The results of the study “A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis” by Corpechot el at. were published in June 2018 in the New England Journal of Medicine (DOI:10.1056/NEJMoa1714519). This “BEZURSO” trial investigated the role of bezafibrate as a second-line treatment for patients with primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis). Second-line treatments are urgently needed for PBC patients with inadequate biochemical responses to ursodeoxycholic acid (UDCA), the current standard treatment for PBC, as these patients are at high risk of disease progression. Inadequate biochemical response was defined in the “BEZURSO” trial using the Paris II criteria (ALT or AST >1.5 times the upper limit of the normal range or an abnormal total bilirubin level after 6 months or more of treatment). “BEZURSO” was conducted as a double-blind, randomized, placebo-controlled French multicenter trial in which 400mg of bezafibrate, a pan-PPAR agonist, was added to UDCA in PBC patients with insufficient biochemical response to UDCA monotherapy. Patients with a total bilirubin > 3mg/dl or a variant syndrome of PBC with signs of autoimmune hepatitis were excluded. About 50% of patients were in an advanced stage of PBC (Ludwig stage 3 or 4).
The primary endpoint in the “BEZURSO” trial was defined as normalization of total bilirubin, AST, ALP, albumin and prothrombin index at 24 months. This primary outcome was reached in 31% of the bezafibrate group and in 0% of the placebo group. Factors independently associated with an inadequate response to bezafibrate were very high levels of ALP and advanced liver cirrhosis. The “BEZURSO” trial was not large or long enough to assess the effect of bezafibrate on hard endpoints such as death or liver transplantation.
In addition, secondary endpoints such as ALP normalization at 24 months were also analyzed (normalization having been reached in 67% in the bezafibrate group and in 2% in the placebo group) as well as the timely course of liver stiffness measured with transient elastography (which decreased in 15% of patients in the bezafibrate group and increased in 22% of patients in the placebo group). Most relevantly from a patient’s perspective, pruritus was alleviated by way of adding bezafibrate: the difference of changes from baseline to 24 months measured by the itch intensity score was -95% between the bezafibrate and the placebo group. Relevant side effects were a rise in creatinine levels (in 5% of the bezafibrate group) and myalgias (in 20% of the bezafibrate group).
About two years before the publication of the “BEZURSO” trial, Nevens et al. published the study “A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis”. This study led to the approval of obeticholic acid (OCA), a farnesoid X receptor agonist, as a second-line treatment for PBC patients with incomplete biochemical response to UDCA or patients intolerant to UDCA. In parallel to bezafibrate in the “BEZURSO” trial, OCA is added to UDCA for PBC patients with an inadequate response to UDCA. The primary endpoint in the study by Nevens et al. was an ALP level of less than 1.67 times the upper limit of the normal range with a reduction of at least 15% from baseline and a normal total bilirubin level at 12 months. The primary endpoint was reached in about 45% of the 5-10mg and the 10mg OCA dosage group (in comparison to 10% in the placebo group). However, pruritus was a frequent adverse event due to OCA (56% of patients in the 5–10mg OCA group and 68% in the 10mg OCA group reported pruritus vs. 38% in the placebo group). After the approval of OCA as a second-line treatment for PBC, it became evident that in patients with advanced stage of liver cirrhosis, OCA treatment was associated with lethal complications and therefore dose reduction of OCA is required for cirrhotic PBC patients.
In summary, for the second-line treatment of PBC with inadequate biochemical response to UDCA, the addition of OCA to UDCA is an approved therapy. Limitations of OCA are side effects, primarily pruritus, uncertainties for its use in late stage liver cirrhosis, unclear long term effects on fibrosis development and its relatively high costs. After the current publication of the “BEZURSO” trial, bezafibrate can now serve as a cheap and effective alternative to OCA and may even alleviates pruritus. However, it is not approved for the use in PBC and has to be prescribed as off-label treatment. Real-life experience will show the relevance of side effects such as renal failures and myalgias under bezafibrate. We also need to learn from the experience with OCA that new second-line treatments for PBC should be used with caution in advanced stage of liver cirrhosis. This is probably also true for bezafibrate. Hopefully, long term studies will reveal whether hard outcomes like death or liver transplantation are influenced by bezafibrate or OCA.
I. Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany