Toxicogenomics in drug development: a match made in heaven?

Compound toxicity accounts for approximately half of all drug failures during development. Currently accepted preclinical studies for drug safety evaluation are time, resource, and animal intensive with often limited clinical predictivity. It is thus highly desirable to develop more efficient and predictive tools for early detection and assessment of potential compound liabilities. The emergence of genomics technologies over the last two decades promised to provide a solution. The premise of toxicogenomics (TGx) is straight forward: compounds with similar toxicity mechanisms and outcomes should perturb the transcriptome similarly and these perturbations could be used as more efficient and/or more predictive biomarkers of downstream toxicity outcome. This concept was reinforced by a number of pioneering studies demonstrating, for example, strong correlations between histopathology, clinical chemistry, and gene expression when different hepatocellular injuries were induced by chemical agents as reviewed in.[1,2] With such early advances, TGx was poised for earlier detection of a vast variety of drug-related outcomes, covering histopathologies across various organs, carcinogenicity, reproductive toxicity, etc., while deciphering mechanisms of action to create a more predictive and resource-sparing battery of tests for hazard identification, risk assessment, toxicity monitoring, and problem-solving across the drug development pipeline. This paradigm shift was anticipated to liberate the pharmaceutical and chemical industries from the current burden of toxicity liabilities, by enabling faster development of clinically safer compounds while reducing cost, infrastructure, and animal requirements.[1–3] TGx and drug discovery/development was expected to be a match made in heaven.