VIENNA –
Mitchel L. Zoler/MDedge News
Lena Smets
In addition to producing drops in levels of alkaline phosphatase and bilirubin, key surrogate markers for ultimate clinical benefit, the addition of bezafibrate also led to reduced pruritis among five of eight patients who had this symptom when they started on bezafibrate, Lena Smets said at the meeting, sponsored by the European Association for the Study of the Liver. Pruritis is a bothersome adverse effect from obeticholic acid (OCA) treatment that also occurs in patients with untreated primary biliary cholangitis (PBC), so the drop in pruritis in patients who started bezafibrate was notable. Overall, the triple regimen of ursodeoxycholic acid (UDCA), OCA, and bezafibrate was “well tolerated,” said Ms. Smets, a researcher at KU Leuven, Belgium.
Bezafibrate is available in Europe as a lipid-lowering treatment, especially for lowering triglycerides, so there might be a temptation to use it off label in routine practice as an add-on to UDCA and OCA in PBC patients who are not fully responsive to this dual therapy, Ms. Smets acknowledged. But she stressed that what’s needed now is a multicenter, randomized trial of bezafibrate as part of triple-therapy regimen with many more than the 10 patients included in her review.
Both UDCA and OCA have Food and Drug Administration approval for U.S. treatment of PBC. Bezafibrate is not approved for U.S. marketing, but the related agent fenofibrate has FDA approval and has shown preliminary evidence of acting like bezafibrate in PBC patients in small pilot studies or case reports, showing that “growing evidence supports the use of fibrates, but their safety has not been firmly established, and caution should be used,” according to a recent review by clinicians from the University of California, Davis (Gastroenterol Hepatol [NY]. 2018 March;14[3]:154-63).
The series of 10 PBC patients who received triple therapy at KU Leuven began as part of a cohort of 16 PBC patients treated at that center with UDCA monotherapy for an average of 6 years before entering the POISE (Phase 3 Study of Obeticholic Acid in Patients With Primary Biliary Cirrhosis) phase 3 trial that ran at KU Leuven and 57 other sites in 13 countries. POISE randomized 216 PBC patients with persistently elevated alkaline phosphatase and bilirubin levels despite UDCA treatment to added treatment with OCA. The results showed incremental benefit to these patients from a tolerable OCA acid regimen (N Engl J Med. 2016 Aug 18;375[7]631-43). The findings helped OCA (Ocaliva) get FDA marketing approval in 2016 for treatment of PBC when added to UDCA in patients not fully responsive to UDCA monotherapy.
The case for bezafibrate as an add-on to UDCA for refractory PBC patients was documented by a 2018 report from the BEZURSO (Phase 3 Study of Bezafibrate in Combination With Ursodeoxycholic Acid in Primary Biliary Cirrhosis) trial. Run at multiple centers in France, the trial randomized 100 patients on UDCA treatment to added bezafibrate or placebo, and showed that bezafibrate produced significant incremental decreases in and normalizations of alkaline phosphatase and bilirubin levels. It also had the expected effect of increasing serum creatinine level by an average of 5% (N Engl J Med. 2018 June 7;378[23]:2171-81).
Among the 16 participants in the POISE trial at KU Leuven, 13 completed that trial and then agreed to start on a triple regimen with bezafibrate added because of persistent elevations in alkaline phosphatase, and 10 patients completed 6 months on triple treatment. After 6 months, alkaline phosphatase levels reached the normal range in 5 of these 10 patients, Ms. Smets reported. Bilirubin levels also decreased in each of the 10 patients, although bilirubin had already been at a normal level in 9 of the 10 patients at the start of bezafibrate treatment, and this rate remained at 9 of 10 after 6 months. Eight of the 10 had pruritis when they started bezafibrate, and five of these eight reported decreased symptoms on treatment. Patients also showed no biochemical evidence of hepatotoxicity on the triple regimen, Ms. Smets said.
Guidelines published in 2017 from the European Association for the Study of the Liver cited evidence from small studies showing possible efficacy of fibrates as an add-on for PBC patients refractory to UDCA monotherapy, but stopped short of any endorsement of their use (J Hepatol. 2017 July;67[1]:145-72). However, guidelines from the American Association for the Study of Liver Diseases, released several months later and after publication of the BEZURSO results, said that “fibrates can be considered as off-label alternatives for patients with PBC and inadequate response to UDCA,” but also warned that “use of OCA and fibrates is discouraged in patients with decompensated liver disease (Child Pugh–Turcotte B or C)” (Hepatology. 2018 Jan;69[1]:394-419).
SOURCE: Smets L et al. J Hepatol. 2019 April;70[1]:e130.