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.
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