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The Nonclinical Disposition and PK/PD Properties of GalNAc-conjugated siRNA Are Highly Predictable and Build Confidence in Translation to Man

Saeho Chong, Sagar Agarwal, Saket Agarwal, Krishna C. Aluri, Michael Arciprete, Christopher Brown, Klaus Charisse, Joseph Cichocki, Kevin Fitzgerald, Varun Goel, Yongli Gu, Dale Guenther, Bahru Habtemariam, Vasant Jadhav, Maja Janas, Muthusamy Jayaraman, Jeff Kurz, Jing Li, Steven Liou, Ju Liu, Xiumin Liu, Christopher Maclauchlin, Martin Maier, Muthiah Manoharan, Robin McDougall, Jay Nair, Diane Ramsden, Gabriel Robbie, Karyn Schmidt, Peter Smith, Christopher Theile, Akshay Vaishnaw, Scott Waldron, Jing-Tao Wu, Yuanxin Xu, Xuemei Zhang, Ivan Zlatev and Elena castellanos-Rizaldos
Drug Metabolism and Disposition June 21, 2021, DMD-MR-2021-000428; DOI: https://doi.org/10.1124/dmd.121.000428
Saeho Chong
1Drug Metabolism and Pharmacokinetics, Alnylam Pharmaceuticals Inc., United States
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Sagar Agarwal
2Clinical Pharmacology, Alnylam Pharmaceuticals, United States
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Saket Agarwal
3Investigative Toxicology, Alnylam Pharmaceuticals, United States
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Krishna C. Aluri
4Early Development, Alnylam pharmaceuticals, United States
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Michael Arciprete
5Alnylam Pharmaceuticals Inc., United States
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Christopher Brown
6Biology, Alnylam Pharmaceuticals, United States
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Klaus Charisse
7Chemistry, Alnylam Pharmaceuticals, United States
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Joseph Cichocki
8Toxicology, Vertex Pharmaceuticals, United States
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Kevin Fitzgerald
9Research, Alnylam Pharmaceuticals, United States
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Varun Goel
10Clinical Pharmacology, Avidity Bioscience, United States
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Yongli Gu
11Bioanalytical Science, Alnylam Pharmaceuticals, United States
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Dale Guenther
12RNAi Discovery, Alnylam Pharmaceuticals, United States
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Bahru Habtemariam
2Clinical Pharmacology, Alnylam Pharmaceuticals, United States
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Vasant Jadhav
6Biology, Alnylam Pharmaceuticals, United States
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Maja Janas
3Investigative Toxicology, Alnylam Pharmaceuticals, United States
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Muthusamy Jayaraman
13CRISPR Therapeutics, United States
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Jeff Kurz
14DMPK, Alnylam Pharmaceuticals, United States
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Jing Li
5Alnylam Pharmaceuticals Inc., United States
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  • ORCID record for Jing Li
Steven Liou
14DMPK, Alnylam Pharmaceuticals, United States
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Ju Liu
5Alnylam Pharmaceuticals Inc., United States
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Xiumin Liu
14DMPK, Alnylam Pharmaceuticals, United States
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Christopher Maclauchlin
14DMPK, Alnylam Pharmaceuticals, United States
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Martin Maier
14DMPK, Alnylam Pharmaceuticals, United States
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Muthiah Manoharan
9Research, Alnylam Pharmaceuticals, United States
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Robin McDougall
1Drug Metabolism and Pharmacokinetics, Alnylam Pharmaceuticals Inc., United States
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Jay Nair
7Chemistry, Alnylam Pharmaceuticals, United States
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Diane Ramsden
15DMPK, Takeda, United States
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Gabriel Robbie
2Clinical Pharmacology, Alnylam Pharmaceuticals, United States
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Karyn Schmidt
6Biology, Alnylam Pharmaceuticals, United States
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Peter Smith
5Alnylam Pharmaceuticals Inc., United States
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Christopher Theile
7Chemistry, Alnylam Pharmaceuticals, United States
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Akshay Vaishnaw
9Research, Alnylam Pharmaceuticals, United States
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Scott Waldron
9Research, Alnylam Pharmaceuticals, United States
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Jing-Tao Wu
16DMPK, Alnylam, United States
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  • For correspondence: jtwu@alnylam.com
Yuanxin Xu
5Alnylam Pharmaceuticals Inc., United States
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Xuemei Zhang
5Alnylam Pharmaceuticals Inc., United States
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Ivan Zlatev
7Chemistry, Alnylam Pharmaceuticals, United States
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Elena castellanos-Rizaldos
6Biology, Alnylam Pharmaceuticals, United States
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Abstract

Conjugation of oligonucleotide therapeutics, including small interfering ribonucleic acids (siRNAs) or antisense oligonucleotides (ASOs) to N-acetylgalactosamine (GalNAc) ligands has become the primary strategy for hepatocyte-targeted delivery, and with the recent approvals of GIVLAARI® (givosiran) for the treatment of acute hepatic porphyria, OXLUMOTM (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio® (inclisiran) for the treatment of hypercholesterolemia, the technology has been well-validated clinically. While much knowledge has been gained over decades of development there is a paucity of published literature on the DMPK properties of GalNAc-siRNA. With this in mind the goals of this mini-review are to provide an aggregate analysis of these nonclinical ADME data to build confidence on the translation of these properties to human. Upon subcutaneous administration, GalNAc-conjugated siRNAs are quickly distributed to the liver, resulting in plasma pharmacokinetic (PK) properties that reflect rapid elimination through ASGPR-mediated uptake from circulation into hepatocytes. These studies confirm that liver PK, including half-life and, most importantly, siRNA levels in RNA-induced silencing complex (RISC) in hepatocytes are better predictors of pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical studies were conducted to characterize the absorption, distribution, metabolism and excretion (ADME) properties of GalNAc-conjugated siRNAs. These studies demonstrate that the PK/PD and ADME properties of GalNAc-conjugated siRNAs are highly conserved across species, largely predictable, and can be accurately scaled to human, allowing us to identify efficacious and safe clinical dosing regimens in the absence of human liver PK profiles.

Significance Statement Several nonclinical ADME studies have been conducted in order to provide a comprehensive overview of the disposition and elimination of GalNAc-conjugated siRNAs and the PK/PD translation between species. These studies demonstrate that the ADME properties of GalNAc-conjugated siRNAs are well correlated and predictable across species building confidence in the ability to extrapolate to human.

  • ADME
  • pharmacodynamics
  • pharmacokinetics
  • RNA/siRNA
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
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Drug Metabolism and Disposition: 51 (10)
Drug Metabolism and Disposition
Vol. 51, Issue 10
1 Oct 2023
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Disposition and PK/PD of GalNAc-siRNA

Saeho Chong, Sagar Agarwal, Saket Agarwal, Krishna C. Aluri, Michael Arciprete, Christopher Brown, Klaus Charisse, Joseph Cichocki, Kevin Fitzgerald, Varun Goel, Yongli Gu, Dale Guenther, Bahru Habtemariam, Vasant Jadhav, Maja Janas, Muthusamy Jayaraman, Jeff Kurz, Jing Li, Steven Liou, Ju Liu, Xiumin Liu, Christopher Maclauchlin, Martin Maier, Muthiah Manoharan, Robin McDougall, Jay Nair, Diane Ramsden, Gabriel Robbie, Karyn Schmidt, Peter Smith, Christopher Theile, Akshay Vaishnaw, Scott Waldron, Jing-Tao Wu, Yuanxin Xu, Xuemei Zhang, Ivan Zlatev and Elena castellanos-Rizaldos
Drug Metabolism and Disposition June 21, 2021, DMD-MR-2021-000428; DOI: https://doi.org/10.1124/dmd.121.000428

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Disposition and PK/PD of GalNAc-siRNA

Saeho Chong, Sagar Agarwal, Saket Agarwal, Krishna C. Aluri, Michael Arciprete, Christopher Brown, Klaus Charisse, Joseph Cichocki, Kevin Fitzgerald, Varun Goel, Yongli Gu, Dale Guenther, Bahru Habtemariam, Vasant Jadhav, Maja Janas, Muthusamy Jayaraman, Jeff Kurz, Jing Li, Steven Liou, Ju Liu, Xiumin Liu, Christopher Maclauchlin, Martin Maier, Muthiah Manoharan, Robin McDougall, Jay Nair, Diane Ramsden, Gabriel Robbie, Karyn Schmidt, Peter Smith, Christopher Theile, Akshay Vaishnaw, Scott Waldron, Jing-Tao Wu, Yuanxin Xu, Xuemei Zhang, Ivan Zlatev and Elena castellanos-Rizaldos
Drug Metabolism and Disposition June 21, 2021, DMD-MR-2021-000428; DOI: https://doi.org/10.1124/dmd.121.000428
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