Current and emerging therapies for PBC

Sept. 16, 2017

Primary biliary cholangitis (PBC), a rare autoimmune liver disease, causes progressive damage to small, intrahepatic bile ducts. PBC signs include a persistently elevated serum alkaline phosphatase (ALP) level, presence of anti-mitochondrial antibodies (AMAs) and characteristic histology.

Positive diagnosis of PBC can be established using clinical and serologic parameters, including:

  • ALP 1.5 times > normal value
  • Positive AMA
  • Aspartate aminotransferase (AST) level of < five times the upper limit of normal

In patients lacking this biochemical profile, liver biopsy may also be useful in confirming diagnosis.

Current approved therapies

Left untreated, PBC can progress to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Ursodeoxycholic acid (UDCA) is currently recommended for any patient with suspected PBC with abnormal liver associated enzymes. Approved in the United States in 1998 for the treatment of PBC, UDCA is generally well-tolerated and has several benefits. It can:

  • Improve serum biochemistries
  • Decrease the risk of varices
  • Delay histological progression to cirrhosis
  • Delay or prevent the need for liver transplantation

Patients with PBC that has not progressed to cirrhosis who are treated with UDCA have a 10-year survival rate similar to that of healthy individuals.

The recommended dose for UDCA is 13 to 15 milligrams (mg) per kilogram (kg) per day in divided dosing. UDCA's specific mechanism of action is currently unknown, but researchers believe that the drug protects against cholestatic injury related to inflammation via multiple pathways.

Although UDCA has proven clinical efficacy, approximately 25 to 40 percent of patients do not respond to UDCA monotherapy. This fact has prompted an extensive search for treatment alternatives. In 2016, the Food and Drug Administration approved obeticholic acid (OCA), an analogue of chenodeoxycholic acid, for treatment of PBC. When used in combination with UDCA, OCA has been shown to improve the biochemical profile in refractory patients. OCA has also been approved for use as monotherapy in patients who cannot tolerate UDCA.

OCA is an agonist of the farnesoid X receptor (FXR), a target for bile acids with the ability to downregulate inflammation and reduce bile acid synthesis. Recent studies have linked FXR activation with reductions in inflammation, fibrosis and cholestasis.

The recommended dose for obeticholic acid is typically 5 mg per day for three months, which can be increased to as high as 10 mg per day in patients with insufficient response. Patients with cirrhosis typically require 5 mg per week, with a sequential increase to 10 mg twice weekly, depending on response. Dose interruption or de-escalation may be necessary in patients who experience pruritus.

Novel therapeutic agents under investigation

Over the last 20 years, researchers have identified a number of new therapeutic targets in PBC. The list that follows highlights several avenues of ongoing research.

Fibrates: With their ability to downregulate bile acid production, multiple fibrates, including bezafibrate and fenofibrate, are being evaluated as potential treatments for PBC.

Fibroblast growth factor 19 and apical sodium-dependent bile acid transporter inhibitors: These agents are of interest due to their role in modulating bile acid production and reabsorption.

Glucocorticoids: Prednisone and other steroids have been shown to have beneficial effects on ALP and liver histology in the early stages of PBC.

Immunomodulators: Methotrexate, mycophenolate and multiple other immune modulators are being evaluated as possible therapies for PBC.

B cell depletion: Because the presence of anti-mitochondrial antibodies is a sign of PBC, immune modulation with B cell depleting agents such as rituximab is being studied.

T cell modulation: Inhibiting T cell activation and recruitment and cytokine release via T cell modulation is also the focus of ongoing research.

Interleukin modulation: Several trials are exploring potential therapeutic targets related to immune system regulation and activation, including interleukin-12 (IL-12) and IL-23.

Stem cell transplantation: Multiple studies are exploring whether bone marrow, umbilical cord or mesenchymal stem cell transplantation can improve hepatic biomarkers and arrest the damage caused by PBC.

Antiviral therapy: Several small studies have examined antiretroviral therapy as a possible treatment for PBC.

Microbiome therapy: This avenue of research explores the possible causative role played by aberrant gut microbiota in the pathogenesis of PBC.

Anti-fibrotic agents: Researchers are also attempting to identify agents with the potential to reverse fibrosis and those that can target pathways related to collagen and elastin production.

In articles recently published in Expert Opinion on Emerging Drugs and Liver International, Mayo Clinic gastroenterologist and hepatologist Elizabeth J. Carey, M.D., and co-authors summarize the current and emerging treatments available to slow progression of PBC and provide symptom relief. Dr. Carey is a specialist in transplant hepatology practicing at Mayo Clinic's campus in Arizona.

"The majority of patients with PBC will respond well to UDCA at the appropriate weight-based dosage," explains Dr. Carey. "Patients who cannot tolerate or have an incomplete response to UDCA may be candidates for OCA or clinical trials using novel agents. These patients may benefit from referral to centers like Mayo Clinic that treat a high volume of patients with PBC."

For more information

Ali AH, et al. Emerging drugs for the treatment of primary biliary cholangitis. Expert Opinion on Emerging Drugs. 2016;21:39.

Chascsa D, et al. Old and new treatments for primary biliary cholangitis. Liver International. 2017;37:490.