Public Release: 

Budesonide add-on therapy improves markers of disease activity but fails to improve histology in patients with primary biliary cholangitis

European Association for the Study of the Liver

13 April 2018, Paris, France: 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.1,2 The condition typically occurs in middle-aged women, with features frequently including fatigue, pruritis, jaundice, xanthomas, osteoporosis, and dyslipidaemia.3,3 Ursodeoxycholic acid is the first-line therapy for PBC; however, up to 40% of patients have an insufficient response to this therapy.1,5 Second-line licensed therapy is with obeticholic acid.1 Previous studies evaluating the combination of budesonide and UDCA in patients with PBC reported promising results,6 although relevant budesonide toxicity was reported in patients with late-stage disease.7

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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About The International Liver Congress™

This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2018 will take place from 11¬-15 April 2018 at the Paris Convention Centre, Paris, France.

About The European Association for the Study of the Liver (EASL)

Since its foundation in 1966, this not-for-profit organization has grown to over 4,000 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European Association with international influence, with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.

Contact

For more information, please contact the ILC Press Office at:

Onsite location reference

Session title: General session II and award ceremony I
Time, date and location of session: 13. April 2018, 10:00 AM - 10:15 AM , Main Plenary
Presenter: Gideon Hirschfield, UK
Abstract: Results of a randomised controlled trial of budesonide add-on therapy in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid (2095)

Author disclosures

Author disclosures are as declared in the ILC 2018 programme. The clinical trial sponsor is Dr Falk Pharma GmbH. Roland Greinwald and Markus Proels are employees of Dr Falk Pharma.

References

1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67(1):145-72.

2. Mousa H, et al. Advances in pharmacotherapy for primary biliary cirrhosis. Expert Opin Pharmacother. 2015;16(5):633-43.

3. Webb GJ, Hirschfield GM. Primary biliary cholangitis in 2016: high-definition PBC: biology, models and therapeutic advances. Nat Rev Gastroenterol Hepatol. 2017;14(2):76-8.

4. Purohit T, Cappell MS. Primary biliary cirrhosis: pathophysiology, clinical presentation and therapy. World J Hepatol. 2015;7(7):926-41.

5. Lleo A, et al. Primary biliary cholangitis: a comprehensive overview. Hepatol Int. 2017;11(6):485-99.

6. Rautiainen H, et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology. 2005;41(4):747-52.

7. Hempfling W, et al. Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis. Hepatology. 2003;38(1):196-202.

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