Long-term elafibranor therapy improves PBC outcomes

More than 3.0 years of efficacy findings and safety data for 4.5 years of follow-up for the peroxisome proliferator-activated receptor (PPAR) alpha/delta agonist were presented at AASLD The Liver Meeting in Washington, DC, USA, by Jörn Schattenberg (Saarland University Medical Center, Homburg, Germany).

The double-blind period of the phase 3 trial previously demonstrated that after 52 weeks of treatment elafibranor 80 mg was well tolerated and led to a significant improvement in cholestatic biomarkers compared with placebo, as well as benefits in fatigue and pruritus, the presenter said.

The ongoing OLE includes 93 patients who continued to receive elafibranor and 45 patients who were initially given placebo but crossed over to elafibranor, with 83% of participants remaining on treatment until data cutoff at week 182 in May 2025, he explained.

At baseline of the OLE, the participants were aged an average of 58 years (94.9% women), and 91.3% were White, with an average duration of 9.3 years since PBC diagnosis. The majority (96.4%) were also receiving ursodeoxycholic acid therapy.

The average alkaline phosphatase (ALP) levels at this time were lower among the patients who were already using elafibranor than those switching from placebo (192.5 vs 335.8 U/L).

The presenter noted that 42% of participants, both in the initial elafibranor and placebo groups, had an ALP level three times the upper limit of normal (ULN) before receiving their first dose of elafibranor, which he said reflected a patient population with “high disease activity” and this should be considered when reviewing the proportion of patients who achieved normal ALP levels.

At week 182, 72% of the 43 patients with data available had a biochemical response, defined as ALP below 1.67 times the ULN and at least a 15% reduction compared with baseline and a total bilirubin below ULN. Schattenberg commented that this rate was “consistent” with the 66% and 67% rates among the 77 and 73 patients at weeks 130 and 156, respectively.

ALP normalization, defined as an ULN of 104 U/L in women and 129 U/L in men, was achieved by 17–27% of patients between weeks 104 and 156, with 19% of 43 patients reaching this at week 182.

Stabilization or continued improvement in biomarkers and symptoms

Following the previously reported “rapid drop” in ALP by week 4 of the double-blind period, Schattenberg noted there was a sustained decrease in ALP until week 182. In addition, there was no change in total bilirubin levels from the mandatory baseline level of less than 2.2 mg/dL, and there was a downward trend in alanine aminotransferase over the full study period. Finally, the presenter said that there was a similar pattern for gamma-glutamyl transferase as for ALP levels, with a rapid decline and a “persistent response.”

Turning to markers of liver fibrosis and fibrogenesis, the researcher said that “it was interesting to see that there were differences in behavior,” with a “flat line” for the liver stiffness and enhanced liver fibrosis measurements between baseline and week 182. By contrast, Schattenberg pointed to a “consistent decline over time” for the N-terminal propeptide of type III collagen, which he believes is “suggestive of a decrease in fibrogenesis.”

In addition, among patients with moderate-to-severe symptoms of fatigue at baseline, there was a “rapid” and “clinically meaningful” decrease in scores on the PROMIS Fatigue Short Form from week 4 of the study with a “consistent decline” up to week 156 indicating improved fatigue with increasing duration of treatment, he said.

Similarly, patients with moderate-to-severe pruritus on the Worst Itch Numerical Rating Scale at baseline had an initial decline in severity between weeks 4 and 13, followed by a further decline from week 78 to 156. Again, the improvement on the measure “exceeded the clinically meaningful threshold,” the presenter said.

Elafibranor remains well tolerated

“Elafibranor demonstrated a similar safety profile in the OLE to that observed in the [double-blind period], [after] up to 4.5 years’ exposure,” Schattenberg continued.

Overall, 87.0% of patients had a treatment-emergent adverse event (TEAE) in the OLE, most commonly abnormal weight gain (16.7%), urinary tract infection (13.0%), and pruritus (10.1%), with 7.2% experiencing a severe TEAE and 12.3% a serious TEAE. There were no fatal treatment-related TEAEs, and just one (0.7%) patient experienced a transaminase increase, with no other AEs of special interest reported, such as myalgia, rhabdomyolysis, acute kidney injury, or creatine phosphokinase elevation.

“Elafibranor led to rapid and sustained responses in several clinically relevant biomarkers of cholestasis, and stabilization or reduction in markers of fibrosis/fibrogenesis, suggesting potential for slowing disease progression through to 3.5 years,” Schattenberg summarized.

Acknowledging the “favorable safety profile” of the OLE, he concluded that the trial results “support elafibranor in the long-term treatment of PBC.”