Biomarkers of histological response in lanifibranor-treated patients with metabolic dysfunction-associated steatohepatitis.

Abstract

Background and aims: Lanifibranor, a pan-peroxisome proliferator-activated receptor agonist, has demonstrated therapeutic efficacy on MASH resolution and fibrosis improvement in the phase 2b NATIVE study. The histological endpoints MASH resolution and fibrosis improvement (E1), MASH resolution without worsening of fibrosis (E2) and fibrosis improvement without worsening of MASH (E3) were investigated with the aim to identify biological signatures of E1, E2, and E3 responders based on serum biomarkers in patients treated with lanifibranor.

Methods: NATIVE evaluated lanifibranor 800 and 1200 mg daily versus placebo in patients with non-cirrhotic MASH treated over 24 weeks. Liver biopsy was obtained at baseline and the end of treatment (EOT). Patients receiving lanifibranor were pooled and those with liver biopsies were selected (N=142). A panel of 65 biomarkers were evaluated by assessing baseline and absolute as well as relative changes at EOT.

Results: The biomarkers included in E1-score (baseline adiponectin and ferritin; delta of matrix metalloproteinase 9 and transferrin), E2-score (baseline cytokeratin 18 Fragment M65; delta of hyaluronic acid, fructosamine and ALT) and E3-score (baseline cytokeratin 18 Fragment M65 and gamma-GT; delta of AST, insulin, and urea) represented metabolic, apoptotic and fibrosis aspects of the disease. These signatures provided good accuracy for the non-invasive identification of histological response under lanifibranor with AUROC at 0.81±0.08 for E1-score, 0.80±0.08 for E2-score and 0.81±0.08 for E3-score.

Conclusions: Results from this analysis show evidence that baseline values and changes in selected serum biomarkers can aid in predicting histological response in MASH under lanifibranor treatment. These findings support utilizing a similar approach in a larger sample size (NATiV3, NCT03008070).