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

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.

Serum biomarkers of drug‐induced liver injury: Current status and future directions

“…While the observed biomarker elevations were sufficient to qualify these participants as Hy's law cases and were clearly glial growth factor 2‐related, DILIsym modeling based on the serial ALT values estimated that the percentage of hepatocyte loss was well less than the 30% predicted to cause a rise in TBIL >2× ULN and this was true whether the hepatocyte death was modeled as apoptotic or necrotic. This supported the conclusion that these two participants should not be considered Hy's law cases . Subsequent studies in cultured human hepatocytes have suggested that the rise in serum bilirubin value may have resulted from the altered expression of bilirubin transporters …”

“…DILIsym is also being used to interpret the significance of TBIL elevations in clinical trials. A recent example is cimaglermin alfa, a recombinant version of glial growth factor 2, that caused both ALT and TBIL elevations in two participants during a phase I clinical trial, prompting a suspension of further clinical studies . While the observed biomarker elevations were sufficient to qualify these participants as Hy's law cases and were clearly glial growth factor 2‐related, DILIsym modeling based on the serial ALT values estimated that the percentage of hepatocyte loss was well less than the 30% predicted to cause a rise in TBIL >2× ULN and this was true whether the hepatocyte death was modeled as apoptotic or necrotic.…”

Systems Toxicology Approach to Identifying Paracetamol Overdose

“…Furthermore, this can be adjusted as a parameter within our model to reflect the clinical situation. There are a number of clinical studies now published that have measured these biomarkers from human studies in a time‐dependent way . The approach we describe to modify dose adjustment can also be undertaken to reflect biomarker kinetic differences.…”

The transformation in biomarker detection and management of drug‐induced liver injury

“…This estimate has been used together with the AUC of serum ALT in two subjects who experienced elevations in serum ALT >3× ULN and serum TBIL >2× ULN believed as a result of study drug, ie both were Hy's Law cases by current definition. The serial serum ALT values resulted in estimates predicting the loss of hepatocytes as far <40% in each subject . The conclusion from the modelling was that the rise in serum TBIL was not due solely to hepatocellular toxicity.…”