Antoine

Boyd

Clarke

Davidson

Harrill

Howell

Kramer

Longo

Mosedale

Murayama

Nicoll

Poelzl

Portmann

Prescott

Remien

Samsky

Schiødt

Schmidt

Shoda

Singer

Smit

Sohlenius-Sternbeck

Starkey Lewis

Stutchfield

Temple

Thulin

Vyskocilova

Watkins

Woodhead

Yang

DM Longo

GT Generaux

BA Howell

SQ Siler

DJ Antoine

D Button

A Caggiano

A Eisen

J Iaci

R Stanulis

T Parry

M Mosedale

PB Watkins

Crossref

Clinical Pharmacology & Therapeutics

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

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 &lt;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.</p

Longo, D M

Generaux, G T

Bengry-Howell, A

Siler, S Q

Antoine, Daniel

Button, D

Caggiano, J.A.

Eisen, Jonathan A

Iaci, J

Stanulis, R

Parry, T

Mosedale, M

Watkins, P B

Edinburgh Research Explorer

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

https://www.pure.ed.ac.uk/ws/files/55790946/Antoine_D_Refining_Liver_Safety....pdf

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

Abstract

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Crossref

Edinburgh Research Explorer