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Phase 1B, randomized, double‐blind, dose‐escalation trial of CPG 10101 in patients with chronic hepatitis C virus
Author(s) -
McHutchison John G.,
Bacon Bruce R.,
Gordon Stuart C.,
Lawitz Eric,
Shiffman Mitchell,
Afdhal Nezam H.,
Jacobson Ira M.,
Muir Andrew,
AlAdhami Mohammed,
Morris Mary L.,
LekstromHimes Julie A.,
Efler Susan M.,
Davis Heather L.
Publication year - 2007
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21773
Subject(s) - medicine , placebo , cpg oligodeoxynucleotide , tlr9 , hepatitis c virus , cpg site , adverse effect , agonist , gastroenterology , interferon , cytokine , pharmacology , receptor , immunology , virus , biology , pathology , gene expression , dna methylation , gene , biochemistry , alternative medicine
CPG 10101, a synthetic oligodeoxynucleotide (ODN), is a toll‐like receptor 9 (TLR9) agonist with antiviral and immunomodulatory properties that could potentially influence chronic infection with HCV. In this multicenter Phase 1b trial, 60 HCV‐positive patients (50 genotype 1 HCV) were randomized and received either placebo or CPG 10101 at 0.25, 1, 4, 10, or 20 mg subcutaneously (SC) twice weekly for 4 weeks or at 0.5 or 0.75 mg/kg SC once weekly for 4 weeks. Dose‐dependent cytokine induction was observed after administration of CPG 10101. At 24 hours after administering the highest dose of 0.75 mg/kg CPG 10101, interferon (IFN)‐γ‐inducible protein 10 (IP‐10) had a mean increase over baseline levels (±SD) of 15,057 (±9769) pg/ml ( P < 0.01, compared to placebo); IFN‐α had a 106 (±63.3) pg/ml increase ( P < 0.01); and 2′5′‐oligoadenylate synthetase (OAS) had a 163 (±120.6) pmol/dl increase ( P < 0.01). Decreases in HCV RNA also were dose‐dependent, with the greatest group geometric mean maximum reduction of 1.69 ± 0.618 log 10 ( P < 0.05) observed in the 0.75 mg/kg dose group. Decreases ≥1 log 10 were seen in 22 of 40 patients who received ≥1 mg CPG 10101, with 3 patients exceeding a 2.5‐log 10 reduction. CPG 10101 was well tolerated, and adverse events were consistent with CPG 10101's mechanism of action. Conclusion: In this Phase 1 study, CPG 10101 was associated with dose‐dependent increases in markers of immune activation and decreases in HCV RNA levels. The data support further clinical studies of CPG 10101 for treating chronic HCV infection. (H EPATOLOGY 2007.)