Nonclinical safety assessment of epigenetic modulatory drugs: Current status and industry perspective

Regul Toxicol Pharmacol. 2020 Nov;117:104746. doi: 10.1016/j.yrtph.2020.104746. Epub 2020 Sep 8.


Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines. Survey themes addressed (1) general levels of interest and activity with EEs as therapeutic agents, (2) potential safety concerns, and (3) possible future efforts to develop targeted strategies for nonclinical safety assessment of EEs. Thirteen companies contributed data to the survey. Overall, the survey data indicate the consensus opinion that existing ICH guidelines are effective and appropriate for nonclinical safety assessment activities with EEs. Attention in the framework of study design should, on a case by case basis, be considered for delayed or latent toxicities, carcinogenicity, reproductive toxicity, and the theoretical potential for transgenerational effects. While current guidelines have been appropriate for the nonclinical safety assessments of epigenetic targets, broader experience with a wide range of epigenetic targets will provide information to assess the potential need for new or revised risk assessment strategies for EE drugs.

Keywords: Carcinogenicity; Drug development; Drug safety; Epigenetic; Epigenetic drugs; Epigenetic toxicity; Nonclinical; Safety pharmacology; Toxicology; Transgenerational.

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical / standards
  • Drug Evaluation, Preclinical / trends
  • Drug Industry / standards*
  • Drug Industry / trends
  • Drug and Narcotic Control* / trends
  • Drug-Related Side Effects and Adverse Reactions / epidemiology
  • Drug-Related Side Effects and Adverse Reactions / prevention & control
  • Epigenesis, Genetic / drug effects*
  • Epigenesis, Genetic / genetics
  • Humans
  • Pharmaceutical Preparations / administration & dosage
  • Pharmaceutical Preparations / standards*
  • Risk Assessment / standards
  • Risk Assessment / trends
  • Surveys and Questionnaires*


  • Pharmaceutical Preparations