Quantitative Systems Pharmacology Modeling of FGF19 Pathway Using NAFLDsym Prospectively Predicted Liver Fat and Serum Biomarker Responses to MET409 in NASH Patients

Authors: Yang K, Woodhead JL, Kenz Z, Generaux GT, Siler SQ
Conference: ASCPT
Keywords: FGF19, fibroblasts, NAFLDsym, NASH, nonalcoholic steatohepatitis (NASH), qsp, QSP modeling, QST, quantitative systems pharmacology (QSP), Quantitative Systems Toxicology (QST)
Software: NAFLDsym®
Division: DILIsym Services

Background

Treatment of nonalcoholic steatohepatitis (NASH) is a significant unmet medical need. In this work therapeutic effects of MET409 via fibroblast growth factor 19 (FGF19) pathway were predicted in NASH patients using NAFLDsym, a quantitative systems pharmacology (QSP) modeling platform.

Methods

  • Representation of steatosis, lipotoxicty, inflammation, and fibrosis pathophysiology of NASH within NAFLDsym
  • Representation and optimization of FGF19 PD effects within NAFLDsym using clinical data from tropifexor, cilofexor, and NGM282 studies [1]
  • Prediction of liver fat and biomarker responses in NASH patients administered 50 and 80 mg QD MET409 for 12 weeks

Results

Simulations of clinical protocols of MET409 using NAFLDsym reasonably recapitulated observed liver fat and serum marker responses in NASH patients. [2]

References

  1. Yang et al., AAPS PharmSci 360, 2021, Poster W7145V
  2. Harrison et al., J Hepatol, 2021, 75(1):25-33

By: Kyunghee Yang, Jeffrey L. Woodhead, Zackary Kenz, Grant Generaux, and Scott Q. Siler

Presented at American Society for Clinical Pharmacology & Therapeutics (ASCPT), March 16-18, 2022