Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/76221
Title: Safety, tolerability, and pharmacokinetics of ARC-520 injection, an RNA interference-based therapeutic for the treatment of chronic hepatitis b virus infection, in healthy volunteers
Authors: Schluep, T
Lickliter, J
Hamilton, J
Lewis, DL
Lai, CL
Lau, JYN 
Locarnini, SA
Gish, RG
Given, BD
Keywords: Viral hepatitis
Hepatitis B
Treatment
RNA interference
RNAi
Pharmacology
Pharmacokinetics
Safety
Tolerability
Phase 1
Volunteers
Issue Date: 2017
Publisher: John Wiley & Sons
Source: Clinical pharmacology in drug development, 2017, v. 6, no. 4, p. 350-362 How to cite?
Journal: Clinical pharmacology in drug development 
Abstract: ARC-520 Injection, an RNA interference drug for the treatment of hepatitis B that targets cccDNA-derived viral mRNA transcripts with high specificity, effectively reduces the production of viral proteins and HBV DNA. In this phase 1 randomized, double-blind, placebo-controlled study, 54 healthy volunteers (half male, half female) received a single, intravenous dose of 0.01-4.0 mg/kg ARC-520 Injection (n = 36) or placebo (n = 18). Assessments included safety, tolerability, pharmacokinetics, and pharmacodynamics (cytokines and complement). Pharmacokinetics of the siRNA and peptide excipient components contained in ARC-520 Injection showed a relatively short half-life of 3-5 and 8-10 hours, respectively. Dose exposure linearity was demonstrated within the dose range. ARC-520 Injection was well tolerated, with adverse-event frequency the same as placebo and no serious adverse events. ARC-520 Injection was initially found to induce histamine release through mast cell degranulation, resulting in 2 moderate hypersensitivity reactions. However, after initiation of pretreatment with oral antihistamine, no further hypersensitivity reactions occurred. Low-level, transient complement induction and sporadic, mild, and transient elevations of several cytokines were observed but not associated with any symptoms. ARC-520 Injection showed a favorable tolerability profile in this single-dose study in healthy volunteers. Oral antihistamine pretreatment is recommended in the future to offset mast cell degranulation stimulation.
URI: http://hdl.handle.net/10397/76221
ISSN: 2160-7648
DOI: 10.1002/cpdd.318
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