Elafibranor Benefits Fatigue-Related Pathways Linked to Mitochondrial Function in PBC

New research is shedding light on a significant association between changes in the expression of 10 proteins with a potential role in fatigue or mitochondrial function and the severity of fatigue in patients with primary biliary cholangitis (PBC) treated with elafibranor.1

The data were presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025 by Mark Swain, MD, a professor of medicine at Cumming School of Medicine and full member of The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases at the University of Calgary, and highlight expression changes of proteins linked to fatigue or mitochondrial function following treatment with elafibranor. Of note, these changes significantly correlated with each other and with fatigue improvement, suggesting that PPARα/δ agonism beneficially impacts fatigue-associated pathways linked to mitochondrial function.1

“Fatigue, a common, debilitating symptom in patients with primary biliary cholangitis, has poorly understood pathophysiology,” Swain and colleagues wrote.1 “Elafibranor, a PPAR α/δ agonist approved for PBC second-line treatment, has shown clinically meaningful improvements in fatigue.”

In a previous analysis presented at the European Association for the Study of the Liver (EASL) Congress 2025, expression levels of 10 proteins associated with a potential role in fatigue or mitochondrial function were found to be impacted in patients treated with elafibranor, including ATAD3B, BAX, CA14, CA5A, ECI1, GRPEL1, HPD, KYNU, MECR, and SOD2.2

To build upon this research and examine the relationship between changes in expression of these proteins and fatigue severity with elafibranor, investigators assessed serum samples collected from patients in the phase 3 ELATIVE trial at baseline and week 52 and analyzed them using the Olink® Explore HT proteomic panel. Spearman correlations were evaluated between Patient-Reported Outcome (PRO) Measurement Information System (PROMIS) Fatigue Short Form 7a (PFSF 7a), PBC-40 Fatigue domain (PBC-40 F), and expression levels of the 10 proteins impacted by elafribanor treatment.1

Analyses were conducted in the overall population and in patients with baseline moderate-to-severe fatigue, defined as PFSF 7a T-score ≥60 or PBC-40 F score ≥29.1

Of 161 patients in ELATIVE, samples were included from 119. Of these patients, 46 and 63 had baseline moderate to severe fatigue according to PFSF 7a and PBC-40 F, respectively.1

At baseline, in the overall population, significant moderate-to-strong correlations were observed between the expression of all proteins (r=0.29–0.89; P <.05). In patients with baseline moderate to severe fatigue according to both PROs, expression of CA5A, ECI1, GRPEL1, KYNU, MECR, and SOD2 were significantly correlated with fatigue at baseline (r=0.25–0.39; P <.05). Of these patients treated with elafribanor (baseline moderate to severe fatigue, PFSF 7a, n = 33; PBC-40 F, n = 41), moderate-to-strong correlations (r=0.27–0.88) were observed between expression changes from baseline to week 52 of all proteins, which were all significant (P <.05) except for CA5A and ATAD3B, and MECR and CA14.1

In the 33 elafibranor-treated patients with baseline moderate to severe fatigue according to PFSF 7a, significant correlations between CfB to W52 in BAX, ECI1, GRPEL1, HPD, KYNU, MECR, and SOD2 expression and PFSF 7a were observed (r=0.35–0.54; P <.05). Changes from baseline to week 52 in SOD2 and PBC-40 F were significantly correlated in the 41 patients with baseline moderate to severe fatigue according to PBC-40 F (r=0.32; P <.05).1

“Elafibranor treatment led to expression changes of proteins linked to fatigue or mitochondrial function, significantly correlated with each other and with fatigue improvement,” investigators concluded.1 “This suggests that PPARα/δ agonism beneficially impacts fatigue-associated pathways linked to mitochondrial function, providing a foundation for further research into the mechanistic contribution of PPARα/δ agonism to fatigue improvement in PBC.”

References

1. Swain M, del Pilar Schneider M, Plas P, et al. Elafibranor-associated changes in proteins linked to mitochondrial function correlate with fatigue improvement: Proteomic results from the ELATIVE® trial. Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025. Washington, DC. November 7-11, 2025.

2. Swain M, Plas P, del Pilar Schneider M, et al. LBP-025 Elafibranor impacts inflammatory, fibrotic and symptom-associated markers in patients with primary biliary cholangitis: Proteomic results from the ELATIVE® trial. Journal of Hepatology. doi:10.1016/S0168-8278(25)00444-1