A recent study presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025 has identified a significant correlation between the expression of ten proteins related to fatigue and mitochondrial function and the severity of fatigue in patients with primary biliary cholangitis (PBC) treated with elafibranor. The findings were shared by Mark Swain, MD, a professor of medicine at the Cumming School of Medicine in Calgary.
Elafibranor, a PPARα/δ agonist approved for second-line treatment of PBC, has demonstrated clinically significant improvements in fatigue symptoms. According to Swain and his colleagues, fatigue remains a debilitating symptom in PBC, with its underlying mechanisms poorly understood. The new research indicates that the treatment with elafibranor may positively influence pathways associated with fatigue through its impact on mitochondrial function.
In a prior analysis presented at the European Association for the Study of the Liver (EASL) Congress 2025, researchers found that the expression levels of ten specific proteins—including ATAD3B, BAX, CA14, CA5A, ECI1, GRPEL1, HPD, KYNU, MECR, and SOD2—were altered in patients receiving elafibranor. To further investigate the relationship between these protein expression changes and fatigue severity, investigators assessed serum samples collected from participants in the phase 3 ELATIVE trial at baseline and week 52, utilizing the Olink® Explore HT proteomic panel.
Analysis of the data involved evaluating Spearman correlations between the Patient-Reported Outcome (PRO) Measurement Information System (PROMIS) Fatigue Short Form 7a (PFSF 7a), the PBC-40 Fatigue domain (PBC-40 F), and the expression levels of the ten proteins influenced by elafibranor treatment. Out of 161 patients enrolled in the ELATIVE trial, serum samples from 119 participants were included in the analysis. Notably, 46 patients exhibited moderate to severe fatigue based on PFSF 7a, while 63 met the criteria using the PBC-40 F assessment.
At baseline, the study identified moderate to strong correlations among the expression of all ten proteins (r=0.29–0.89; P <.05) within the overall population. Particularly in patients categorized with moderate to severe fatigue, the expression levels of CA5A, ECI1, GRPEL1, KYNU, MECR, and SOD2 demonstrated significant correlations with fatigue severity (r=0.25–0.39; P <.05). Among the 33 patients treated with elafibranor who reported moderate to severe fatigue according to PFSF 7a, significant correlations were found between changes in expression of BAX, ECI1, GRPEL1, HPD, KYNU, MECR, and SOD2 from baseline to week 52 (r=0.35–0.54; P <.05). In the subgroup of 41 patients assessed via the PBC-40 F, changes in SOD2 expression and fatigue severity were also significantly correlated (r=0.32; P <.05). The research team concluded that elafibranor treatment resulted in expression changes among proteins linked to fatigue and mitochondrial function, with these changes significantly correlated with each other and with improvements in fatigue. This suggests that PPARα/δ agonism may beneficially affect pathways associated with fatigue, paving the way for further investigations into the mechanistic roles of this treatment in alleviating fatigue in PBC patients.