(T-100) Beyond Subcutaneous Dosing: Efficiency of liver-targeting siRNAs dosed via alternates routes and formulations.

Lekshmi Dharmarajan, PhD – Senior Principal Scientist, Novartis; Jeffrey Kearns, PhD – Director, Novartis; Thien-Khoi Phung, PhD – Principal Scientist I, Novartis

Objectives & Methods

The discovery of trimeric N-galactosamine (GalNAc) conjugation revolutionized the delivery of siRNAs to the human liver because of the high specificity of GalNAc for the asialoglycoprotein receptor (ASGPR) abundantly expressed on hepatocytes [1]. At present, several GalNAc-conjugated oligonucleotides (siRNA or ASO) are approved or in clinical development with a subcutaneous bolus (SC) dosing regimen, each with a mechanism of action to down-regulate target gene expression in the liver. Modeling platforms for the development of GalNAc-siRNAs have matured recently [2], however, assessing optimal dosing routes and regimens to maximize pharmacodynamic effect for patients remains unexplored. Here, we present a model-driven analysis of the pharmacokinetic (PK) and pharmacodynamic (PD) effects of different dosing routes and formulations.
Results & Conclusions

There is increasing understanding that the relative biodistribution of GalNAc-siRNAs to the liver and other organs (mainly kidney) is dependent on both dose and route of administration. It has been reported that bolus intravenous (IV) dosing, for example, biases the biodistribution away from the liver and presumably towards renal clearance. Subcutaneous (SC) administration of the drug allows for slower absorption in the blood, and a lower maximal plasma concentration (Cmax) compared to IV bolus, increasing efficiency of ASGPR-mediated endocytosis that transports drug to the cells [3]. Here, we report a mechanistic PBPK/PD modeling approach to characterize traditional IV bolus and IV infusion routes and explore potential continuous infusion or slow-release formulations. Using a reference dataset for vutrisiran [4], we predict pharmacodynamics for alternative dosing regimens and compare to the current standard of SC administration. Leveraging the wealth of data available for this modality, we propose model-informed dosing routes and regimens that can maximize pharmacodynamic effect in patients.

Citations: [1] Nair, J. K. et al. Multivalent N -acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc 136, 16958–16961 (2014).
[2] Ayyar, V. S. & Song, D. Mechanistic Pharmacokinetics and Pharmacodynamics of GalNAc-siRNA: Translational Model Involving Competitive Receptor-Mediated Disposition and RISC-Dependent Gene Silencing Applied to Givosiran. J Pharm Sci 113, 176–190 (2024).
[3] McDougall, R. et al. The Nonclinical Disposition and Pharmacokinetic/Pharmacodynamic Properties of N-Acetylgalactosamine-Conjugated Small Interfering RNA Are Highly Predictable and Build Confidence in Translation to Human. Drug Metabolism and Disposition vol. 50 781–797
[4] Habtemariam, B. A. et al. Single-Dose Pharmacokinetics and Pharmacodynamics of Transthyretin Targeting N-acetylgalactosamine–Small Interfering Ribonucleic Acid Conjugate, Vutrisiran, in Healthy Subjects. Clin Pharmacol Ther 109, 372–382 (2021).