High doses of FXR agonist tropifexor reduce hepatic fat, serum ALT in patients with NASH

BOSTON – Alanine aminotransferase, hepatic fat, and body weight all decreased in patients with nonalcoholic steatohepatitis (NASH) treated for 12 weeks with higher doses of tropifexor, an investigational farnesoid X receptor agonist, according to interim results of a randomized trial.

Mild pruritus and minor decreases in LDL cholesterol were seen with tropifexor, similar to what has been seen with other farnesoid X receptor agonists, according to investigators, including senior study author Arun Sanyal, MD, professor in the gastroenterology division of the department of internal medicine at Virgina Commonwealth University in Richmond.

“Changes in liver histology resulting from this trial, along with trials of tropifexor in combination with drugs with other mechanisms of action, will define future therapeutic options in fibrotic NASH,” Dr. Sanyal and coauthors said in a late-breaking abstract for the study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

That randomized, double-blind, placebo-controlled, phase 2 study, called FLIGHT-FXR, is designed to evaluate tropifexor (LJN452) in patients with NASH at several different doses, according to Dr. Sanyal and coinvestigators.

Previous reports on the trial demonstrated that lower doses of tropifexor (60 and 90 mcg) had favorable safety with anti-inflammatory and antisteatotic efficacy based on biomarker analysis, according to investigators.

This latest report from FLIGHT-FXR includes 152 patients randomly allocated to receive placebo or tropifexor at one of two higher doses (140 or 200 mcg).

At the highest tropifexor dose of 200 mcg, decreases in alanine aminotransferase (ALT), hepatic fat fraction (HFF), gamma-glutamyl transferase (GGT), and body weight were all significant, compared with the decreases in the placebo arm, according to reported data, while in the 140-mcg arm, the findings were significant versus placebo for GGT and body weight.

Relative HFF reduction by at least 30% was seen in 64% of patients in the tropifexor 200-mcg arm, 32% in the tropifexor 140-mcg arm, and 20% in the placebo arm, the investigators reported.

Pruritus was mild among tropifexor-treated patients in more than 60% of cases, investigators said, and pruritus-related discontinuation rates were low, at 2% (1 patient) for the 140-mcg dose and 6% (3 patients) for 200 mcg.

Investigators noted a dose-related increase in LDL cholesterol with tropifexor treatment, but those lipid changes didn’t lead to reduced doses or stopped treatment, they said.

Serious adverse events were infrequent, with a comparable incidence across treatment and placebo groups, investigators added.

Dr. Sanyal provided disclosures related to Sanyal Bio, Exhalenz, Akarna, Fractyl Laboratories, Genfit, Durect, Tiziana, Novartis, Merck, Galectin, and Janssen, among others.

BOSTON – Alanine aminotransferase, hepatic fat, and body weight all decreased in patients with nonalcoholic steatohepatitis (NASH) treated for 12 weeks with higher doses of tropifexor, an investigational farnesoid X receptor agonist, according to interim results of a randomized trial.

Mild pruritus and minor decreases in LDL cholesterol were seen with tropifexor, similar to what has been seen with other farnesoid X receptor agonists, according to investigators, including senior study author Arun Sanyal, MD, professor in the gastroenterology division of the department of internal medicine at Virgina Commonwealth University in Richmond.

“Changes in liver histology resulting from this trial, along with trials of tropifexor in combination with drugs with other mechanisms of action, will define future therapeutic options in fibrotic NASH,” Dr. Sanyal and coauthors said in a late-breaking abstract for the study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

That randomized, double-blind, placebo-controlled, phase 2 study, called FLIGHT-FXR, is designed to evaluate tropifexor (LJN452) in patients with NASH at several different doses, according to Dr. Sanyal and coinvestigators.

Previous reports on the trial demonstrated that lower doses of tropifexor (60 and 90 mcg) had favorable safety with anti-inflammatory and antisteatotic efficacy based on biomarker analysis, according to investigators.

This latest report from FLIGHT-FXR includes 152 patients randomly allocated to receive placebo or tropifexor at one of two higher doses (140 or 200 mcg).

At the highest tropifexor dose of 200 mcg, decreases in alanine aminotransferase (ALT), hepatic fat fraction (HFF), gamma-glutamyl transferase (GGT), and body weight were all significant, compared with the decreases in the placebo arm, according to reported data, while in the 140-mcg arm, the findings were significant versus placebo for GGT and body weight.

Relative HFF reduction by at least 30% was seen in 64% of patients in the tropifexor 200-mcg arm, 32% in the tropifexor 140-mcg arm, and 20% in the placebo arm, the investigators reported.

Pruritus was mild among tropifexor-treated patients in more than 60% of cases, investigators said, and pruritus-related discontinuation rates were low, at 2% (1 patient) for the 140-mcg dose and 6% (3 patients) for 200 mcg.

Investigators noted a dose-related increase in LDL cholesterol with tropifexor treatment, but those lipid changes didn’t lead to reduced doses or stopped treatment, they said.

Serious adverse events were infrequent, with a comparable incidence across treatment and placebo groups, investigators added.

Dr. Sanyal provided disclosures related to Sanyal Bio, Exhalenz, Akarna, Fractyl Laboratories, Genfit, Durect, Tiziana, Novartis, Merck, Galectin, and Janssen, among others.

BOSTON – Alanine aminotransferase, hepatic fat, and body weight all decreased in patients with nonalcoholic steatohepatitis (NASH) treated for 12 weeks with higher doses of tropifexor, an investigational farnesoid X receptor agonist, according to interim results of a randomized trial.

Mild pruritus and minor decreases in LDL cholesterol were seen with tropifexor, similar to what has been seen with other farnesoid X receptor agonists, according to investigators, including senior study author Arun Sanyal, MD, professor in the gastroenterology division of the department of internal medicine at Virgina Commonwealth University in Richmond.

“Changes in liver histology resulting from this trial, along with trials of tropifexor in combination with drugs with other mechanisms of action, will define future therapeutic options in fibrotic NASH,” Dr. Sanyal and coauthors said in a late-breaking abstract for the study, which will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

That randomized, double-blind, placebo-controlled, phase 2 study, called FLIGHT-FXR, is designed to evaluate tropifexor (LJN452) in patients with NASH at several different doses, according to Dr. Sanyal and coinvestigators.

Previous reports on the trial demonstrated that lower doses of tropifexor (60 and 90 mcg) had favorable safety with anti-inflammatory and antisteatotic efficacy based on biomarker analysis, according to investigators.

This latest report from FLIGHT-FXR includes 152 patients randomly allocated to receive placebo or tropifexor at one of two higher doses (140 or 200 mcg).

At the highest tropifexor dose of 200 mcg, decreases in alanine aminotransferase (ALT), hepatic fat fraction (HFF), gamma-glutamyl transferase (GGT), and body weight were all significant, compared with the decreases in the placebo arm, according to reported data, while in the 140-mcg arm, the findings were significant versus placebo for GGT and body weight.

Relative HFF reduction by at least 30% was seen in 64% of patients in the tropifexor 200-mcg arm, 32% in the tropifexor 140-mcg arm, and 20% in the placebo arm, the investigators reported.

Pruritus was mild among tropifexor-treated patients in more than 60% of cases, investigators said, and pruritus-related discontinuation rates were low, at 2% (1 patient) for the 140-mcg dose and 6% (3 patients) for 200 mcg.

Investigators noted a dose-related increase in LDL cholesterol with tropifexor treatment, but those lipid changes didn’t lead to reduced doses or stopped treatment, they said.

Serious adverse events were infrequent, with a comparable incidence across treatment and placebo groups, investigators added.

Dr. Sanyal provided disclosures related to Sanyal Bio, Exhalenz, Akarna, Fractyl Laboratories, Genfit, Durect, Tiziana, Novartis, Merck, Galectin, and Janssen, among others.