Journal of Hepatology
Volume 47, Issue 2 , Pages 174-182, August 2007

Oral resiquimod in chronic HCV infection: Safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies☆☆☆

  • Paul J. Pockros

      Affiliations

    • Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 858 554 8040; fax: +1 858 554 8065.
    • ,
  • Dominque Guyader

      Affiliations

    • Clinique Medicale A – Hepatologie, Centre Hospitalier Regionale Universitaire de Pontchaillou, Rennes, France
    • ,
  • Heather Patton

      Affiliations

    • Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA, USA
    • Present address: University of California San Diego Medical Center, San Diego, CA, USA.
    • ,
  • Myron J. Tong

      Affiliations

    • Liver Center, Huntington Medical Research Institute, Pasadena, CA, USA
    • ,
  • Terry Wright

      Affiliations

    • Division of Gastroenterology/Hepatology, University of California, San Francisco, CA, USA
    • Present address: Roche Molecular Labs, San Francisco, CA, USA.
    • ,
  • John G. McHutchison

      Affiliations

    • Division of Gastroenterology/Hepatology, Scripps Clinic, La Jolla, CA, USA
    • Present address: Duke Clinical Research Institute, Durham, NC, USA.
    • ,
  • Tze-Chiang Meng

      Affiliations

    • Medical and Scientific Affairs, 3M Pharmaceuticals, Saint Paul, MN, USA

Received 26 November 2006; received in revised form 5 February 2007; accepted 14 February 2007. published online 04 May 2007.

Background/Aims

To explore safety, pharmacokinetics, and pharmacodynamics of oral administration of resiquimod, a Toll-like receptor 7 and 8 agonist that induces endogenous interferon-alpha, in subjects with chronic hepatitis C virus infection.

Methods

Two randomized, double-blind phase IIa studies of resiquimod administered two times per week for 4weeks. Multicenter study (U.S.): 12 subjects received resiquimod 0.01mg/kg and 4 received placebo. Single center study (France): 6 subjects received 0.01mg/kg, 11 received 0.02mg/kg and 6 received placebo.

Results

Resiquimod 0.01mg/kg was tolerated; two 0.2mg/kg subjects discontinued treatment. More subjects reported severe grade adverse events at 0.02mg/kg; events were consistent with systemic cytokine induction, including fever, headache, shivering, and lymphopenia. Mean maximum serum resiquimod concentrations were 3.82±1.47 and 7.55±4.17ng/mL for 0.01mg/kg and 0.02mg/kg, respectively. At 0.02mg/kg, two, three and one subjects had maximal reductions in viral levels of at least 1-, 2- and 3-logs, respectively; reductions were generally transient. Interferon-alpha levels appeared correlated with decreases in viral titer and lymphocyte counts, as well as increase in neutrophil counts.

Conclusions

Oral administration of resiquimod 0.02mg/kg transiently reduced viral levels but was associated with adverse effects similar to interferon-alpha.

Keywords: Resiquimod, Hepatitis C virus, Toll-like receptor, TLR7 agonist, TLR8 agonist, Clinical trial, Treatment, Pharmacokinetics, Pharmacodynamics

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☆ T.W. declared that she received funding from the manufacturers to carry out the research and she is an advisory board member of Vernalis Ltd. M.J.T. declared that he has no relationship with the manufacturers of the drug involved either in the past or present and he received funding from the manufacturers to carry out the research. He received funding from SC Liver Research Consortium which enabled him to carry out the study. He is an advisory board member of Vernalis, Ltd. J.G.M. declared that he received funding from the sponsor of this study which enabled him to carry out the study and he is an advisory board member of Vernalis Ltd. H.P. declared that she has no relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out the research. She did not receive funding from any source to carry out the study. D.G. declared that she has no relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out the research. She did not receive funding from any source to carry out the study. P.J.P. declared that he has a relationship with the manufacturers of the drug involved either in the past or present and that he received funding from Vernalis, Ltd. which enabled him to carry out the study. He is an advisory board member of Vernalis, Ltd. and 3M Pharmaceuticals.

☆☆ T.C.M. declared that he has a relationship with the manufacturers of the drugs involved either in the past or present and he received funding from the manufacturers to carry out the research. He received funding from Vernalis plc (formerly Vanguard Medica Limited) which enabled him to carry out the study. T.C.M. is an employee of 3M Pharmaceuticals, the manufacturers of resiquimod (R-848). Vernalis plc, formerly Vanguard Medica Limited, funded the conduct of the studies under a joint development agreement with 3M Pharmaceuticals.

PII: S0168-8278(07)00256-5

doi:10.1016/j.jhep.2007.02.025

Journal of Hepatology
Volume 47, Issue 2 , Pages 174-182, August 2007

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