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

Area of Science:

• Pharmacology
• Toxicology
• Drug Development

Background:

• Epigenetic drugs are approved for advanced cancer, with growing interest in non-oncology indications.
• Small molecule direct epigenetic effectors (EEs) represent a therapeutic frontier.
• Pharmaceutical companies are actively assessing the development of EEs.

Purpose of the Study:

• To survey pharmaceutical companies on their interest and concerns regarding the development of small molecule direct epigenetic effectors (EEs).
• To evaluate current practices and future needs for nonclinical safety assessment of EEs.

Main Methods:

• A survey was conducted among thirteen pharmaceutical companies.
• Survey themes included interest in EEs, safety concerns, and strategies for nonclinical safety assessment.

Main Results:

• A consensus emerged that existing International Council for Harmonisation (ICH) guidelines are effective for nonclinical safety assessment of EEs.
• Case-by-case consideration for specific toxicities like delayed effects, carcinogenicity, reproductive toxicity, and transgenerational effects is recommended.
• Current guidelines are considered appropriate, but broader experience may necessitate revised risk assessment strategies.

Conclusions:

• Existing ICH guidelines are suitable for the nonclinical safety assessment of epigenetic effectors.
• Further experience with diverse epigenetic targets will inform potential updates to risk assessment strategies for EE drugs.
• Targeted strategies for specific toxicities should be considered during study design for EEs.