Viral Hepatitis

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Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection†

  1. Yves Horsmans1,
  2. Thomas Berg2,
  3. Jean-Pierre Desager1,
  4. Tobias Mueller2,
  5. Eckart Schott2,
  6. Simon P. Fletcher3,
  7. Kevin R. Steffy3,
  8. Lisa A. Bauman3,
  9. Bradley M. Kerr3,
  10. Devron R. Averett3,‡,*

Article first published online: 22 AUG 2005

DOI: 10.1002/hep.20839

Issue

Hepatology

Hepatology

Volume 42, Issue 3, pages 724–731, September 2005

Additional Information

How to Cite

Horsmans, Y., Berg, T., Desager, J.-P., Mueller, T., Schott, E., Fletcher, S. P., Steffy, K. R., Bauman, L. A., Kerr, B. M. and Averett, D. R. (2005), Isatoribine, an agonist of TLR7, reduces plasma virus concentration in chronic hepatitis C infection. Hepatology, 42: 724–731. doi: 10.1002/hep.20839

Author Information

  1. 1

    Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Unit de Pharmacologie Clinique, Brussels, Belgium

  2. 2

    Universitätsklinikum Charité, Humboldt-Unversität zu Berlin, Campus Virchow, Hepatologie und Gastroenterologie, Berlin, Germany

  3. 3

    Anadys Pharmaceuticals, Inc., San Diego, CA

  1. ‡

    fax: 858-527-1540

*Anadys Pharmaceuticals, Inc., San Diego, CA

  1. †

    Potential conflict of interest: DR Averett, SP Fletcher, BM Kerr, LA Bauman, and KR Steffy own stock in and are employed by Anadys Pharmaceuticals. Y Horsmans, T Berg, JP Desager, T Mueller, and E Schott were compensated by Anadys for clinical study services. T Berg and E Schott received a research grant from Anadys. Y Horsmans and T Berg are consultants to Anadys.

Publication History

  1. Issue published online: 22 AUG 2005
  2. Article first published online: 22 AUG 2005
  3. Manuscript Accepted: 24 JUN 2005
  4. Manuscript Received: 31 JAN 2005

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Abstract

Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new investigational anti-HCV compounds are direct-acting antivirals for which durability of response and risk of viral mutations and resistance are not yet known. Therefore, continuing discovery and development of new immune-based treatments is desirable. Toll-like receptors (TLRs) are pathogen recognition receptors that initiate the innate immune response. The responsiveness of HCV or other ongoing chronic systemic infections to treatment with a selective TLR agonist has not been reported. Isatoribine is a selective agonist of TLR7. In a proof-of-concept study, we found that once-daily 7-day treatment with intravenous isatoribine 800 mg caused a significant (P = .001) reduction of plasma HCV RNA (mean, −0.76; range, −2.85 to +0.21 log10 units) in otherwise untreated patients (n = 12) who were chronically infected with HCV. Viral load reduction occurred in patients infected with genotype 1 as well as non-genotype 1 HCV. The reduction of viral load was correlated with induction of markers of a heightened immune antiviral state, including 2′-, 5′- oligoadenylate synthetase levels in whole blood. This treatment was well tolerated, with a low frequency of mild to moderate adverse events. In conclusion, systemic administration of the selective TLR7 agonist isatoribine resulted in dose-dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects. (HEPATOLOGY 2005;42:724–731.)

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