Development of siRNA Therapeutics: What Data are Needed for PK and ADA Assessment

siRNA therapeutics, which work by silencing specific genes at the mRNA level, offer a groundbreaking approach to disease treatment. However, their unique mechanism of action and clinical pharmacology characteristics present distinct challenges in pharmacokinetic (PK) and anti-drug antibody (ADA) assessment during clinical development. In this presentation, we will explore the complexities of siRNA PK evaluation, discussing the need to understand metabolite profile and strategies for a more pharmacologically relevant assessment using techniques such as LC-MS/MS, qPCR, and hybridization ELISA. We will also review immunogenicity data from various RNA-based oligonucleotide therapeutics, which generally demonstrate minimal immunogenicity with no clinical impact. Based on these observations, a risk-based approach for ADA assessment in early clinical trials will be proposed. RNA-based oligonucleotide therapeutics (e.g., antisense oligos, siRNA etc) are currently treated analytically at the intersection of small (metabolite assessment) and large (immunogenicity assessment) molecules. We seek to acknowledge the unique properties of siRNA therapeutics while attempting to guide the bioanalytical strategy to facilitate more effective and efficient clinical development.