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PARIS -- Tropifexor, a non-bile acid FXR agonist, had a dose-dependent effect on gamma-glutamyl transferase (GGT) levels in patients with (PBC) compared with placebo, researchers said here.

In addition to a significant reduction in GGT levels, a reduction was observed in other liver tests, such as alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (ASP) among patients who received the drug, reported Christopher Schramm, MD, of the University Medical Centre Hamburg-Eppendorf in Hamburg, Germany, and colleagues.

The drug was also well-tolerated, with an acceptable safety profile, they said at a late-breaking trial presentation at the International Liver Congress, the annual meeting for the European Association for the Study of the Liver (EASL).

Schramm noted that FXR is "a recognized therapeutic target for PBC," as it protects from bile acid accumulation in the liver and intestine, inhibits bile acid synthesis, and increases bile acid conjugation, transport and excretion. They added that tropifexor (LJN452) is a non-bile acid investigational compound that potently activates FXR, and was shown to reduce cholestasis and hepatocellular damage in pre-clinical studies.

The current research was part of an ongoing phase II study of patients with an inadequate response to ursodiol, a first-line therapy for primary biliary cholangitis. The interim phase II study examined both the effect of tropifexor on GGT, which the authors noted was chosen to avoid the confounding effect of FXR-mediated ALP gene induction, as well as the safety and tolerability of tropifexor. To participate, patients needed to be currently taking ursodiol, as well as meet several PBC diagnosis criteria and disease severity markers.

Patients were randomized in cohorts to receive 30 μg, 60 μg, or 90 μg of tropifexor once daily or matching placebo for 4 weeks. Approximately 10 patients received active drug to every five patients receiving placebo, the authors noted. This is an early analysis of a planned interim analysis of these patient cohorts.

These cohorts were an average age of around 54 to 59, the vast majority were women, and nearly all were Caucasian. There were no significant differences between groups.

Overall, there was a significant dose-dependent decrease in GGT from baseline versus placebo. The authors also noted a significant reduction in ALP, ALT, and AST. In addition, they said that "transient changes observed in cholesterol levels returned to baseline" by end of study.

In addition, tropifexor showed an acceptable safety and tolerability profile at all examined doses. There were no serious adverse events, no discontinuations due to itch, no incidence of severe itch, and no adverse events related to elevation in liver transaminases, ALT, and AST.

Paul Thuluvath, MD, of Mercy Medical Center in Baltimore, characterized tropifexor as "another FXR agonist, along with a few others in the pipeline." While he said this "preliminary study" had "promising results," he sounded a few notes of caution.

"The only disadvantage of obeticholic acid is pruritus which could be bothersome in 10-20% of patients," Thuluvath, who was not involved in the study, told 番茄社区app. "It is important to show improvements in histology before we can comment on the efficacy or superiority of this drug over UDCA or OCA [obeticholic acid]."

Schramm's group stated that these findings justify "further investigation of dose range and longer treatment duration."

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