Reduced Genotoxicity Testing Is Possible for Noncoding Oligonucleotide-Based Therapeutics Containing Well-Characterized Modifications: A European Regulatory Perspective.

Abstract

There is a current lack of harmonized regulatory guidance in evaluating the genotoxic potential of oligonucleotide-based therapeutics (ONTs). In particular, guidance has not established the circumstances under which it is acceptable to deviate from the standard test battery. In this study, we analyzed genotoxicity testing strategies and supporting rationales for 91 noncoding ONTs receiving European Scientific Advice between 2004 and 2024. While the standard test battery was performed for the majority of ONTs, reduced test approaches were proposed for 10 products. Furthermore, we examined both the positions of applicants and corresponding European Union (EU) regulatory opinions to identify critical considerations in evaluating genotoxicity. Our findings show that EU regulators see opportunities to deviate from the standard test battery for ONTs if sufficient evidence for class experience can be demonstrated. This was confirmed for several ONTs with well-characterized chemical modifications (ie, phosphorothioate, 2'-methoxyethyl, and 2'-Omethyl), making the standard battery redundant in these cases. Although all reported genotoxicity tests have been uniformly negative, uncertainty remains for future modifications. Ideally, what constitutes sufficient evidence for class experience should be defined in the upcoming International Council for Harmonisation guideline addressing the nonclinical safety evaluation of ONTs (ICH S13), which would allow regulators to accept reduced testing. Together with the industry sharing more knowledge and underlying data that support growing class experience, this development can promote a harmonized approach for future genotoxicity testing of noncoding ONTs.