Phase 2 studies of two novel treatments for primary biliary cholangitis report encouraging results

ILC 2018: Ongoing Phase 2 studies of tropifexor and seladelpar report promising preliminary efficacy, safety and tolerability results, paving the way for longer-term studies in patients with primary biliary cholangitis

13 April 2018, Paris, France: Preliminary results from two ongoing Phase 2 studies of novel agents under investigation for the treatment of primary biliary cholangitis (PBC) have suggested promising efficacy, safety and tolerability profiles in patients not responding to current standard of care, potentially paving the way for longer-term studies. In the first study presented this week at The International Liver Congress™ 2018 in Paris, France, the non-bile acid farnesoid X receptor (FXR) agonist, tropifexor, demonstrated dose-dependent activity on markers of cholestasis and hepatocellular damage over 4 weeks, with no apparent increase in itching. The second study evaluated 12-26 weeks of treatment with the selective peroxisome proliferator-activated receptor-delta (PPAR-δ), seladelpar, at doses of 2, 5, and 10 mg/day, and reported potent and sustained anti-cholestatic and anti-inflammatory activity without an increase in pruritus.

Primary biliary cholangitis is a progressive cholestatic liver disease characterized by an immune-mediated destruction of intrahepatic bile ducts.1,10 Ursodeoxycholic acid (UDCA) has been the mainstay of treatment for PBC for more than 20 years, however, up to 40% of patients receiving UDCA have persistent elevations of alkaline phosphatase (ALP) or bilirubin, and a further 3-5% of patients are unable to tolerate treatment.1,11 The bile acid FXR agonist obeticholic acid (OCA) is approved as an add-on therapy in patients with PBC, or for those intolerant of UDCA;1 however, approximately 50% of patients in the Phase 3 study of added OCA did not meet the trial's pre-specified dichotomous biochemical efficacy endpoint.12

Tropifexor is a novel, selective, non-bile acid FXR agonist that reduced cholestasis and hepatocellular damage in rodent models.13 The ongoing Phase 2 study reported this week enrolled PBC patients with an inadequate response to UDCA (ALP ?1.67 x ULN or bilirubin >ULN), who were randomized to receive tropifexor 30 μg, 60 μg, or 90 μg once daily or a matching placebo for 4 weeks. The primary endpoint was change from baseline in gamma-glutamyltransferase (GGT).

Dose-dependent decreases in GGT, ALP, bilirubin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed and, by Day 28, a 72% reduction in GGT and a 41% reduction in ALT were reported in the highest tropifexor dosing group (90 μg/day; p

'The dose-dependent activity of tropifexor on markers of cholestasis and hepatocellular damage indicates the potential benefit of FXR agonism in patients with PBC', said Prof. Dr Christoph Schramm from the University Medical Centre in Hamburg, Germany, who presented the study results. 'The absence of a discernible increase in itch could be a major advantage of this FXR agonist, with a resulting impact on patient quality of life'.

In the second study presented in Paris, patients with an inadequate response to UDCA or intolerance to treatment were randomized to receive one of three doses of the selective PPAR-δ agonist, seladelpar, 2 mg, 5 mg, or 10 mg/day. The primary efficacy outcome was change from baseline in ALP. At 12 weeks, changes in ALP were reported to be -21%, -33%, and -45% in the 2 mg/day (n=6), 5 mg/day (n=25), and 10 mg/day (n=22) treatment groups, respectively. At 26 weeks, 69%, 67%, and 79% of patients had an ALP

According to the investigators, seladelpar was generally well tolerated, with no aminotransferase safety signal observed. 'Seladelpar continues to demonstrate an impressive level of activity that is now sustained over 26 weeks of treatment. In the absence of a transaminase safety signal,14 the doses of 5 and 10 mg/day appear to represent an appropriate risk/benefit profile,' said Professor Gideon Hirschfield from the University of Birmingham, UK. 'Moreover, in our study seladelpar treatment was not associated with an increase in pruritus, indeed a substantial decrease was observed in some treatment groups at Week 26, suggesting anti-pruritic activity'.

'Clinical research in PBC is very active at present and these two studies indicate how much scientists are engaged in designing studies aimed at providing patients with effective treatments', said Prof. Marco Marzioni from the University Hospital of Ancona, Italy, and EASL Governing Board Member.

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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, 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: Late Breaker Session

Time, date and location of session: 14. April 2018, 05:30 PM – 05:45 PM, Main Plenary

Presenter: Christoph Schramm, Germany
Abstract: Early assessment of safety and efficacy of tropifexor, a potent non bile-acid FXR agonist, in patients with primary biliary cholangitis: An interim analysis of an ongoing phase 2 study (5581)

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: Gideon Hirschfield, UK
Abstract: Treatment efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor delta agonist, in primary biliary cholangitis patients: 12- and 26-week analysis from an ongoing international, randomized, dose ranging phase 2 study (5588)

Author disclosures

Gideon Hirschfield and co-authors: as stated in the ILC 2018 programme.

Christoph Schramm and co-authors: none reported.

References

9. 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.
10. Suraweera D, et al. Treatment of primary biliary cholangitis ursodeoxycholic acid non-responders: a systematic review. Liver Int. 2017;37(12):1877-86.
11. Invernizzi P, et al. Primary biliary cholangitis: advances in management and treatment of the disease. Dig Liver Dis. 2017;49(8):841-6.
12. Nevens F, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med. 2016;375(7):631-43.
13. Tully DC, et al. Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J Med Chem. 2017;60(24):9960-73.
14. Jones D, et al. Seladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol. 2017;2(10):716-26.

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