SomaLogic proteomics reveals new biomarkers and provides mechanistic, clinical insights into Acetyl coA Carboxylase (ACC) inhibition in Non-alcoholic Steatohepatitis (NASH)

Sci Rep. 2024 Jul 24;14(1):17072. doi: 10.1038/s41598-024-67843-8.

Abstract

Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH) are major metabolic diseases with increasing global prevalence and no approved therapies. There is a mounting need to develop biomarkers of diagnosis, prognosis and treatment response that can effectively replace current requirements for liver biopsies, which are invasive, error-prone and expensive. We performed SomaLogic serum proteome profiling with baseline (n = 231) and on-treatment (n = 72, Weeks 12 and 16, Placebo and 25 mg PF-05221304) samples from a Phase 2a trial (NCT03248882) with Clesacostat (PF-05221304), an acetyl coA carboxylase inhibitor (ACCi) in patients with NAFLD/NASH. SomaSignal NASH probability scores and expression data for 7000+ analytes were analyzed to identify potential biomarkers associated with baseline clinical measures of NAFLD/NASH [Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF), alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] as well as biomarkers of treatment response to ACCi. SomaSignal NASH probability scores identified biopsy-proven/clinically defined NIT-based (Presumed) NASH classification of the cohort with > 70% agreement. Clesacostat-induced reduction in steatosis probability scores aligned with observed clinical reduction in hepatic steatosis based on MRI-PDFF. We identify a set of 69 analytes that robustly correlate with clinical measures of hepatic inflammation and steatosis (MRI-PDFF, ALT and AST), 27 of which were significantly reversed with ACC inhibition. Clesacostat treatment dramatically upregulated Wnt5a protein and Apolipoproteins C3 and E, with drug-induced changes significantly correlating to changes on MRI-PDFF. Our data demonstrate the utility of SomaLogic- analyte panel for diagnosis and treatment response in NAFLD/NASH and provide potential new mechanistic insights into liver steatosis reduction, inflammation and serum triglyceride elevation with ACC inhibition. (Clinical Trial Identifier: NCT03248882).

Keywords: Acetyl CoA Carboxylase; Biomarkers; Liver fibrosis; NAFLD/NASH; SomaLogic proteomics.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Acetyl-CoA Carboxylase* / antagonists & inhibitors
  • Acetyl-CoA Carboxylase* / metabolism
  • Adult
  • Biomarkers* / blood
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease* / blood
  • Non-alcoholic Fatty Liver Disease* / diagnosis
  • Non-alcoholic Fatty Liver Disease* / drug therapy
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Proteomics* / methods

Substances

  • Acetyl-CoA Carboxylase
  • Biomarkers
  • Enzyme Inhibitors

Associated data

  • ClinicalTrials.gov/NCT03248882