An Industry Perspective on Key Considerations for the ICH S13 Guidance: Nonclinical Safety Evaluations of Oligonucleotide-Based Therapeutics

Oligonucleotide therapeutics (ONTs) are a growing class of nucleic acid-based therapies with the potential to treat a variety of diseases through several different mechanisms of action (MoA). The most prevalent MoA entails the inhibition of therapeutically relevant levels of protein expression via mRNA degradation, exemplified by numerous approved ONTs. ONTs have unique physicochemical properties, pharmacokinetic characteristics, and MoAs that are distinct from other drug classes. The result can be a disconnect between the administered dose, plasma drug concentrations, pharmacodynamics, and toxicity. Thus, ONT development poses unique scientific and regulatory challenges that are not fully addressed by current International Council for Harmonisation (ICH) guidelines. The complexity of ONT development has recently been recognized with the acceptance of the new ICH topic proposal "ICH S13-Nonclinical Safety Evaluation of Oligonucleotide-based Therapeutics." In preparation for the ICH S13 Step 2 public consultation period, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) DruSafe ONT Working Group convened to identify and discuss key considerations for ONT development, and to communicate areas where regulatory clarity and harmonization are most needed. Specifically, these include strategies to assess off-target toxicities, safety pharmacology, general toxicity studies, First-In-Human dose selection, genotoxicity studies, reproductive and developmental toxicity studies, carcinogenicity assessments, and the appropriate use of a surrogate molecule in development. The intended goals of this paper are to provide a means for communicating input towards the ICH process and to provide a resource for assisting with the public review of the draft ICH S13 Guidance.