SomaLogic proteomics reveals new biomarkers and provides mechanistic, clinical insights into Acetyl coA Carboxylase (ACC) inhibition in Non-alcoholic Steatohepatitis (NASH)
Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH) are prevalent metabolic disorders with rising global incidence and no approved treatments. There is an urgent need for the development of biomarkers for diagnosis, prognosis, and treatment response that can serve as alternatives to liver biopsies, which are invasive, prone to error, and costly. In a Phase 2a trial (NCT03248882) involving Clesacostat (PF-05221304), an acetyl coA carboxylase inhibitor (ACCi), we conducted SomaLogic serum proteome profiling on baseline (n = 231) and on-treatment (n = 72, at Weeks 12 and 16, placebo and 25 mg PF-05221304) samples from patients with NAFLD/NASH. We analyzed SomaSignal NASH probability scores and expression data from over 7,000 analytes to identify potential biomarkers linked to baseline clinical indicators of NAFLD/NASH [Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)] and biomarkers of treatment response to ACC inhibition.
SomaSignal NASH probability scores demonstrated over 70% alignment with biopsy-confirmed or clinically defined NIT-based (Presumed) NASH classification. Reductions in steatosis probability scores induced by Clesacostat corresponded with observed clinical reductions in hepatic steatosis, as measured by MRI-PDFF. We identified 69 analytes that strongly correlated with clinical markers of hepatic inflammation and steatosis (MRI-PDFF, ALT, and AST), 27 of which were significantly reversed with ACC inhibition. Clesacostat treatment notably increased the levels of Wnt5a protein and Apolipoproteins C3 and E, with changes in these proteins significantly correlating with reductions in MRI-PDFF. Our findings highlight the potential of the SomaLogic analyte panel for both diagnosis and treatment response in NAFLD/NASH and provide new insights into mechanisms of liver steatosis reduction, inflammation, and serum triglyceride elevation following ACC inhibition.