Developmental and Reproductive Toxicity Testing Strategies for Oligonucleotides: A Workshop Proceedings

Area of Science:

• Pharmacology and Toxicology
• Drug Development
• Regulatory Science

Background:

• Oligonucleotide (ONT) therapeutics represent a rapidly advancing class of drugs.
• Robust safety assessment, particularly developmental and reproductive toxicity (DART), is crucial for ONT approval.
• Existing DART assessment strategies may require adaptation for unique ONT properties.

Purpose of the Study:

• To convene stakeholders to discuss and identify strategies for enhancing DART assessments of ONTs.
• To foster consensus on best practices and address knowledge gaps in ONT DART evaluation.
• To inform the development of harmonized international guidance for ONT safety assessment.

Main Methods:

• A workshop format brought together regulators, industry experts, consultants, and contract research organizations.
• Discussions included case studies, consensus-building on approaches, and identification of areas for further research.
• Review of strategies for dose selection, dosing frequency, species selection, and alternative models.

Main Results:

• Exploration of surrogate ONT use and assessment of exposure in placental and embryo/fetal compartments.
• Discussion of weight-of-evidence approaches for comprehensive DART evaluation.
• Identification of specific methods and case studies to optimize DART strategies for ONTs.

Conclusions:

• The workshop provided valuable insights into optimizing DART strategies for oligonucleotide therapeutics.
• The proceedings aim to guide the development of harmonized international regulatory expectations for ONT safety.
• Collaborative efforts are essential for establishing robust and efficient DART assessments in this field.