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.
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.
authors.affiliation: Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schluep
authors.affiliation: Nucleus Network, Melbourne, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Lickliter
authors.affiliation: Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hamilton
authors.affiliation: Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Lewis
authors.affiliation: The University of Hong Kong, Hong Kong, China.
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Lai
authors.affiliation: The Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Johnson Yn
authors.initials: JY
authors.lastname: Lau
authors.affiliation: Victorian Infectious Diseases Reference Laboratory, Victoria, Australia.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Locarnini
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Stanford, CA, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gish
authors.affiliation: Arrowhead Pharmaceuticals, Inc., Pasadena, CA, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Given
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D019694:Hepatitis B, Chronic / Q000188:drug therapy; D006633:Histamine Antagonists / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D065129:Pre-Exposure Prophylaxis / Q000379:methods; D034622:RNA Interference; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D006633:Histamine Antagonists
keywords: RNA interference; RNAi; hepatitis B; pharmacokinetics; pharmacology; phase 1; safety; tolerability; treatment; viral hepatitis; volunteers