholangitis (PBC) treated with obeticholic acid (OCA), only about one-third achieved a biochemical response after 6 and 12 months, indicating limited efficacy in this population.

Key risk factors for serious adverse events (SAEs) during OCA therapy included high bilirubin levels (≥1.4 mg/dl), lower albumin levels, and a higher Child-Pugh score, suggesting that careful baseline assessments are essential to identify patients who may not safely benefit from OCA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid. De Vincentis, A., D'Amato, D., Cristoferi, L., et al.[2023]

Obeticholic acid (OCA) significantly reduced alkaline phosphatase (ALP) levels in patients with primary biliary cirrhosis who did not respond adequately to ursodeoxycholic acid, with reductions of 21%-25% compared to only 3% in the placebo group over 3 months.

The treatment was effective across all doses (10 mg, 25 mg, and 50 mg), but the 10 mg dose had the lowest incidence of pruritus, a common side effect, while maintaining significant biochemical improvements, which were sustained in a 12-month extension study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Hirschfield, GM., Mason, A., Luketic, V., et al.[2022]

In a study involving 8 patients with primary biliary cholangitis (PBC) who were inadequately responding to ursodeoxycholic acid (UDCA), obeticholic acid (OCA) significantly improved the hepatic transport of bile acids, increasing their movement from blood into bile by 73%.

OCA treatment also reduced the time that hepatocytes were exposed to potentially harmful bile acids by about 30%, suggesting a protective mechanism against liver damage in PBC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis. Kjærgaard, K., Frisch, K., Sørensen, M., et al.[2022]

In a study involving cirrhotic rats, obeticholic acid (OCA) was found to have higher plasma and liver concentrations compared to control rats, indicating a potential risk for increased toxicity in cirrhotic conditions.

Despite having similar metabolic pathways to endogenous bile acids, OCA concentrations were significantly lower than those of natural bile acids, suggesting that OCA may be less cytotoxic than endogenous bile acids in this model.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis. Roda, A., Aldini, R., Camborata, C., et al.[2018]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Obeticholic Acid: First Global Approval. [2018]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Real-world experience with obeticholic acid in patients with primary biliary cholangitis. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Obeticholic Acid and Fibrates in Primary Biliary Cholangitis: Comparative Effects in a Multicentric Observational Study. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of obeticholic acid in a Southern European multicentre cohort of patients with primary biliary cholangitis and suboptimal response to ursodeoxycholic acid. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Obeticholic acid improves hepatic bile acid excretion in patients with primary biliary cholangitis. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Metabolic Profile of Obeticholic Acid and Endogenous Bile Acids in Rats with Decompensated Liver Cirrhosis. [2018]