13 April 2018, Paris, France: The first results from the POISE biopsy sub-study have today confirmed that long-term treatment with obeticholic acid (OCA) leads to the reversal or stabilization of fibrosis/cirrhosis in patients with primary biliary cholangitis (PBC) who have had an incomplete response to ursodeoxycholic acid (UDCA). These results provide the first evidence that improvements in biochemical markers of PBC observed in previous studies are accompanied by anti-fibrotic effects in line with those observed in pre-clinical trials.
'There is strong evidence from clinical trials that OCA leads to significant reductions in alkaline phosphatase (ALP) that are predicted to improve clinical outcomes of patients with PBC who do not respond adequately to or do not tolerate UDCA',1 said Dr Christopher Bowlus from the University of California, Davis in the USA, who presented the results today at The International Liver Congress™ 2018 in Paris, France. 'This study offers the first evidence from paired liver biopsies that OCA is indeed a disease-modifying therapy'.
Primary biliary cholangitis is a rare autoimmune liver disease characterized by biliary destruction, progressive cholestasis, and, ultimately, the development of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).1,3 The primary medical treatment for PBC is UDCA, however, up to 40% of patients have an insufficient response to this treatment, putting them at risk of potentially life-threatening complications.1,3
Obeticholic acid is a potent agonist of the farnesoid X receptor (FXR), which regulates bile acid synthesis and transport.1 Two previously reported Phase 2 studies4,5 and a pivotal Phase 3 study (POISE)6 confirmed that OCA, primarily in combination with UDCA, leads to significant reductions in serum ALP and improvements in other biochemical liver markers, leading to the recent approval of the treatment by the US Food and Drug Administration (FDA).3
The biopsy sub-study of POISE involved patients undergoing liver biopsies prior to, and after 3 years of, treatment with OCA. Biopsies were centrally read and assessed using a six-tier staging system (from no fibrosis to cirrhosis). Thirteen patients - all receiving treatment with UDCA at baseline - had paired biopsies that were adequate for analysis.
At baseline, nine of the 13 patients (69%) presented with pre-cirrhotic fibrosis and four (31%) with cirrhosis. At the last visit before the final biopsy, serum ALP was reduced and direct bilirubin levels were comparable to baseline (median changes from baseline: -99 U/L and 0.0 μmol/L, respectively). After 3 years of OCA treatment, the majority of patients improved (n=6; 46%) or maintained (n=5; 38%) their histological stage, while two patients (15%) deteriorated. Of the four patients with baseline cirrhosis, three (75%) improved to fibrosis without cirrhosis while receiving OCA treatment.
'Eighty-five percent of the patients with PBC in this study with an incomplete response to UDCA had regression or no worsening of their fibrosis or cirrhosis after 3 years of OCA treatment - a period of time during which we would have expected some degree of fibrosis progression', said Dr Bowlus. 'OCA represents the first new treatment approved for PBC in decades, and these results support the potential of OCA to slow disease progression in this group of patients who have the greatest need for new treatments. The results of the ongoing COBALT study will determine if the biochemical improvements of the POISE study and the histological results reported here translate to improved clinical outcomes' (NCT02308111).
'Relevant changes are on the way for the management of patients with PBC, for which ursodeoxycholic acid has been the only treatment option for a long time', said Prof. Marco Marzioni from the University Hospital of Ancona, Italy, and EASL Governing Board Member. 'Now new medicines are coming and the first of these to be available, obeticholic acid, has been shown to ameliorate surrogate markers of disease progression. The current study, however, reports the first evidence that OCA is also able to halt the deposition of collagen tissue in the liver, a significant outcome for the natural history of PBC'.
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, and with an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.
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Onsite location reference
Session title: Poster Late Breakers
Time, date and location of session: 12. April 2018, 09:00 AM - 14. April 2018, 05:00 PM, Poster Area
Presenter: Christopher Bowlus, USA
Abstract: Long-term obeticholic acid (OCA) treatment associated with reversal or stabilization of fibrosis/cirrhosis in patients with primary biliary cholangitis (PBC) (5662)
Christopher L Bowlus has received grant support from Intercept, CymaBay, Gilead, BMS, GSK, Takeda, and Genkyotex; and has served as an Advisor to Contaus, Patara, Intercept, and GSK. Alberto Pares Darnaculleta has participated in advisory boards and lectures for Intercept Pharma. Paul Pockros has received consultancy and speaker honoraria from Intercept and research funding from Scripps Health. Pierre Bedossa has received funding from Intercept. Richard Pencek, Leigh MacConell, David Shapiro, Elizabeth Malecha, and Uchenna
Iloeje own stock in and are employees of Intercept. Joost PH Drenth has served on advisory boards for AbbVie, Gilead, and Intercept, and his department receives research funding from AbbVie, Ipsen and Gilead - all reimbursements received go to the Radboudumc.
Andreas Kremer has served as a consultant or advisor for Beiersdorf, Elsevier, GSK, Intercept, Janssen, MSD, and has received speaker honoraria from BMS, Falk, Intercept, Janssen, MSD. Lisa Forman and Stephen Ryder report no conflicts of interest.
1. Bowlus CL. Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection. Hepat Med. 2016;8:89-95.
2. 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.
3. Lleo A, et al. Primary biliary cholangitis: a comprehensive overview. Hepatol Int. 2017;11(6):485-99.
4. Kowdley KV, et al. A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis. Hepatology. 2017;doi: 10.1002/hep.29569 [Epub ahead of print].
5. Hirschfield GM, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148(4):751-61.
6. Nevens F, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631-43.