Jennifer Lang2, Adele Collin6, Abdelrahman Saqr7, Thomas Beyer3, Gregory Lackner4, Christopher Wiethoff5, Aurelie Lombard1
1Global PK/PD & Pharmacometrics, Eli Lilly & Company, 2Global PK/PD & Pharmacometrics, Eli Lilly & Company, 3Biology, ASCVD and novel modalities, Eli Lilly & Company, 4RNA Therapeutics and Discovery, Eli Lilly & Company, 5Biologics Investigational ADME, Eli Lilly & Company, 6Department of Biomedical Informatics, Harvard Medical School, 7Experimental and Clinical Pharmacology Department, College of Pharmacy, University of Minnesota
Introduction: Small interfering ribonucleic acid (siRNA) is an emerging class of targeted therapies that aims to regulate the expression of specific genes by preventing the protein translation process. LY is a tris N-acetylgalactosamine (GalNAc)3 conjugated siRNA designed to target a specific liver protein involved in lipid metabolism. Following subcutaneous administration, GalNAc-conjugated siRNAs are rapidly internalised by hepatocytes via endocytosis and released in the cytoplasm as free siRNAs. Then, free siRNAs bind to the RNA-induced silencing complex (RISC), leading to the target mRNA degradation. The interspecies translation of PK and PD is challenging, notably due to the differences between the short systemic exposure (i.e., plasma half-life ~2-10 hours) and the prolonged pharmacodynamic activity (i.e., several weeks to months). Ayyar et al. published a minimal Physiologically-Based Pharmacokinetic/Pharmacodynamic (mPBPK/PD model) that mechanistically describes the disposition and pharmacological effect in mice, rats, cynomolgus monkeys and humans of Fitusiran, a liver-targeted GalNAc siRNA [1]. However, there are only few examples of applications of this mPBPK-PD model to other liver-targeted GalNAc-conjugated siRNAs [2]. Therefore, further investigations are needed to understand if this model could be generalised to other GalNAc siRNAs. The objectives of this study were (i) to adapt the mPBPK/PD model to a liver-targeted GalNAc-conjugated siRNA using mice data developed by Lilly (LY) and (ii) to translate the model from mice to cynomolgus monkeys using allometric scaling and parameter estimation. Methods: LY is a GalNAc-siRNA that was investigated in a multiple dose level single dose PK/PD study in mice and a single dose PK/PD study in cynomolgus monkeys. Firstly, the mPBPK-PD model developed by Ayyar et al. was used to describe PK and PD data in mice which included plasma, total liver and RISC-bound concentrations of LY, target mRNA in liver and lipid levels [1]. Selection of the influential model parameters was performed based on local sensitivity analyses. Parameter estimation followed a stepwise approach (i.e., each PK and PD entity was fitted one-by-one). Secondly, allometric scaling based on body weight were applied for the interspecies translation of the mouse model to cynomolgus monkeys. Further parameter estimation was considered in the case where allometric scaling was not sufficient to describe PK and PD data in cynomolgus monkeys. Parameter estimation was performed based on a population PK/PD approach using the Stochastic Approximation Expectation-Maximization (SAEM) algorithm in Monolix. Results: The mPBPK-PD model was first adapted to a novel liver-targeted GalNAc conjugated siRNA using mice data with only minimal changes and parameter estimation needed compared to the original model. A dose-dependent absorption model was included to account for the slower absorption rate at the high dose level. The liver uptake clearance and binding to ASGPR (drug-specific parameters) were estimated and enabled to describe plasma and liver PK. The fraction of drug escaping endosomal degradation was slightly higher for LY in mice. Drug efficacy parameters were also estimated and enabled to characterize the PD maximum effect and durability in mice. Allometric scaling and minimal parameter estimation (i.e. fraction escape) were performed to scale the model to cynomolgus monkey, allowing suitable description of plasma, total liver, RISC-bound siRNA concentrations, and mRNA knockdown. Conclusion: The mPBPK-PD model was successfully adapted to another liver-targeted GalNAc-siRNA mice and monkey data with minimal changes. Allometric scaling allowed adequate characterisation of interspecies changes in liver uptake clearance and physiological processes such as the endosomal siRNA degradation rate. Minimal optimisation was needed to account for differences in absorption and minor changes in physiological processes for this specific target were shown between mice and cynomolgus monkeys. This provides a mechanistic model-informed drug development (MIDD) framework for first-in-human dose prediction and support for clinical trial design.
[1] V.S. Ayyar, D. Song, S. Zheng, T. Carpenter, D.L. Heald, J Pharmacol Exp Ther 379 (2021) 134–146. [2] A. Lumen, X. Zhang, S. Dutta, V.V. Upreti. Clin Pharmacol Ther. 2024 May;115(5):1054-1064.
Reference: PAGE 33 (2025) Abstr 11549 [www.page-meeting.org/?abstract=11549]
Poster: Drug/Disease Modelling - Absorption & PBPK