Phase 2 studies of two novel treatments for primary biliary cholangitis report encouraging results
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. 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. 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.
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<0.001 vs. placebo). Tropifexor was reported to be generally safe and well tolerated at the doses tested.
"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 <1.67 x ULN in the 5 mg/day (n=13), 5-10 mg/day (n=6), and 10 mg/day (n=19) treatment groups, respectively, with similar reductions in ALP observed in each group (-43% to -45%). Overall, 29% of patients had normal ALP at 26 weeks.
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.