Bezafibrate + ursodeoxycholic acid suitable as second-line treatment for primary biliary cholangitis
The addition of bezafibrate to ursodeoxycholic acid improves biochemical responses over ursodeoxycholic acid alone in patients with primary biliary cholangitis, according to results of the BEZURSO* trial.
Researchers of this multicentre (21 centres in France), phase III trial randomized 100 patients (mean age 53 years, 95 percent Caucasian women) with primary biliary cholangitis and inadequate response to treatment with ursodeoxycholic acid (at a dose of 13–15 mg/kg/day for ≥6 months) to receive bezafibrate (400 mg/day; n=50) or placebo (n=50) in addition to ursodeoxycholic acid for 24 months.
At 24 months, patients who received bezafibrate had a significantly better outcome than those who received placebo in terms of achieving a complete biochemical response (defined as normal total bilirubin, alkaline phosphatase, aspartate and alanine aminotransferase, and albumin levels, and normal prothrombin index; difference, 31 percent vs 0 percent; p<0.001). [N Engl J Med 2018;378:2171-2181]
Patient-reported symptoms such as pruritus and fatigue also improved among patients on bezafibrate compared with placebo.
Sixty-seven percent of patients on bezafibrate achieved normal levels of alkaline phosphatase compared with 2 percent of patients on placebo at 24 months. Total bilirubin levels decreased by 14 percent and increased by 18 percent in the bezafibrate and placebo groups, respectively.
“[B]ezafibrate was associated with a rapid and sustained decrease in alkaline phosphatase level and a parallel decrease in total bilirubin, the two most important prognostic indicators in primary biliary cholangitis,” said the researchers.
Liver stiffness decreased by 15 percent among patients on bezafibrate and increased by 22 percent among patients on placebo. Two patients in each group developed liver complications, and symptoms pointing to portal hypertension occurred at a similar rate in each group.
Adverse event (AE) incidence was comparable between bezafibrate and placebo recipients (49 percent vs 51 percent), as was incidence of serious AEs (14 and 12 patients, respectively).
Creatinine levels increased by 5 percent from baseline in patients on bezafibrate and decreased by 3 percent among patients on placebo, while three and one patients in the bezafibrate and placebo groups, respectively, experienced elevations in aminotransferase levels >5 times the upper limit of normal.
Trial drug discontinuation, be it temporary or permanent, occurred in seven and 13 patients on bezafibrate and placebo, respectively.
High alkaline phosphatase levels and portal hypertension at baseline were independent predictors of inadequate biochemical response to bezafibrate. “Advanced cirrhosis and severe cholestasis should therefore be considered as potential limiting factors for adjunctive therapy with bezafibrate,” said the researchers.
“In the past 2 decades, it has become apparent that approximately 40 percent of patients with primary biliary cholangitis do not have an adequate biochemical response to ursodeoxycholic acid. This group remains at risk for progression of liver disease and development of liver failure,” said Associate Professor Elizabeth Carey from the Mayo Clinic in Phoenix, Arizona, US, in an editorial. [N Engl J Med 2018;378:2234-2235]
“This pivotal trial effectively doubles the limited options for second-line therapy of primary biliary cholangitis,” she said, referring to obeticholic acid as the other available option.
While a single treatment is sufficient for patients who respond to ursodeoxycholic acid, patients with a subpar response will benefit from second-line options, she said. Nonetheless, Carey cautioned that the long-term survival benefit conferred by bezafibrate is currently undetermined, and even in this trial, the primary outcome was only observed in about 30 percent of the patients on bezafibrate.
“[Still], any agent that both delays disease progression and alleviates symptoms is a potential boon for patients with the debilitating symptoms of primary biliary cholangitis,” she concluded.