Cross-Species Translation of Biophase Half-Life and Potency of GalNAc-Conjugated siRNAs

• DOI: 10.1089/nat.2022.0010
• Publication Date: 2022-07-22T14:46:22Z
• Authors: Alessandro Boianelli; Yasunori Aoki; Maxim Ivanov; Anders Dahlén; Peter Gennemark
• Keywords: Pharmacodynamics; Human liver

Small interfering RNAs (siRNAs) with N-acetylgalactosamine (GalNAc) conjugation for improved liver uptake represent an emerging class of drugs to treat diseases. Understanding how pharmacokinetics and pharmacodynamics translate is pivotal in vivo study design human dose prediction. However, the literature sparse on translational data this modality, seldom measured. To overcome these difficulties, we collected time-course biomarker 11 GalNAc-siRNAs various species applied kinetic-pharmacodynamic modeling approach estimate biophase (liver) half-life potency. Our analysis indicates that 0.6-3 weeks mouse, 1-8 monkey, 1.5-14 human. For individual siRNAs, times longer than generally 1-3 monkey. The siRNAs are more potent mouse