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 <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.

Ocular dysfunction during the amytal suppression test.

We assessed the following parameters of visual function in 16 patients during amytal suppression test (AST): pupillary light response, consensual reflex, pupillary symmetry, monocular reading and monocular visual recognition. Significant visual impairment in the eye ipsilateral to injection (EII) occurred in 7 of 16 patients ranging from blurring to complete, transient loss of vision. We conclude that visual dysfunction of the EII during the AST is common and represents an important component of the test. Intracarotid amytal reaches the EII via ophthalmic artery and probably impairs vision in the EII due to cycloplegia, iridoplegia and retinal suppression.