4-6 In patients with genotype 1 infection who failed to achieve SVR with a prior EPZ015666 nmr pegIFN/RBV regimen, retreatment with pegIFN and RBV for 48 weeks resulted in SVR rates ranging from 4% in nonresponders (did not achieve undetectable HCV RNA levels at any time during therapy) to 23% in relapsers (HCV RNA undetectable at end of treatment but returned following discontinuation of treatment).7 PegIFN and RBV therapy is

also associated with substantial side effects, including fatigue, headache, myalgia, fever, nausea, insomnia, and anemia.4-6, 8 Such side effects often necessitate discontinuations or dose reductions, which decreases the probability of achieving an SVR. Consequently, there is an urgent clinical need for more effective and better-tolerated anti-HCV therapies that can achieve higher SVR rates with shorter treatment duration.9, 10 A number of direct-acting anti-HCV agents,9, 10 including the nonstructural

protein 3/4A (NS3/4A) protease inhibitors and the nucleoside and non-nucleoside polymerase inhibitors, are being evaluated for use in combination with pegIFN and RBV. The addition of a direct-acting anti-HCV agent to pegIFN and RBV has been shown to significantly BGJ398 price increase the proportion of patients achieving an SVR and may reduce the duration of therapy to 24 or 28 weeks in some HCV genotype 1–infected patients.11-13 Furthermore, direct-acting MCE anti-HCV agents may ultimately be used in novel combination regimens that eliminate pegIFN and/or RBV. Such combination regimens may further improve SVR rates and

address the safety and tolerability concerns associated with the current standard of care. Filibuvir (formerly PF-00868554; Pfizer, Inc.) is a novel, potent, and selective non-nucleoside inhibitor (NNI) of the HCV nonstructural 5B protein (NS5B) RNA-dependent RNA polymerase, and it binds noncovalently in the “Thumb 2” pocket of NS5B (Fig. 1).14, 15In vitro, filibuvir is equipotent against genotype 1a and 1b replicons, with an overall mean median effective concentration (EC50) of 0.059 μM.16 In HCV-negative healthy volunteers, multiple oral doses of up to 300 mg three times daily (TID) administered over 14 days were safe and well tolerated and achieved plasma concentrations in excess of the in vitro protein binding–corrected EC50.15 Given the promising preclinical and clinical data, filibuvir was evaluated in HCV genotype 1–infected, treatment-naive (TN) and treatment-experienced (TE) patients. The primary objectives were to assess the antiviral activity, pharmacokinetics (PK), and safety and tolerability of multiple oral doses of filibuvir. This article presents data from two phase 1b studies: protocol number A8121002, NCT00445315 (study 1), and protocol number A8121006, NCT00671671 (study 2).