Safe and effective – identifying toxicity in drug discovery

Part 1 of Prioritizing of drug safety

It is estimated that for every eight active substances entering Phase I clinical trials, only one product is approved and marketed.[1] The low success rate for clinical trials is largely driven by poor efficacy in humans and adverse events leading to the discontinuation of a drug development research program.[2]

Findings related to the inherent properties of the drug itself and the nuanced role of genetics for individual responses can be used to improve the overall success rates of a drug development program. In this three-part blog series, we discuss how each step in the drug discovery phase is crucial to improving success rates and best practices that could be incorporated into toxicity testing.


Starting early

For every drug that is approved by a regulatory agency, only a few hundred out of 5,000 to 10,000 chemicals in the early discovery stage are pursued for preclinical development.[2] With global R&D expenditures projected to reach $92 billion by 2022, it is critical to advance the most robust and least risky candidate to the clinic to ensure new patient therapies are accessible[1]. Therefore, during the discovery stage, we need to consider the following aspects to assure safety:

  • target liability;
  • analysis;
  • drug design, triage and hit; and
  • drug repurposing.

Target liability

The foundation for early discovery research is almost always published literature. Thus, the focus at this stage is to replicate the validity of existing evidence and identify druggable targets and/or disease areas for drug development. While establishing proof of concept can be a challenging task in itself, potential safety liabilities for a given target need also be assessed. Pursuit of a novel target, in an effort to be first-in-class, could result in wasted time, money and resources if the drug is associated with adverse side effects.

Integrated approach to data analysis

A more holistic approach to understanding preclinical toxicity is combining multi-OMICS datasets (genomics, transcriptomic, metabolomic and proteomic) to identify toxicity-specific biomarkers and pathways impacted by treatment with a candidate drug. This approach helps to clarify overall pathways and processes perturbed by a drug.[3][4]

Drug design, triage, hit to lead and lead optimization

The main objectives of lead identification are to identify drugs of the highest potency that are well-tolerated in the experimental system. There are several strategies that can be deployed to identify leads to progress for preclinical development, including a target-centric approach and high-throughput phenotypic screens.

Exploring potency in other disease areas as monotherapy or as part of combination therapy is an appealing alternative to the time and resources invested to discover new drug candidates.


Drug repurposing

As drug development costs continue to rise, finding a new use for an old drug has been widely embraced by drug developers as a faster, less resource intensive way to deliver therapies to patients. For drugs demonstrated to be safe and well-tolerated in clinical trials but which failed to show efficacy, exploring potency in other disease areas as monotherapy or as part of combination therapy is often a more feasible alternative to the hefty resources invested to discover new drug candidates. Correspondingly, drugs with known safety issues can be repurposed with minimal or no side effects for an application different from their original intended use.

In part two of this blog series about best practices in toxicology, we’ll discuss how the drug researchers can start considering a drug’s effects on toxicity of specific organs and specific patients via toxicogenomics, pharmacogenomics, and pharmacoepigenomics.

Can’t wait for the next installment? Read the full report, Prioritizing drug safety: Implementing toxicity testing best practices in every phase of drug research.



[1] In CMR International Pharmaceutical R&D Factbook. (2019).

[2] Matthews H, Hanison J, Nirmalan N. “Omics”-Informed Drug and Biomarker Discovery: Opportunities, Challenges and Future Perspectives. Proteomes. 2016;4(3).

[3] Holmgren G, Sartipy P, Andersson C, Lindahl A, Synnergren J. Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicological Sciences. 2018;163(1):182-195.

[4] Holmgren G, Synnergren J, Bogestål Y, et al. Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells. Toxicology. 2015;328:102-111.