Quantitative Systems Toxicology (QST) Modeling of Cimaglermin Alfa (GGF2) Hepatotoxicity Shows the Potential of BIOLOGXsym to Predict Biologics-Induced Liver Injury (BILI)

Authors: Beaudoin J, Vernetti L, Taylor DL, Gough A, Clemens L, Battista C, Siler SQ, Shoda LKM, Howell BA, Yang K
Conference: SOT
Keywords: (v)LAMPS, BILI, BIOLOGXsym, gastroplus, GGF2, hepatotoxicity, QST, QST modeling, Quantitative Systems Toxicology (QST)
Software: BIOLOGXsym, GastroPlus®
Division: Quantitative Systems Pharmacology (QSP)

Background

  • Biologics continue to address various unmet medical needs, but the occurrence of BILI can terminate clinical development of otherwise promising treatments
  • Phase I clinical trials of the growth factor protein GGF2 in heart failure patients were suspended after observing elevations of the BILI biomarkers plasma alanine aminotransferase (ALT) and total bilirubin (TB)
  • To evaluate the clinical BILI risks of biologics such as GGF2, a novel QST modeling platform, BIOLOGXsym™, was developed in conjunction with assay outputs from 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 (10 ng/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 in BIOLOGXsym™

Results

  • Compared to vehicle treatment, GGF2-treated (v)LAMPS significantly decreased bile acid secretion (Fig. 2)
  • These and other GGF2 data were used to derive mechanistic toxicity parameters in BIOLOGXsym™
  • Simulations furthermore incorporating interindividual physiological differences related to hepatotoxicity susceptibility 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. Longo 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. Shoda, Brett A. Howell, Kyunghee Yang

Presented at Society of Toxicology (SOT) 61st Annual Meeting and ToxExpo, March 27-31, 2022