Refining Liver Safety Risk Assessment: Application of Mechanistic Modeling and Serum Biomarkers to Cimaglermin Alfa (GGF2) Clinical Trials

D M Longo, G T Generaux, A Bengry-Howell, S Q Siler, Daniel Antoine, D Button, J.A. Caggiano, Jonathan A Eisen, J Iaci, R Stanulis, T Parry, M Mosedale, P B Watkins

Research output: Contribution to journalArticlepeer-review

Abstract

Cimaglermin alfa (GGF2) is a recombinant human protein growth factor in development for heart failure. Phase I trials were suspended when two cimaglermin alfa-treated subjects experienced concomitant elevations in serum aminotransferases and total bilirubin, meeting current US Food and Drug Administration criteria for a serious liver safety signal (i.e., "Hy's Law"). We assayed mechanistic biomarkers in archived clinical trial serum samples which confirmed the hepatic origin of the aminotransferase elevations in these two subjects and identified apoptosis as the major mode of hepatocyte death. Using a mathematical model of drug-induced liver injury (DILIsym) and a simulated population, we estimated that the maximum hepatocyte loss in these two subjects was <13%, which would not result in liver dysfunction sufficient to significantly increase serum bilirubin levels. We conclude that the two subjects should not be considered Hy's Law cases and that mechanistic biomarkers and modeling can aid in refining liver safety risk assessment in clinical trials.

Original languageEnglish
Pages (from-to)961-969
Number of pages9
JournalClinical pharmacology and therapeutics
Volume102
Issue number6
Early online date17 Apr 2017
DOIs
Publication statusPublished - Dec 2017

Keywords

  • Alanine Transaminase
  • Apoptosis
  • Bilirubin
  • Biomarkers
  • Clinical Trials as Topic
  • Humans
  • Liver
  • Models, Statistical
  • Neuregulin-1
  • Recombinant Proteins
  • Risk Assessment
  • Journal Article

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