Nonclinical Development of Oligonucleotide-Based Therapeutics: Insights from an IQ DruSafe ONT Working Group Survey

Oligonucleotide-based therapeutics (ONTs) present unique nonclinical development challenges that are not fully addressed by paradigms established for small molecule pharmaceuticals or biologic therapeutics. To better understand current industry practice, the IQ DruSafe ONT Working Group conducted an industry survey examining species selection and high-dose selection in GLP repeat-dose toxicology studies, parameters used to determine safety margins, and human equivalent dose (HED) scaling used to support initial dose selection for first-in-human studies. Twenty companies provided responses, largely reflecting experience with systemically administered siRNA and RNase H antisense ONTs. Common themes identified in the survey included frequent use of both rodent and non-rodent species, with nonhuman primates used extensively, and high-dose selection based on an integrated consideration of maximum tolerated dose, pharmacodynamic response, and exposure-based criteria. Safety margins were most often based on steady-state exposure, generally using plasma rather than tissue exposure. For HED scaling, body surface area was the predominant approach, although some respondents reported use of body weight- or platform-informed alternatives. Overall, the survey identifies areas of convergence in current ONT nonclinical practice while highlighting unresolved areas where nonclinical practices diverge. The survey also identified areas where future ONT-specific regulatory guidance could improve consistency across ONT development programs.