Primary biliary cholangitis (PBC) is a chronic cholestatic and immune-mediated liver disease of unknown aetiology. Ursodeoxycholic acid (UDCA), a choleretic and hepatoprotective endogenous bile acid, is the first-line treatment that improves prognosis. However, approximately 40% of patients display an incomplete response, or even intolerance, to UDCA highlighting the need for novel effective therapies.1, 2

The combination of UDCA with bezafibrate, a dual peroxisome proliferator-activated receptors (PPAR)/pregnane X receptor (PXR) agonist, has shown promising results for the short-term treatment (up to 2 years) of patients with PBC who display an inadequate response to UDCA, improving serum markers of cholestasis and liver injury.3-7 Sorda et al8 recently evaluated, within a prospective longitudinal open label study, the long-term (5 years) efficacy and safety of bezafibrate, in combination with UDCA, for the treatment of 59 patients with PBC refractory to UDCA monotherapy (Figure 1). Serum markers of cholestasis and liver injury rapidly improved in patients receiving the combination regimen. This response was sustained during treatment, with 86% of the patients normalising alkaline phosphatase levels. Paired liver biopsy performed at the end of the trial revealed a decrease in liver damage in parallel with fibrosis regression in 48% of patients, and a reduction in the proportion of patients with cirrhosis. Bezafibrate was well tolerated, with only two patients experiencing mild adverse events (myalgia and cutaneous rash) that led to treatment discontinuation. GLOBE and UK-PBC prognosis scores predicted a decreased risk of liver transplant or liver-related death and an increase in liver transplant-free survival, highlighting the benefit of bezafibrate for the long-term treatment of PBC. These data support previous retrospective results where patients with PBC receiving UDCA and bezafibrate displayed a decrease in liver-related mortality or need for liver transplantation, being associated with improved prognosis.9

Main outcomes of bezafibrate for the treatment of PBC refractory to UDCA

This important study opens new opportunities and questions that deserve attention and further investigation. For instance, the therapeutic benefit of the UDCA-bezafibrate combination must be validated in long-term randomised controlled studies in comparison with UDCA and bezafibrate monotherapies. Future studies should also confirm the therapeutic efficacy of bezafibrate in late-stage PBC, since, to date, most trials have only included patients with early-stage PBC, and also, the proportion of patients with cirrhosis included in this current trial was low. In parallel, it would be relevant to evaluate the long-term efficacy and safety of UDCA-bezafibrate in patients with PBC and other concomitant liver diseases (e.g., viral hepatitis, alcoholic and/or non-alcoholic fatty liver disease). Furthermore, the improvement in prognosis of patients undergoing UDCA-bezafibrate therapy needs to be prospective validated in large international cohorts of patients. Further studies should provide more insights on the efficacy of bezafibrate monotherapy in PBC, as well as its combination with other drugs, and also the identification of predictive biomarkers of response to the different therapies in order to improve personalised medicine in PBC. In line with this, the triple combination of UDCA, obeticholic acid and a fibrates in patients with PBC refractory to first- and second-line therapies normalises serum markers of cholestasis and improves pruritus.10 Overall, bezafibrate is a promising novel therapy for these difficult-to-treat patients with PBC who usually display dismal prognosis, thus deserving special focus in the next years.

Declaration of personal interests: The authors disclose no conflict related to this study.