Cells, Tox and Rock 'n' Roll - Cell Validation and Drug-Induced Liver Injury Using a Human Liver Microphysiological System

Ninety percent of therapeutic agents reaching clinical trial fail to reach entry to market, with safety concerns being a  major cause for failures in phase I and II clinical trials. Drug-induced liver injury (DILI) is one of the most common reasons for acute liver failure in both Europe and US and is also one of the leading causes for cessation of drug development. This is predominantly due to traditional preclinical models failing to adequately predict human responses to a drug . Moreover, Drugs with human-specific modes of action, such as ASOs or siRNA, are less well served by in vivo animal models due to their human-specific modes of action.

Incorporating more predictive, human relevant models into drug development workflows is key to reducing drug attrition. Microphysiological systems (MPS), also known as organ-on-a-chip (OOC), bridge the gap between preclinical testing and the clinic. MPS enable us to better recapitulate human physiology via the use of human cells and circulating flow to simulate the blood stream. Yet, without the supply of good quality cells, validated for use in 3D assay formats, the advantages of MPS over current preclinical models can't be fully realized. This presentation will demonstrate the clinical predictability of a Liver MPS using OOC-validated liver cells and a validation set of mildly to severely hepatotoxic compounds, plus two new drug modalities (ASOs).

Learning Objectives

1. Discuss a Liver MPS for drug safety testing.

2. Demonstrate the critical need for 3D cell validation to reliably predict DILI.   

3. Explain the ability of MPS to improve safety assessment predictions earlier in drug development workflows.