Antiviral Activity of ANA773, an Oral Inducer of Endogenous Interferons that Acts Via TLR7, in Chronic Hepatitis C Patients

Jilling F Bergmann (1) , Joep de Bruijne (2) , Daphne M Hotho (1) , Robert de Knegt (3) , Andre Boonstra (3) , Christine J Weegink (2) , Andre van Vliet (4) , Jeroen van de Wetering (4) , Simon Fletcher (5) , Lisa A Bauman (6) , Mohamad Rahimy (6) , James Appleman (6) , James Freddo (6) , Harry L Janssen (7) , H Reesink (2)

1 Gastroenterology & Hepatology
2 Gastroenterology and Hepatology
3 Gastroenterology and Hepatology
4 PRA International EDS
5 Anadys Pharmaceuticals Inc.
6 Anadys Pharmaceuticals, Inc.,
7 Gastroenterology & Hepatology

BACKGROUND: ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous interferon-α) (IFN-α) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection. AIM: To examine safety, tolerability, pharmacodynamics, pharmacokinetics and antiviral activity of ANA773. METHODS: ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naïve or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000 mg). In each group, 6-8 patients received ANA773 and 2 received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600 mg) or 10 days (2000 mg). RESULTS: Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-α response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26 log₁₀). in the placebo, 800, 1200, 1600 and 2000 mg cohorts, respectively. At the 2000 mg dose, ANA773 significantly (p=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10 log₁₀). CONCLUSIONS: ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000 mg dose group.

Mots clés: Medicine

Jilling F Bergmann, Joep de Bruijne, Daphne M Hotho, Robert de Knegt, Andre Boonstra, et al.. Antiviral Activity of ANA773, an Oral Inducer of Endogenous Interferons that Acts Via TLR7, in Chronic Hepatitis C Patients. Alimentary Pharmacology and Therapeutics, 2011, 34 (4), pp.443. ⟨10.1111/j.1365-2036.2011.04745.x⟩. ⟨hal-00655065⟩