title: Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate.
abstract: 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.
authors.affiliation: Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA. Electronic address: tzimmermann@alnylam.com.
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Zimmermann
authors.affiliation: Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
authors.forename: Verena
authors.initials: V
authors.lastname: Karsten
authors.affiliation: Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Chan
authors.affiliation: Covance Clinical Research Unit Ltd., Leeds LS2 9LH, UK.
authors.forename: Joseph
authors.initials: J
authors.lastname: Chiesa
authors.affiliation: Hammersmith Medicines Research Ltd., London NW10 7EW, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Boyce
authors.affiliation: Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Bettencourt
authors.affiliation: Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
authors.forename: Renta
authors.initials: R
authors.lastname: Hutabarat
authors.affiliation: Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
authors.forename: Saraswathy
authors.initials: S
authors.lastname: Nochur
authors.affiliation: Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
authors.forename: Akshay
authors.initials: A
authors.lastname: Vaishnaw
authors.affiliation: Alnylam Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
authors.forename: Jared
authors.initials: J
authors.lastname: Gollob
mesh_terms: D000116:Acetylgalactosamine / Q000737:chemistry; D000328:Adult; D037263:Asialoglycoprotein Receptor / Q000235:genetics / Q000378:metabolism; D016903:Drug Monitoring; D005260:Female; D020868:Gene Silencing; D064368:Healthy Volunteers; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011228:Prealbumin / Q000235:genetics; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D037263:Asialoglycoprotein Receptor; D011228:Prealbumin; D034741:RNA, Small Interfering; D000116:Acetylgalactosamine; C000614277:revusiran
keywords: GalNAc-siRNA; RNAi; asialoglycoprotein receptor; revusiran