Oligonucleotides: Evolution of Carcinogenicity and Risk Assessment Strategy

Since 2006, the carcinogenic potential of antisense oligonucleotides (ASOs) has primarily been evaluated using standard 2-year rodent bioassays. To date, no human-relevant tumor findings have been identified across nonclinical ASO studies. As the field matures and more therapeutics advance into development, there is increasing support for carcinogenicity strategies that built on prior data, leverage platform-based risk assessments, and align with evolving regulatory guidance. In several programs, traditional 2-year mouse studies have been replaced by short-term assessments, such as the 6-month study in transgenic rasH2 mouse study, often conducted alongside a 2-year rat study in accordance with ICH S1B(R1). Historically, deviations from the standard two-species approach have been uncommon and typically limited to severe neurological indications or cases lacking an endogenous rodent target. Nevertheless, for eplontersen and olezarsen, carcinogenicity assessment was limited to a single Tg.rasH2 mouse study or fully waived, supported by prior two-species carcinogenicity data from inotersen and volanesorsen. With the recent ICH S1B(R1) addendum, sponsors now have a defined pathway to pursue carcinogenicity strategies, including potential waivers of the 2-year rat study when supported by the totality of evidence. This article reviews the evolving landscape of ASO carcinogenicity testing and highlights opportunities to reduce or waive long-term studies.