Disease-modifying therapy in primary biliary cirrhosis

Many immune-modifying drugs have been used in trials - only a few of these agents have shown some benefit (1,2,3)

• ursodeoxycholic acid (UDCA) at a dose of 13-15mg per kg per day has been used on a long term basis aimed to delay the progression to end-stage liver disease; it is well tolerated
  • is the treatment of choice in PBC
  • started at the time of diagnosis of primary biliary cirrhosis
  • more favourable response is seen in patients with an earlier histological stage and it delayes the histological progression of the disease in these patients (1)
  • a marked reduction in serum bilirubin , alkaline phosphatase cholesterol and immunoglobulin M levels is seen with treatment
  • reports have demonstrated that UDCA is associated with a significant reduction in the likelihood of liver transplantation or death in patients with moderate and severe disease (1)
    
    
• up to 40% of PBC patients have an inadequate response to UDCA and may continue to have disease progression
  
  
  • second-line therapies in PBC include obeticholic acid and fibrates
    • obeticholic Acid (OCA)
      • OCA is a potent farnesoid X receptor (FXR) agonist. FXR is a nuclear hormone receptor, which, when bound by its natural occurring ligand (chenodeoxycholic acid), regulates the synthesis and enterohepatic circulation of bile acids
        • within hepatocytes, FXR activation inhibits conversion of cholesterol to bile acids while enhancing their excretion. Increased fecal excretion of bile acids by FXR activation is mediated in the ileum; there, FXR decreases bile acid reabsorption and increases expression of FGF19, which circulates to the liver, where it decreases bile acid synthesis
        • at present, OCA remains the only approved second-line agent for PBC patients with an inadequate response to UDCA while results of long-term studies of its safety and clinical benefit are awaited (3)
          
          
    • fibrates
      • have anticholestatic effects mediated through the peroxisome proliferator-activated receptor (PPAR) - alpha UDP-glucuronosyltransferases signaling axis
      • fibrates can benefit patients who respond suboptimally to UDCA, as reflected by significant improvement in cholestasis, cytolysis, and pruritus after adding fibrates (2,3)
      • a randomized, placebo-controlled trial of bezafibrate (BEZURSO, Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis) in which PBC patients were randomized to receive bezafibrate 400 mg daily or placebo for 2 years (4)
        • the primary endpoint - normal total bilirubin, ALP, aspartate aminotransferase (AST), ALT, albumin, and prothrombin time - was reached more frequently in the bezafibrate group than in the placebo group (30% vs 0%, respectively)
        • there were also significant beneficial changes from baseline to 2 years in serum ALP, ALT, total bilirubin, and albumin
      • of note is that serious adverse effects, including hepatotoxicity and elevations of serum creatinine and creatinine kinase, have been observed with fibrate therapy, and should give caution to its use outside of clinical trials. If fibrates are used, patients should be closely monitored for toxicities (3)

Reference:

• (1) European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. Journal of Hepatology 51 (2009) 237–267
• (2) Poupon R. Primary biliary cirrhosis: a 2010 update. J Hepatol. 2010;52(5):745-58
• (3) Bahar R et al. Update on New Drugs and Those in Development for the Treatment of Primary Biliary Cholangitis.Gastroenterol Hepatol (N Y). 2018 Mar; 14(3): 154-163.
• (4) Corpechot C, Chazouilleres O, Rousseau A, et al. A 2-year multicenter, double- blind, randomized, placebo-controlled study of bezafibrate for the treatment of primary biliary cholangitis in patients with inadequate biochemical response to ursodeoxycholic acid therapy (Bezurso). J Hepatol. 2017;66(1):S89.