AT ILC 2017

AMSTERDAM (FRONTLINE MEDICAL NEWS) – Patients with primary biliary cholangitis (PBC) who are not responding to first-line therapy with ursodeoxycholic acid (UDCA) may benefit from the addition of bezafibrate, randomized, double-blind, placebo-controlled study findings have suggested.

Almost one-third of the 50 patients who were treated with bezafibrate in addition to UDCA in the 2-year, phase III BEZURSO study met the primary endpoint for response, compared with none of the 50 patients in the control arm of the study.

The findings, presented as a late-breaking abstract at the International Liver Congress, sponsored by the European Association for the Study of the Liver (EASL), could be practice changing for a population of patients who have relatively few treatment options.

“PBC is a progressive cholestatic liver disease and UDCA is the universal first-line treatment for this condition, but 30%-40% of the patients gave an inadequate biochemical response to this drug,” study investigator Christophe Corpechot, MD, of Hôpital Saint-Antoine in Paris, said during a press briefing.

Although obeticholic acid was recently approved as a second-line treatment in combination with UDCA for PBC, one of the side effects of obeticholic acid is that it can cause pruritus, which is one of the symptoms of the condition as well. It can be tricky to explain to patients that there is a treatment but that this treatment might also increase their symptoms, Dr. Corpechot observed.

Between October 2012 and December 2014, mostly female patients (more than 92%), mean age 53 years, who were being treated with UDCA were recruited at 21 centers in France. For inclusion in the study, patients had to have an inadequate biochemical response to UDCA, which was defined by the Paris-2 criteria of an alkaline phosphatase (ALP) or an aspartate aminotransferase (AST) of more than 1.5 times the upper limit of normal (ULN), or a total bilirubin level of more than 17 micromol/L.

Patients were randomized to continue UDCA treatment (13-15 mg/kg per day) with or without the addition of bezafibrate, given as a 400-mg daily dose.

The primary endpoint was a complete biochemical response as defined by normal serum levels of total bilirubin, ALP, aminotransferases, albumin, and a normal prothrombin time at 2 years. The hypothesis was that 40% of the patients in the bezafibrate group and only 10% of patients in the UDCA group would reach this primary endpoint. The actual percentages were 30% and 10% (P less than .0001).

A significantly higher (67% vs. 0%) percentage of patients treated with the fibrate versus UDCA also achieved a normal serum ALP by 2 years, Dr. Corpechot reported, with a significant decrease seen by the third month of treatment.

The mean changes in all the biochemical parameters tested from baseline to the end of the study comparing the bezafibrate group with the control group were a respective –14% and +18% (P less than .0001) for total bilirubin, –60% and 0% for ALP (P less than .0001), –36% and 0% for alanine aminotransferase (P less than .0001), –8% and +8% for AST (P less than .05), –38% and +7% for gamma-glutamyl transferase (P less than .0001), 0% and –3% for albumin (P less than .05), and –16% and 0% for cholesterol (P less than .0001).

Other significant findings favoring the fibrate therapy were a significantly (–75% vs. 0%, P less than .01) decreased itch score (assessed with a visual analog scale) and a significantly lower (–10% vs. +10%, P less than .01) liver stiffness (assessed by transient elastography) at 2 years.

Importantly, the frequency of adverse events, including serious adverse events, did not differ significantly between the two groups.

Providing independent comment at the press conference, EASL Vice Secretary Frank Tacke , MD, observed: “We do have the standard treatment, which is UDCA, and we have one drug that is approved in Europe, obeticholic acid, that is very new, expensive, and with some safety concerns of itching.” Although the latter is manageable, it can be annoying for patients.

Fibrates could thus offer a well tolerated and cheaper alternative, as they are already widely used in clinical practice, although they are not licensed for PBC treatment at the current time.

Dr. Tacke, professor of medicine in the department of gastroenterology, metabolic diseases and intensive care medicine at University Hospital Aachen, Germany, also noted that bezafibrate was a drug that “had been on the market for a very long time,” and was very inexpensive in comparison to obeticholic acid and, importantly, seemed to be very well tolerated in the study.

“One question the community will want to know is whether [bezafibrate] is as effective as obeticholic acid in the second-line treatment of PBC,” Dr. Tacke said. This is a question only a head-to-head study can answer and also it is not possible to say whether other fibrates may have the same benefit as bezafibrate as seen in this trial.

Although the study included only 100 patients, this was a relatively large study considering the disease area and that most patients given the primary treatment of UDCA will do well on it, Dr. Tacke acknowledged in an interview.

“What I like about this study is that they treated patients for 2 years and bezafibrate was given as an add-on treatment, so nobody was at risk for not receiving the UDCA, and they saw a very stable and solid improvement in the parameters studied,” Dr. Tacke said.

EASL launched new guidelines for the diagnosis and treatment of PBC to coincide with the meeting, which state that patients should be treated with UDCA for 1 year and then their biochemical response to treatment should assessed to see if they might need additional treatment. “Up to now, the second-line treatment recommended is obeticholic acid but off-label therapy is mentioned,” Dr. Tacke said.

He noted that there were small, nonrandomized studies with two fibrates – bezafibrate and fenofibrate – that have shown “very encouraging” results but that the current findings suggested that bezafibrate therapy may be an alternative, well-tolerated treatment option for patients failing to respond to standard UDCA therapy that could well be added into the guidelines when they are next revised.

The BEZURSO study was an investigator-led trial sponsored by the Assistance Publique – Hôpitaux de Paris. Dr. Corpechot disclosed financial relationships with Arrow Génériques, Intercept Pharma France, Mayoly-Spindler. Dr. Tacke had nothing to disclose.