DDT-IST-000016-LOI-2 a human liver-chip for prediction of drug-induced liver injury proposed for context of use claim for the prediction of dili within preclinical drug development program -…

DDT-IST-000016-LOI-2 a human liver-chip for prediction of drug-induced liver injury proposed for context of use claim for the prediction of dili within preclinical drug development program - RFA-FD-24-030 application identifier: 1690535 project summary/abstract: drug-induced liver injury (dili) is a leading cause of post-market drug withdrawal, clinical trial failures, patient fatality, and liver transplantations. IT is, therefore, a serious cause for concern and thus accurate and timely prediction of dili is required to assure patient safety during clinical trial. But dili is a complex process and human-relevant models, such as organ-chips, are being considered as tools for dili prediction. Organ-chips recreate the complex and dynamic state in which living cells function in vivo which in turn drives appropriate cell morphology, function, differentiation, and gene expression. The emulate quad-culture liver-chip, which consists of primary human hepatocytes, kupffer cells, stellate cells, and liver sinusoidal endothelial cells (lsecs) demonstrated its ability to predict dili across 18 small molecule drugs with a sensitivity of 87% and a specificity of 100%. Furthermore, IT was able to differentiate between toxic and non-toxic drugs within the same class. Although dili risk needs to be evaluated preclinically for all candidate drugs, IT bares particular importance when the new candidate is in the same class as an earlier drug that displayed dili in the clinic. In such cases, there is a higher a priori risk that the new candidate drug will also display dili, and so IT may require a higher level of scrutiny by regulators. Accordingly, regulators may seek data that facilitates the comparison of dili risk between the new candidate and prior drug, for example, to build confidence that the new compound will reduce dili concerns (and would not, to the contrary, introduce an even higher liability). The objective of this project is to determine the suitability of the liver-chip to predict dili risk of a new candidate drug in the same class as an earlier drug that was a clinical dili positive. Suitability will be demonstrated through (inter-lab) reproducibility and (intra-lab) repeatability of the liver-chip as well as performance across a broader panel of human hepatocyte donors. 27 drydock avenue, 5TH floor boston, MA 02210