ANA598 - HCV
A Non-Nucleoside HCV Polymerase Inhibitor
ANA598 is our non-nucleoside polymerase inhibitor that we are developing for the treatment of chronic hepatitis C virus (HCV) infection. We recently completed 12 weeks of dosing ANA598 in combination with pegylated interferon-alpha and ribavirin (standard of care or SOC) in an ongoing Phase II clinical trial. In this study ANA598 was dosed at two doses levels: 200 mg given twice-daily (bid) and 400 mg bid. In May 2010, we reported data from this study for the 400 mg bid dose level, showing a favorable safety profile through 12 weeks and that 75% of patients at this dose level achieved undetectable levels of virus (<15 /IU/mL) at week 12, known as complete Early Virological Response or cEVR. These data confirmed the positive profile previously reported for ANA598 at 200 mg bid through 12 weeks in this study. Only one patient in this study (<2%) demonstrated viral breakthrough during the 12 weeks of receiving ANA598 plus SOC, consistent with a high pharmacological barrier to resistance conferred by ANA598’s favorable pharmacokinetic profile. Based on comparable antiviral potency and excellent safety at both doses, we have identified 200 mg bid as the optimal dose to advance in combination with current SOC in future clinical trials. We believe that lower doses and once daily dosing also merit exploration, especially in combination with other direct acting antivirals.
Phase II Combination Study Design:
In the ongoing Phase II study, treatment-naïve genotype 1 patients have received ANA598 or placebo in combination with Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin, USP) for 12 weeks at dose levels of 200 mg or 400 mg bid, each with a loading dose of 800 mg bid on day one. After week 12, patients are to continue receiving SOC alone. Patients who achieve undetectable levels of virus at weeks 4 and 12 are to be randomized to stop all treatment at week 24 or 48. The primary endpoint of the study is the proportion of patients who achieve undetectable levels of virus at week 12 (cEVR). Additional endpoints include safety and tolerability as well as the proportion of patients with undetectable levels of virus at week 4 (RVR). Patients will be followed for 24 weeks after stopping therapy to determine the rate of Sustained Virological Response, or SVR. Approximately 90 patients have been enrolled in this study - with approximately 30 patients receiving ANA598 plus SOC at each dose level and 30 patients receiving placebo plus SOC. The study is being managed by the Duke Clinical Research Institute (DCRI) and is being conducted at a number of clinical sites in the United States.
Background to Phase II Combination Study:
Anadys laid the foundation for the current Phase II clinical trial with prior clinical and preclinical work. In a Phase I trial in HCV patients, ANA598 demonstrated potent antiviral activity when dosed as monotherapy over three days. No patient at any dose level in the monotherapy study showed evidence of viral breakthrough while on ANA598, and there were no serious adverse events. Anadys has presented in vitro data supporting the use of ANA598 in combination with interferon-alpha as well as with other anti-HCV agents currently in development that act through diverse mechanisms. Data has shown that ANA598 is synergistic in vitro with interferon-alpha as well as representative HCV protease and polymerase inhibitors. In vitro combination treatment at clinically relevant concentrations of interferon-alpha and ANA598 results in clearance of HCV RNA from cells rather than selection of resistant isolates. Furthermore, ANA598 retains full activity in vitro against mutations conferring resistance to protease inhibitors, nucleoside polymerase inhibitors and non-nucleoside polymerase inhibitors that act at binding sites distinct from that of ANA598, while protease and nucleoside polymerase inhibitors retain full activity in vitro against mutations conferring resistance to ANA598.
In 2009 Anadys completed long-term, chronic toxicology studies of ANA598, of 26 weeks duration in rats and 39 weeks duration in monkeys, and has reported favorable results. The completed toxicology studies support the ongoing Phase II clinical study as well as dosing ANA598 for as long as a year in future clinical studies.
Anadys retains full rights to ANA598, which was fully discovered at the Company. Preclinical evaluation of ANA598 was completed in the first quarter of 2008, leading to submission of an Investigational New Drug Application (IND) to the FDA, subsequent allowance of the IND by the FDA and initiation of clinical investigation in the second quarter of 2008.
Last Updated 6/16/2010
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ANA598 - HCV