Director - Investigative Toxicology Genentech, California, United States
As the number of complex in vitro models (CIVMs) entering the non-clinical safety landscape continues to increase; promising the ability to address shortcomings in the prediction of DILI liability for drug candidates. It has become exceedingly important to understand the context of use as well as the benefits and challenges for adopting these diverse CIVMs in drug discovery and lead optimization. Here we present studies conducted at Genentech to evaluate the added value of 3D human liver microtissues and a Liver-chip MPS models over traditional primary human hepatocyte monoculture for the prediction of DILI risk. A diverse set of commercial compounds with well characterized DILI in humans was screened using our traditional tier 1 assay with primary human hepatocytes (PHH), then subsets of compounds were subsequently evaluated using either human liver microtissues (hLiMTs) and/or a liver-chip MPS model to evaluate the added sensitivity to recapitulate toxicity signals in these advanced CIVMs. As part of this effort, we also explored orthogonal endpoints (Albumin, ALT, LDH, Urea, CRP) in parallel to traditional cytotoxicity metrics and assessed the added predictive value of this multiparametric data enabled by these more complex model systems.
Additionally, retrospective studies utilizing these in vitro models were performed to assess an internal molecule; a highly potent inhibitor of a novel (non-oncology) target for Genentech. Although no evidence of liver injury was observed in the non-clinical safety studies of both rats and dogs, the clinical development of this molecule was discontinued following transaminase elevations (with no Hy’s law violations) in healthy volunteers during Phase 1. The subsequent in vitro studies further illustrated the value of CIVMs for prediction of DILI risk, as both hLiMTs and Liver-Chip models were able to detect a positive response where none was observed with compound testing in a tradition PHH screening assay.
As these MPS models present challenges related to compound throughput, cost, and experimental complexity; these internal qualification studies represent a significant commitment required for characterization and adoption of these CIVMs in drug development. However, available evidence continues to build that CIVMs have the have potential to transform how we address DILI risk and elucidate mechanisms of hepatotoxicity. In particular, their value added may be to increase sensitivity to detect risk and/or integrate multiple mechanisms of DILI into a single physiologically-relevant system.