Pemafibrate Improves Cholestatic Markers Regardless of the Presence of Primary Biliary Cholangitis

Pemafibrate, a selective PPARα modulator (SPPARMα), improves cholestatic liver enzymes in primary biliary cholangitis (PBC). However, whether these effects depend on PBC-specific autoimmune mechanisms or reflect broader anti-cholestatic actions remains unclear. This study evaluated the effects of pemafibrate on cholestatic markers by PBC status and explored bile acid and immunological changes in patients with PBC.

This post hoc analysis used data from a 52-week phase III study of pemafibrate in patients with hypertriglyceridemia, including 9 with PBC. Cholestatic markers (ALP, total bilirubin, GGT, and LAP) were assessed serially. Linear regression examined associations between baseline levels and response by PBC status. In patients with PBC, bile acids, FGF19, FGF21, C4, IgM, IgG, and M2BPGi were also evaluated.

Pemafibrate significantly reduced all cholestatic markers from week 4-52, regardless of the presence of PBC. Greater reductions were observed in patients with higher baseline levels. In patients with PBC, C4 decreased without significant change in FGF19, suggesting suppression of de novo bile acid synthesis independent of intestinal feedback. The bile acid profile shifted toward a more hydrophilic composition with reduced hydrophobic species. IgM, IgG, and M2BPGi decreased, whereas FGF21 increased.

Pemafibrate improved cholestatic markers in a baseline-dependent manner, regardless of the presence of PBC, suggesting mechanisms beyond PBC-specific pathology. These findings support a broader anti-cholestatic effect, potentially mediated by coordinated modulation of bile acid metabolism and immunological activity through PPARα activation.

The trials were registered at ClinicalTrials.gov under the identifiers NCT04716595.