The addition of budesonide is associated with clinically meaningful improvements in biochemical markers of disease activity but no improvement in liver histology in high-risk patients with primary biliary cholangitis (PBC) experiencing a sub-optimal response to ursodeoxycholic acid (UDCA), according to the results of a study presented today. The placebo-controlled study, which randomized 62 patients with PBC, was terminated early because of slow recruitment and as a result, insufficient power to detect a significant histological difference between treatment groups.
PBC is an autoimmune liver disease that is characterized by the progressive destruction of the small bile ducts, resulting in intrahepatic cholestasis, parenchymal injury, and, ultimately, end-stage liver disease. The condition typically occurs in middle-aged women, with features frequently including fatigue, pruritis, jaundice, xanthomas, osteoporosis, and dyslipidaemia. Ursodeoxycholic acid is the first-line therapy for PBC; however, up to 40% of patients have an insufficient response to this therapy. Second-line licensed therapy is with obeticholic acid. Previous studies evaluating the combination of budesonide and UDCA in patients with PBC reported promising results, although relevant budesonide toxicity was reported in patients with late-stage disease.
The study presented today at The International Liver Congress 2018 in Paris, France, represents an important, long-awaited, placebo-controlled trial evaluating patients with PBC at high risk of progression. Patients were required to have histologically confirmed PBC and inflammatory activity according to the Ishak score, failure to achieve serum alkaline phosphatase (ALP) <1.5 x the upper limit of normal after at least 6 months of UDCA therapy, and a high risk of disease progression. Patients were randomized to receive either budesonide 9 mg/day or placebo in addition to UDCA for the duration of the study, with the possibility to taper budesonide down to 6 mg/day upon normalization of aspartate aminotransferase (AST). The primary efficacy endpoint was improvement in liver histology with respect to inflammation (an improvement of at least 3 points in the Ishak score or no inflammatory activity) and no progression of fibrosis.
After a mean treatment duration of 25.3 months, the primary histological endpoint in an intention-to-treat analysis was not met, with 11/26 patients (42.3%) in the budesonide group and 5/17 patients (29.4%) in the placebo group having an improvement in liver histology (p=0.225). However, normalization of serum ALP occurred in 14/40 patients (35.0%) in the budesonide group and in 2/22 patients (9.1%) in the placebo group (p=0.023). Serious adverse events occurred in 10 and seven patients in the budesonide and placebo groups, respectively. Similar numbers of patients reported adverse events in each treatment group; adverse drug reactions were reported for 24 patients (60%) in the budesonide group and eight patients (36%) in the placebo group.
'Our study found that add-on budesonide produced clinically meaningful improvements in biochemical markers of disease activity that, unfortunately, did not translate into improved liver histology', said Professor Gideon Hirschfield from the University of Birmingham in the UK. 'The overall safety and tolerability of long-term budesonide treatment in this population was acceptable and in keeping with clinical experience'.
Professor Hirschfield believes that the recruitment challenges that led to a lack of statistical power for the primary histological endpoint in this study are relevant for future studies in PBC. 'Nevertheless', he says, 'the observation that liver biochemical improvements were seen with add-on budesonide is consistent with prior trial data and treatment goals'.
'Study recruitment inevitably pre-dated second-line licensed therapy with obeticholic acid', he noted. 'However, our results suggest that after licensed therapy has been offered to patients, there may be individuals in whom there is a high risk of progression and for whom the addition of budesonide to anti-cholestatic therapy will produce biochemical improvements in disease activity'.
'Clinical research to improve the therapeutic options available for primary biliary cholangitis is key, and studies such as these are important to help understand the measures needed to individualize treatment protocols by identifying the hallmark clinical features of response', said Prof. Marco Marzioni from the University Hospital of Ancona, Italy, and EASL Governing Board Member. 'This study also highlights the complexity of research focusing on cholangiopathies, and how this is impacted by the small pool of patients that are eligible to enter clinical trials. Yet, hepatologists do not leave those patients behind, and continue to work on developing more effective clinical management options'.
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