Obeticholic Acid (OCALIVA): A Liver Disease Drug the FDA Never Should Have Approved

In May 2016 the Food and Drug Administration (FDA) granted accelerated approval to obeticholic acid (OCALIVA), an oral drug that reduces bile acid synthesis, as a second-line treatment for adults with a liver disease known as primary biliary cholangitis.[1] In September 2024, more than eight years later, an FDA advisory committee voted near unanimously that the available post-marketing evidence does not support obeticholic acid’s benefit on clinical outcomes. The committee also was concerned about significant safety issues associated with this expensive drug (priced at approximately $85,000 per year).[2]

Primary biliary cholangitis (previously called primary biliary cirrhosis) is a rare chronic autoimmune disease characterized by a gradual destruction of the small bile ducts.[3] These ducts transport bile (a yellow-green fluid that helps digest fats) from the liver to the intestines. The damage to the bile ducts causes bile to build up in the liver, leading to inflammation and scarring. Progressive scarring can cause liver cirrhosis and failure.

At least 90% of patients with primary biliary cholangitis are women, and most are diagnosed between their 30s and 60s. When first diagnosed, up to 60% of affected patients do not have any symptoms. Fatigue and itching (pruritus) are the most frequent symptoms.

The first-line drug for treating primary biliary cholangitis is ursodeoxycholic acid, commonly known as ursodiol (ACTIGALL, URSO 250, URSO FORTE and generics), which is generally well-tolerated.[4]

Regulatory history of obeticholic acid

The FDA approved obeticholic acid under the accelerated pathway based on a small randomized clinical trial involving 216 subjects (143 of whom received at least one dose of the drug; the remaining subjects received a placebo).[5] The primary endpoint of this trial was a laboratory marker composite of blood levels of alkaline phosphatase and total bilirubin, a surrogate endpoint that was considered “reasonably likely” to predict clinical benefit.

After 12 months of follow-up, about 47% of obeticholic acid-treated subjects achieved a favorable response on the surrogate endpoint, compared with 10% of placebo-treated subjects. The most common adverse effects related to obeticholic acid were liver toxicity and worsening of pruritus (including severe pruritus that led to use of antipruritic products), decrease in drug dosage or frequency, and drug holidays or discontinuation. Although 92% of the subjects in the trial had early-stage primary biliary cirrhosis, the FDA approved the drug for all patients with the disease, regardless of its severity.

In February 2018 the FDA added a boxed warning (the most prominent warning the agency can require) on the labeling of obeticholic acid to highlight an increased risk of death and serious liver injury in patients with moderate to severe primary biliary cholangitis who received higher-than-recommended doses of the drug.[6] This FDA action was triggered by drug-related spontaneous adverse-event reports received by the agency.

Subsequently, the FDA received more reports of serious liver injury leading to liver decompensation or failure due to the use of even appropriate doses of obeticholic acid in patients with advanced cirrhosis. This prompted the agency in 2021 to restrict the use of obeticholic acid to adults with primary biliary cholangitis without advanced liver cirrhosis or with compensated (mild) cirrhosis but no portal hypertension (less than 50% of people initially eligible for the drug, hereafter referred to as the current indicated population).[7]

Post-marketing evidence

In September 2024 the FDA convened an advisory committee meeting to discuss whether post-marketing evidence demonstrated a benefit for obeticholic acid on clinical outcomes in the narrower current indicated population.[8]

The committee reviewed evidence from two studies: a post-marketing clinical trial that was required by the FDA and an observational (non-interventional) study that was voluntarily conducted by Intercept Pharmaceuticals (the drugmaker).

The post-marketing clinical trial involved 334 subjects who were randomized in a 1:1 ratio to receive either obeticholic acid or a placebo.[9] The trial did not demonstrate a clinical benefit for the drug on its primary clinical endpoint (a composite of liver transplant, death and liver decompensation) in all subjects or a subset of 149 subjects who met the criteria for the current indicated population. In the latter group, 11 subjects who received obeticholic acid either died or had a liver transplant, compared with only two subjects in the placebo group. This finding indicates that subjects who received obeticholic acid had a lower chance of surviving without liver transplant than those who received placebo.

In addition, six of the eight subjects who were treated with obeticholic acid and had to receive a liver transplant did not have liver cirrhosis before the trial and were not expected to require a liver transplant during the trial. These findings led FDA scientists to conclude that obeticholic acid causes liver toxicity similar to that caused by the progression of primary biliary cholangitis.

The observational study combined retrospective data from administrative health insurance claims and other sources to compare clinical outcomes during treatment with obeticholic acid to those of untreated patients. The FDA determined that the analysis of this study was flawed for several reasons, including the use of questionable methods for linking claims data with external data sources and the reliance on diagnosis codes for primary biliary cholangitis without confirming that patients had the disease.

Although the study endpoint included two objective outcomes (death and liver transplantation), it also included liver decompensation, which can be miscoded. In fact, a separate FDA analysis of the observational study that excluded liver decompensation from the primary endpoint showed no clinical benefit for obeticholic acid in patients who received the drug compared with similar patients who did not.

Therefore, the FDA advisory committee voted 13-1 that the available evidence does not verify the benefit of obeticholic acid on clinical outcomes in the indicated population.[10] Likewise, the committee voted 10-1 (with three abstentions) that obeticholic acid had an unfavorable benefit-risk ratio.

In November 2024 Intercept Pharmaceuticals announced that the FDA has declined to grant full approval of obeticholic acid for treating primary biliary cholangitis.[11] On Dec. 12, 2024, the agency issued a drug safety communication to alert clinicians and patients about the risk of liver injury resulting in liver transplant in patients for whom the drug is indicated.[12] The FDA also urged clinicians to monitor liver tests frequently in patients taking obeticholic acid.

As of late December 2024, the FDA continues to keep obeticholic acid on the U.S. market by retaining its accelerated approval status. As the FDA should never have approved obeticholic acid based on laboratory data, Public Citizen’s Health Research Group urges the agency to immediately rescind its accelerated approval of obeticholic acid, as the European Medicines Agency did in June 2024.[13]

What You Can Do

If you have primary biliary cholangitis, abstain from drinking alcohol; keep up with your vaccinations for hepatitis A and B viruses, as appropriate; and discuss your treatment options with your clinician.[14] If you need drug therapy, consider ursodiol and do not take obeticholic acid. Be alert to symptoms of liver toxicity, and contact your clinician immediately if you experience certain symptoms, including

• abdominal swelling;
• bloody or black stools;
• coughing up or vomiting blood;
• mental status changes, including confusion, slurred speech, mood swings, personality changes, or increased sleepiness or difficulty waking up; and
• yellow eyes or skin[15]

References

[1] Intercept Pharmaceuticals. Label: obeticholic acid (OCALIVA). February 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207999s008lbl.pdf. Accessed November 26, 2024.

[2] Wehrwein P. ICER gives NASH drug resmetirom high marks, formulary watch (USA). Formul Watch. February 20, 2023.

[3] Poupon R. Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis). Updated October 2024. UpToDate.

[4] Poupon R. Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis). Updated October 2024. UpToDate.

[5] Food and Drug Administration. FDA briefing document for the Gastrointestinal Drugs Advisory Committee (GIDAC) meeting regarding obeticholic acid (NDA# 207999). September 13, 2024. https://www.fda.gov/media/181747/download. Accessed November 26, 2024.

[6] Food and Drug Administration. FDA adds boxed warning to highlight correct dosing of Ocaliva (obeticholic acid) for patients with a rare chronic liver disease. February 1, 2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-highlight-correct-dosing-ocaliva-obeticholic-acid-patients-rare-chronic-liver. Accessed November 26, 2024.

[7] Food and Drug Administration. Due to risk of serious liver injury, FDA restricts use of Ocaliva (obeticholic acid) in primary biliary cholangitis (PBC) patients with advanced cirrhosis Adding and updating warnings. May 26, 2021. https://www.fda.gov/media/149516/download?attachment. Accessed November 26, 2024.

[8] Food and Drug Administration. Final summary minutes of the Gastrointestinal Drugs Advisory Committee meeting regarding obeticholic acid (NDA# 207999). October 10, 2024. https://www.fda.gov/media/182630/download. Accessed November 26, 2024.

[9] Food and Drug Administration. FDA briefing document for the Gastrointestinal Drugs Advisory Committee (GIDAC) meeting regarding obeticholic acid (NDA# 207999). September 13, 2024. https://www.fda.gov/media/181747/download. Accessed November 26, 2024.

[10] Food and Drug Administration. Final summary minutes of the Gastrointestinal Drugs Advisory Committee meeting regarding obeticholic acid (NDA# 207999). October 10, 2024. https://www.fda.gov/media/182630/download. Accessed November 26, 2024.

[11] Intercept Pharmaceuticals. Press release. Intercept receives complete response letter from FDA addressing Ocaliva supplemental new drug application (sNDA). November 12, 2024. https://www.interceptpharma.com/about-us/news/?id=2979130. Accessed November 26, 2024.

[12] Food and Drug Administration. FDA Drug Safety Communication. Serious liver injury being observed in patients without cirrhosis taking Ocaliva (obeticholic acid) to treat primary biliary cholangitis. December 12, 2024. https://www.fda.gov/media/184316/download?attachment. Accessed December 29, 2024.

[13] European Medicines Agency. EMA recommends revoking conditional marketing authorisation for Ocaliva. June 28, 2024. https://www.ema.europa.eu/en/news/ema-recommends-revoking-conditional-marketing-authorisation-ocaliva. Accessed November 26, 2024.

[14] Poupon R. Overview of the treatment of primary biliary cholangitis (primary biliary cirrhosis). Updated October 2024. UpToDate.

[15] Food and Drug Administration. FDA Drug Safety Communication. Serious liver injury being observed in patients without cirrhosis taking Ocaliva (obeticholic acid) to treat primary biliary cholangitis. December 12, 2024. https://www.fda.gov/media/184316/download?attachment. Accessed December 29, 2024.