Randomised clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV.
Author(s): Bergmann JF, de Bruijne J, Hotho DM, de Knegt RJ, Boonstra A, Weegink CJ, van Vliet AA, van de Wetering J, Fletcher SP, Bauman LA, Rahimy M, Appleman JR, Freddo JL, Janssen HL, Reesink HW
Affiliation(s): Department of Gastroenterology and Hepatology, Erasmus MC University Hospital, Rotterdam, The Netherlands.
Publication date & source: 2011-08, Aliment Pharmacol Ther., 34(4):443-53. Epub 2011 Jun 26.
Publication type: Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't
BACKGROUND: The 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-alpha (IFN-alpha) 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 anti-viral activity of ANA773. METHODS: The ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naive or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000mg). In each group, six to eight patients received ANA773 and two received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600mg) or 10days (2000mg). 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-alpha response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26log(10) in the placebo, 800, 1200, 1600 and 2000mg cohorts, respectively. At the 2000mg dose, ANA773 significantly (P=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10log(10) ). CONCLUSION: The 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 2000mg dose group. (c) 2011 Blackwell Publishing Ltd.