Responses to elafibranor in primary sclerosing cholangitis maintained after initial treatment

Moreover, the findings, presented at AASLD The Liver Meeting in Washington, DC, USA, reveal that patients crossing over from placebo experienced reductions in biochemical markers of cholestasis that approached those seen in patients who started on the drug, and the drug was well tolerated.

“Together, these findings support the continued clinical development of elafibranor in PSC,” said study presenter Christopher Bowlus (UC Davis School of Medicine, Sacramento, California, USA). He added that they will be looking at individual patient responses to examine any heterogeneity, once more data is collected.

Bowlus told the audience that there are currently no approved disease-modifying therapies for PSC. However, he added that there is “pathophysiologic evidence suggesting that dysregulation of PPAR [proliferator-activated receptor] pathways play a role in PSC, and therefore dual activation of PPAR alpha and delta may function synergistically in PSC by addressing the cholestasis, inflammation, and fibrosis” seen in patients.

As elafibranor is a PPAR-alpha/delta agonist that is already approved for the treatment of primary biliary cholangitis, the phase 2 ELMWOOD trial was undertaken to assess the safety and efficacy of the drug in PSC.

Double-blind enrolment

For the double-blind period of the study, 68 PSC patients were randomly assigned to receive elafibranor 80 mg or 120 mg, or placebo, daily for 12 weeks. The average age of the participants was 46.5 years, and 54.0% were men. The mean alkaline phosphatase (ALP) level was 376.2 U/L, and “the majority of patients had evidence of advanced fibrosis,” Bowlus said, including 57.1% with a liver stiffness measurement >9.5 kPa, and 47.6% with enhanced liver fibrosis (ELF) graded at more than 9.8.

He also pointed out that “the symptoms of itch were relatively low in this cohort,” with a mean Worst-Itch Numerical Rating Scale (WI NRS) score of 1.9 points across the whole cohort, and 1.3 points among those who started on placebo.

As previously reported, both doses of elafibranor were well tolerated and improved cholestatic biomarkers compared with placebo.

Bowlus explained that the 120 mg dose of elafibranor was selected for the 2-year open-label extension, as it had comparable safety to that of the lower dose and greater efficacy, and was offered to all patients who completed the initial phase of the trial.

Positive efficacy and safety findings in interim analysis

The current presentation focused on the first interim analysis of the open-label extension, at 28 weeks, involving 20 patients initially assigned to placebo, 21 initially assigned to elafibranor 80 mg, and 22 who continued on elafibranor 120 mg.

Bowlus highlighted that, at data cut-off, not all patients had reached the week 28 milestone, and so the median duration of exposure to elafibranor 120 mg was 16 weeks.

He reported that “no new safety signals” occurred. There were just three treatment-related adverse events (TRAEs) leading to treatment discontinuation, all in patients initially assigned to placebo; three serious TRAEs, two of which occurred in placebo-assigned patients; and one liver-related AE of special interest, again in the placebo group.

In terms of efficacy, switching from placebo to elafibranor 120 mg was associated with a “rapid reduction” in ALP levels, Bowlus noted, while patients already on the drug maintained the decreases they experienced during the double-blind period. Overall, reductions over baseline were 40.6% for placebo patients, 35.6% for those started on elafibranor 80 mg, and 46.3% for those treated with the 120 mg dose throughout.

He added that similar patterns were seen for other measures of liver biochemistry, including gamma-glutamyltransferase, alanine aminotransferase, and aspartate aminotransferase levels.

Elafibranor was associated with reductions in ELF, and “these patterns are more pronounced in patients who had an ELF greater than 9.8 at baseline,” Bowlus said, with all three treatment groups showing reductions over baseline.

There were also reductions in N-terminal type III collagen propeptide from baseline in patients switching from placebo and elafibranor 80 mg and in those continuing on elafibranor 120 mg, as well as decreases in WI NRS scores across all three groups.