Back Back
Second Line and Future PBC Therapies
Unresponsive to PBC Treatment: Second-line and Future PBC Therapies

Released: November 08, 2024

Expiration: November 07, 2025

Christopher L. Bowlus
Christopher L. Bowlus, MD
Activity Information

Activity

Progress
1
Course Completed
Key Takeaways
  • Primary biliary cholangitis can be difficult to manage, but therapies such as obeticholic acid and PPAR agonists can be used as second-line add-on agents in patients unresponsive to ursodeoxycholic acid.
  • Several future therapies (eg, setanaxib and CNP-104) are under development.

An important consideration in the management of patients with primary biliary cholangitis (PBC) is determining who would benefit from second-line therapy. For the majority of patients with PBC, treatment with ursodeoxycholic acid (UDCA) will completely normalize their alkaline phosphatase (ALP) level, putting them at low risk for disease progression. However, around 40%-50% of patients will not have normalized ALP levels and many will continue to suffer from symptoms, especially pruritus.

Here are questions that are frequently asked in clinical practice to determine whether second-line therapy is appropriate in patients with PBC.

When is it time to consider initiating second-line therapy for PBC?
After a minimum of 6-12 months on UDCA—by which time the maximum response to UDCA will be known—and regularly during follow-up, the response to UDCA should be assessed and second-line therapy considered, if appropriate. 

In which patients would second-line therapy for PBC be the most beneficial?
The higher the ALP level, the greater the potential benefit of a second-line agent in reducing the risk of death or need for liver transplantation. One factor that should be taken into consideration is the patient’s age. The younger the patient, the less likely they are to respond to first-line therapy, and typically the more aggressive their disease is. 

Another factor to consider is whether the patient has advanced fibrosis, which can be determined by transient elastography—avoiding the need for a liver biopsy. If the patient has advanced fibrosis, then they are less likely to respond to UDCA and more likely to be at risk of liver decompensation or need liver transplantation. 

Also, if the patient’s bilirubin level is at the upper limit of normal (ULN) or above normal, they are at a higher risk of progressive disease and should be considered for second-line agents. 

Which second-line therapy should be used in which patient?
The 3 agents that are indicated by the FDA for PBC are the peroxisome proliferator–activated receptor (PPAR) agonists elafibranor and seladelpar, and the farnesoid X receptor agonist obeticholic acid. PPAR agonists that are used off-label are bezafibrate (not available in the United States) and fenofibrate.

For patients that have any degree of itch, obeticholic acid would not be the correct choice owing to its propensity to induce itch. In addition, obeticholic acid is contraindicated in patients with advanced cirrhosis and evidence of portal hypertension.

Seladelpar and elafibranor are effective options associated with significant improvements in biochemical response (ie, ALP levels 1.67 x ULN) and ALP normalization without worsening itch; in fact, they have evidence of improving itch in these patients.

What does the future look like for PBC treatment?
In the future, there will likely be additional disease-modifying therapies for use in patients with PBC, such as saroglitazar, another PPAR agonist. Two other drugs that are in development include the NADPH oxidase 1/4 (NOX) inhibitor setanaxib and the nanoparticle CNP-104.

The NOX 1/4 inhibitor setanaxib is being investigated in patients with advanced fibrosis and has the potential to serve as a third add-on agent in this patient population.

The nanoparticle CNP-104, coated with the autoantigen that induces PBC, aims to induce tolerance and address the underlying autoimmune mechanisms of the disease.

The PBC armamentarium is growing, with even more agents likely to emerge in the future.

Your Thoughts?
Which second-line add-on agent for PBC are you prescribing the most to your patients? Join the discussion by posting a comment.