Combination therapy with bezafibrate, a fibrate drug used to treat hyperlipidemia, and ursodeoxycholic acid (UDCA) was associated with improved transplant-free survival in Japanese patients with primary biliary cholangitis (PBC), a researcher said.
Patients with PBC treated with bezafibrate and UDCA had a reduced risk of all-cause death or liver transplant versus patients receiving UDCA monotherapy (adjusted HR 0.23, 95% CI 0.15-0.35, P<0.0001), reported Atsushi Tanaka, MD, of Teikyo University School of Medicine in Tokyo.
But UDCA monotherapy was better than nothing for these patients, as those receiving the monotherapy had a reduced risk of all-cause death or liver transplant versus patients receiving no treatment (adjusted HR 0.55, 95% CI 0.47-0.65, P<0.0001).
UDCA is first-line therapy for patients with PBC, and is approved by the FDA to treat PBC in the U.S. However, about 20-30% of patients have an incomplete response to the treatment, which can result in death or liver transplantation, Tanaka said at a presentation at the digital European Association for the Study of the Liver (EASL) conference.
While obeticholic acid (Ocaliva), a selective ligand of the farnesoid X receptor (FXR), was approved to treat PBC in combination with UDCA for certain patients in 2016, there are still concerns regarding its safety and efficacy, he noted. Indeed, the FDA added a black box warning to the drug in 2018 about correct dosing.
So, second-line treatment “has been long-awaited for these patients,” Tanaka said.
Bezafibrate is approved for treating PBC in France, the authors said, and has been used as a “de facto” second-line treatment for patients with PBC and an incomplete response to UDCA (13-15 mg/d) in Japan since the 2000s. However, Tanaka added, “its long-term efficacy on survival remains to be determined.”
Ulrich Beuers, MD, of the Tytgat Institute for Liver and Intestinal Research in Amsterdam, who was not involved with the study, noted that while prospective, randomized, placebo-controlled trials are the gold standard in research, retrospective analyses “can lead to enormous knowledge gain when carefully performed.”
“Japanese clinicians and researchers were the first to combine UDCA with bezafibrate treatment in patients who did not respond adequately to UDCA alone,” said Beuers, who is an EASL governing board member, in a statement. “This report, together with well-designed prospective studies, will have major impact for the future management of PBC worldwide.”
Tanaka acknowledged in a statement that while randomized controlled trials would be ideal to determine the long-term effectiveness of UDCA and bezafibrate, “this is challenging in Japan because bezafibrate is a standard-of-care second-line treatment.”
They did the next best thing. Researchers retrospectively examined long-term efficacy of bezafibrate using a nationwide cohort of PBC patients in Japan. The Japanese PBC cohort was initiated in 1980, and is updated every 3 years by the Japan PBC Study Group.
Of the 9,919 patients currently enrolled, researchers examined data from 8,180 patients (mean age of about 57, 87% women). Of these, 74% received UDCA monotherapy, 12% received a combination of bezafibrate and UDCA, 14% received no treatment, and the remaining 17 patients received bezafibrate monotherapy. Patients had a mean follow-up of about 8 years. Overall, 14% of patients died, 9% had liver-related death, and 1% had a liver transplant.
Patients receiving combination therapy also had a similar reduced risk of liver-related death or liver transplant versus the UDCA-only group (adjusted HR 0.21, 95% CI 0.12-0.37), as did patients in the UDCA-only group versus those with no treatment (adjusted HR 0.50, 95% CI 0.42-0.61).
This work was supported by a Health and Labor Sciences Research Grant issued by the Ministry of Health, Labor and Welfare of Japan.