Opportunities for More Tailored Approaches to Genotoxicity Testing and Carcinogenicity Strategy for Oligonucleotide Therapeutics: Outcome of an Industry Survey

The Oligonucleotide Nonclinical Working Group (WG) of the European Federation of Pharmaceutical Industries and Associations conducted an industry survey to understand current practices and regulatory expectations for genotoxicity and carcinogenicity assessment of oligonucleotide therapeutics (ONTs), along with historical genotoxicity testing results. The survey, involving 29 pharmaceutical and biotechnology companies, revealed a consistent absence of genotoxicity across a diverse range of oligonucleotide classes and chemistries, consistent with previous observations. Despite the lack of genotoxicity, companies continue to follow standard testing guidelines, with only limited divergence. The survey data support the view that well-established ONT modifications can be considered "precedented," in terms of negligible genotoxic risk. As such, further testing of new ONT candidates containing only precedented modifications is unwarranted, when defined criteria are met. Further, we propose a pathway for novel ONT chemical modifications to achieve precedented status. The survey results also indicate that alternative strategies for carcinogenicity assessment (e.g., single-species testing) can be accepted by regulatory agencies under certain circumstances. Overall, the survey findings underscore the need for a more tailored approach to the nonclinical safety assessment of ONTs, and the WG proposes development of supplementary questions for International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S2(R1) guidance to reflect this broad industry experience.