Proof-of-concept Simulations Using BIOLOGXsym, a Novel Quantitative Systems Toxicology (QST) Modeling Platform for Predicting Biologics-induced Liver Injury (BILI), Recapitulate Clinically Observed Hepatotoxicity of GGF2

Authors: Beaudoin J, Vernetti L, Taylor DL, Gough A, Clemens L, Battista C, Siler SQ, Shoda LKM, Howell BA, Yang K
Conference: ASCPT
Keywords: (v)LAMPS, BILI, biochemistry, biologics, BIOLOGXsym, biomarkers, biomimetic, clinical trials, gastroplus, GGF2, liver, Microphysiology systems, pathophysiology, QST, Quantitative Systems Toxicology (QST), treatment
Software: BIOLOGXsym, GastroPlus®
Division: DILIsym Services

Background

  • While biologics continue to address various unmet medical needs, BILI can terminate clinical development of promising treatments such as cimaglermin alfa (GGF2)
  • Elevations of BILI biomarkers (plasma ALT and TB) were observed in phase I clinical trials of GGF2
  • To assess clinical BILI risk of biologics such as GGF2, a novel QST modeling platform, BIOLOGXsym™, was developed in conjunction with assay outputs from a biomimetic liver model

Methods

  • BIOLOGXsym™ software was engineered to mathematically represent relevant liver biochemistry and mechanistic effects of biologics on liver pathophysiology
  • 10-day GGF2 (10ng/mL) treatment of a human (vascularized) liver acinus microphysiology system [(v)LAMPS] provided GGF2-dependent readouts from previously validated assays
  • Mechanistic data on GGF2 from (v)LAMPS and literature¹, and GGF2 exposure predictions using GastroPlus® (Fig. 1) were integrated to simulate GGF2 hepatotoxicity BIOLOGXsym™

Results

  • Treatment of (v)LAMPS with GGF2 significantly decreased bile acid secretion (Fig. 2)
  • These and other¹ GGF2 data were used to derive mechanistic toxicity parameters in BIOLOGXsym™
  • Simulations furthermore incorporating population variability reasonably recapitulated the range of plasma ALT and TB observed in GGF2 clinical trials² (Fig. 3)

References

  1. Mosedale et al. Toxical Sci. 2018 Feb;161(2):401-411
  2. Long et al. Clin Pharmacol Ther. 2017 Dec;102(6):961-969

By James J. Beaudoin, Lawrence A. Vernetti, D. Lansing Taylor, Albert Gough, Lara Clemens, Christina Battista, Scott Q. Siler, Lisl K.M. Sjoda, Brett A. Howell, Kyunghee Yang

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