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
AuthorSchluep, T; Lickliter, J; Hamilton, J; Lewis, DL; Lai, C-L; Lau, JYN; Locarnini, SA; Gish, RG; Given, BD
Source TitleClinical Pharmacology in Drug Development
University of Melbourne Author/sLocarnini, Stephen
AffiliationMicrobiology and Immunology
Document TypeJournal Article
CitationsSchluep, T., Lickliter, J., Hamilton, J., Lewis, D. L., Lai, C. -L., Lau, J. Y. N., Locarnini, S. A., Gish, R. G. & Given, B. D. (2017). 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. CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT, 6 (4), pp.350-362. https://doi.org/10.1002/cpdd.318.
Access StatusOpen Access
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.
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