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Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate
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Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate
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Journal Article
Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate
2017
Overview
Advancement of RNAi-based therapeutics depends on effective delivery to the site of protein synthesis. Although intravenously administered, multi-component delivery vehicles have enabled small interfering RNA (siRNA) delivery and progression into clinical development, advances of single-component, systemic siRNA delivery have been challenging. In pre-clinical models, attachment of a triantennary N-acetylgalactosamine (GalNAc) ligand to an siRNA mediates hepatocyte uptake via the asialoglycoprotein receptor enabling RNAi-mediated gene silencing. In this phase 1 study, we assessed translation of this delivery approach by evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of a GalNAc-siRNA conjugate, revusiran, targeting transthyretin (TTR). Subjects received a placebo or ascending doses of revusiran subcutaneously ranging from 1.25–10 mg/kg in the single and 2.5–10 mg/kg in the multiple ascending dose phases. Revusiran was generally well tolerated, with transient, mild to moderate injection site reactions the most common treatment-emergent adverse events. Doses of 2.5–10 mg/kg revusiran elicited a significant reduction of serum TTR versus the placebo (p < 0.01), with mean TTR reductions of approximately 90% observed with multiple dosing. These results demonstrate translation of this novel delivery platform, enabling clinical development of subcutaneously administered GalNAc-siRNAs for liver-based diseases.
This phase I study of revusiran demonstrated proof of concept for a subcutaneously administered siRNA that utilizes an N-acetylgalactosamine (GalNAc) ligand for hepatocyte-specific delivery. These results enabled clinical development of siRNA-GalNAc conjugates for treatment of liver-derived diseases and supported adoption of this delivery approach for other oligonucleotide-based therapeutics, including antisense oligonucleotides and anti-microRNAs.
Publisher
Elsevier Inc,Elsevier Limited,American Society of Gene & Cell Therapy
Subject
Acetylgalactosamine - chemistry
/ Adult
/ Asialoglycoprotein Receptor - genetics
/ Asialoglycoprotein Receptor - metabolism
/ Dosage
/ Female
/ Humans
/ Ligands
/ Male
/ Mutation
/ Original
/ RNA, Small Interfering - chemistry
/ RNA, Small Interfering - genetics
/ RNA, Small Interfering - pharmacology
/ RNA, Small Interfering - therapeutic use
/ RNAi
/ siRNA
