Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate

• Published in: Molecular therapy Vol. 25; no. 1; pp. 71 - 78
• Main Authors: Zimmermann, Tracy S., Karsten, Verena, Chan, Amy, Chiesa, Joseph, Boyce, Malcolm, Bettencourt, Brian R., Hutabarat, Renta, Nochur, Saraswathy, Vaishnaw, Akshay, Gollob, Jared
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.01.2017; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: Acetylgalactosamine - chemistry; Adult; asialoglycoprotein receptor; Asialoglycoprotein Receptor - genetics; Asialoglycoprotein Receptor - metabolism; Cardiomyopathy; Dosage; Drug dosages; Drug Monitoring; Female; GalNAc-siRNA; Gene Silencing; Healthy Volunteers; Hepatocytes - metabolism; Humans; Ligands; Liver diseases; Male; Middle Aged; Mutation; N-Acetylgalactosamine; Original; Pharmacodynamics; Pharmacokinetics; Prealbumin - genetics; Protein biosynthesis; revusiran; RNA, Small Interfering - chemistry; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacology; RNA, Small Interfering - therapeutic use; RNA-mediated interference; RNAi; siRNA; Translation; Transthyretin; Young Adult; RNAi; revusiran; asialoglycoprotein receptor; GalNAc-siRNA
• ISSN: 1525-0016; 1525-0024; 1525-0024
• DOI: 10.1016/j.ymthe.2016.10.019

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.