CHAPTER 12: Safety Considerations for Epigenetic Mechanisms as Drug Targets: Are Existing Toxicology Studies Fit for Purpose?

Epigenetic mechanisms have emerged as attractive therapeutic targets because of their pleiotropic role in diseases processes and the ability to pharmacologically modulate their activities. One key question in the safety assessment of epigenetic drug targets is whether existing toxicity testing paradigms require modification to adequately characterize and address safety concerns, given the potential long-term consequences as a result of changes in gene expression. Currently approved epigenetic drugs are for the treatment of cancer, with additional disease indications now being explored outside of oncology. What can one learn about safety considerations from these recently marketed compounds as well as approved non-epigenetic drugs as epigenetic modulators? This chapter provides an overview of toxicological considerations for epigenetic therapeutics, outlines currently known and theoretical target organ toxicities, including the potential concerns for transgenerational transmission of epigenetic alterations, and offers recommendations for screening and risk mitigation strategies. Regulatory and risk–benefit considerations for epigenetic therapies are also discussed. Sharing knowledge and understanding around what comprises a comprehensive drug safety assessment should further increase confidence in advancing compounds that modulate epigenetic proteins to significantly improve lives by treating a wide variety of diseases.