Senior Scientist Janssen Research & Development, LLC, Pennsylvania
Advances in RNA-based therapeutics have unlocked the clinical potential to modulate proteins of therapeutic relevance by selectively regulating their messenger RNA (mRNA). By harnessing RNA interference (RNAi), small interfering RNA (siRNA) potently silence mRNA preventing synthesis of disease-causing proteins. Tris N-acetylgalactosamine (GalNAc)3–conjugated siRNA therapeutics enable liver-targeted gene therapy and precision medicine. The disposition and pharmacodynamic (PD) durability of GalNAc-siRNA is distinct from small molecules or biologics, characterized by significant temporal disconnects and potential nonlinearities between transient plasma pharmacokinetics (PK) and prolonged PD activity. By leveraging in vitro–derived biomeasures, in vivo PK-PD studies in animals, and observed clinical PK-PD responses, a minimal physiologically-based PK-PD (mPBPK-PD) model was developed to mathematically relate key rate-limiting PK-PD mechanisms governing the disposition and PD of GalNAc-siRNA. This approach has enabled bench-to-bedside translation informing early clinical development. This talk will cover the translational insights and ‘lessons learned’ through mechanistic modeling (e.g., delineating drug vs. system characteristics, physiological interspecies relationships, and future experiments needed to close current gaps). Guidelines, including a general PK/PD workflow to inform translational modeling for early clinical development, will be presented.
Learning Objectives:
Understand pharmacological and PK/PD considerations for preclinical to clinical translation of siRNAs
Learn about mechanistic modeling approaches that can be taken to bridge the preclinical to clinical translation gaps
Apply learnings to other siRNA and other novel modality programs
