1. Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist.
- Author
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Vicari AP, Schmalbach T, Lekstrom-Himes J, Morris ML, Al-Adhami MJ, Laframboise C, Leese P, Krieg AM, Efler SM, and Davis HL
- Subjects
- Adult, Cytokines blood, Dose-Response Relationship, Drug, Double-Blind Method, Drug Administration Schedule, Female, Humans, Immune System cytology, Immune System metabolism, Injections, Subcutaneous, Leukocyte Count, Leukocytes drug effects, Male, Middle Aged, Oligodeoxyribonucleotides administration & dosage, Oligodeoxyribonucleotides adverse effects, Oligodeoxyribonucleotides pharmacokinetics, Reference Values, Toll-Like Receptor 9 metabolism, Treatment Outcome, Up-Regulation, Adjuvants, Immunologic administration & dosage, Adjuvants, Immunologic adverse effects, Adjuvants, Immunologic pharmacokinetics, Antiviral Agents administration & dosage, Antiviral Agents adverse effects, Antiviral Agents pharmacokinetics, Immune System drug effects, Immunity, Innate drug effects, Toll-Like Receptor 9 agonists
- Abstract
Unlabelled: CPG 10101 (ACTILON) is a novel potent and selective unmethylated cytidine-phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV., Objectives and Methods: In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks., Results: A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2',5'-oligoadenylate synthetase were sustained for several days., Conclusion: This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV.
- Published
- 2007