Discovery Toxicology: Can we predict the previously unpredictable for early phase drug discovery?

Abstract: Drug induced liver injury (DILI) is a major health issue and contributor to the attrition of novel compounds during development. Toxicology and clinical safety have been highlighted as the major causes of project closures during preclinical and phase I drug development, with the liver identified as a major organ system (Kramer 2007; Cook, 2014). Earlier and concurrent assessment to identify and ideally predict safety concerns in drug discovery to enable better design and selection of candidate molecules. However, whilst the ability to predict safety earlier in the drug development process is clearly desirable, are existing techniques and assay cascades capable of identifying complex and previously undetectable liabilities?

Cincophen and Fialuridine, both of which exhibit complex and partially understood mechanisms of hepatotoxicity, were used to investigate whether modern drug discovery techniques and strategies could identify and flag safety concerns and liabilities. Cincophen, used in the treatment of gout in the early 20th century, was one of the first cases of recorded DILI. In cases of toxicity, fatality occurred in nearly 50% of patients. Fialuridine, a nucleoside analogue developed for the treatment of chronic hepatitis B, was withdrawn during phase II clinical trials in 1993 after severe & fatal hepatotoxicity was observed in 5 of 15 patients (Manning & Swartz, 1995). Fialuridine toxicity was not predicted with mainstay in vitro methods or in vivo animal safety assessments.

Model compounds were assessed alongside compounds with known toxicity mechanisms using a battery of in vitro assays central to the current early stage drug discovery process. Additionally, a number of retrospective cell based assays were conducted utilising high content imaging and multiplexed fluorescence and luminescence approaches. Using typical strategies and experimental conditions, neither compound could be identified has having toxicological liabilities. Further work and profiling is underway to elucidate and understand their toxicological profiles.