bims-limsir 2023-08-20 papers

Issue of 2023‒08‒20
two papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS

J Clin Pharmacol. 2023 Aug 17.

Pharmacokinetics and Pharmacodynamics of GalNAc-Conjugated siRNAs.

Guohua An.

Small interfering RNAs (siRNAs) represent a new class of drugs with tremendous potential for battling previously undruggable diseases. After nearly two decades of efforts in addressing the problems of the poor drug profile of naked unmodified siRNAs, this new modality has finally come to fruition, with five agents (patisiran, givosiran, lumasiran, inclisiran, and vutrisiran) being approved since 2018 and many others in the different phases of clinical development. Unlike small-molecule drugs and protein therapeutics, siRNAs have different sizes, distinct mechanism of action, different physicochemical and pharmacological properties, and accordingly a unique PK/PD relationship. To support the continuous development of siRNA, it is important to have a thorough and deep understanding of the PK/PD and clinical pharmacology related features of siRNAs. Since most of the current siRNA products are conjugated by N-acetylgalactosamine (GalNAc), this review focuses on the PK/PD and clinical pharmacology of GalNAc-conjugated siRNAs, including their absorption, distribution, metabolism, excretion (ADME) properties, PK/PD models, drug-drug interactions, clinical pharmacology in special populations, and safety evaluation. In addition, necessary background information related to the development of siRNA as a therapeutic modality, including its mechanism of action, the advantages of siRNAs, the problems of naked siRNAs, as well as the strategies used to enhance the clinical utility of siRNA, have also been covered. The goal of this review is to serve as a "primer" on siRNA PK/PD, and I hope the readers, especially those who have limited background on siRNA therapeutics, will have a fundamental understanding on siRNA PK/PD after reading this review. This article is protected by copyright. All rights reserved.

Keywords: Clinical pharmacology of siRNAs; GalNAc-conjugated siRNAs; Givosiran; Inclisiran; Lumasiran; Vutrisiran; siRNA PK/PD; siRNA pharmacometrics modeling

DOI: https://doi.org/10.1002/jcph.2337

Mol Ther Nucleic Acids. 2023 Sep 12. 33 469-482

25 years of maturation: A systematic review of RNAi in the clinic.

Ida Juhl Corydon, Bjørn Kristensen Fabian-Jessing, Thomas Stax Jakobsen, Asbjørn Cortnum Jørgensen, Emilie Grarup Jensen, Anne Louise Askou, Lars Aagaard, Thomas Juhl Corydon.

The year 2023 marks the 25th anniversary of the discovery of RNAi. RNAi-based therapeutics enable sequence-specific gene knockdown by eliminating target RNA molecules through complementary base-pairing. A systematic review of published and ongoing clinical trials was performed. Web of Science, PubMed, and Embase were searched from January 1, 1998, to December 30, 2022 for clinical trials using RNAi. Following inclusion, data from the articles were extracted according to a predefined protocol. A total of 90 trials published in 81 articles were included. In addition, ongoing clinical trials were retrieved from ClinicalTrials.gov, resulting in the inclusion of 48 trials. We investigated how maturation of RNAi-based therapeutics and developments in delivery platforms, administration routes, and potential targets shape the current landscape of clinically applied RNAi. Notably, most contemporary clinical trials used either N-acetylgalactosamine delivery and subcutaneous administration or lipid nanoparticle delivery and intravenous administration. In conclusion, RNAi therapeutics have gained great momentum during the past decade, resulting in five approved therapeutics targeting the liver for treatment of severe diseases, and the trajectory depicted by the ongoing trials emphasizes that even more RNAi-based medicines also targeting extra-hepatic tissues are likely to be available in the years to come.

Keywords: LNP; MT: Oligonucleotides: Therapies and Applications; N-acetylgalactosamine; RNA interference; RNAi; clinical trials; miR-shRNA; shRNA; siRNA; systematic review

DOI: https://doi.org/10.1016/j.omtn.2023.07.018