1052 Antiviral Activity of Filibuvir in Combination With Pegylated Interferon Alfa-2a and Ribavirin for 28 Days in Treatment Naive Patients Chronically Infected With HCV Genotype 1

Jacobson, Ira M.; Pockros, Paul J.; Lalezari, J.; Läwitz, E.; Rodrı́guez-Torres, Maribel; DeJesus, Edwin; Haas, F.; Martorell, Claudia; Pruitt, Ronald E.; Durham, Katelin M.; Srinivasan, Subasree; Rosário, María do; Jagannatha, Shyla; Hammond, Jennifer

doi:10.1016/s0168-8278(09)61054-0

Cited by 39 publications

(17 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In TN HCV GT-1 patients (n = 35), the addition of filibuvir (200, 300, or 500 mg [n = 8] BID) to PegIFN/RBV for 4 weeks significantly increased the proportion of patients achieving RVR compared with PegIFN/RBV plus placebo (p <0.05), ranging from 60% to 75% for filibuvir plus PegIFN/RBV vs. 0% for PegIFN/RBV plus placebo [23][24][25]. The RVR rates from these latter two studies are similar to those achieved in the current study with BI 207127.…”

Section: Discussionmentioning

confidence: 99%

Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin

Larrey¹,

Lohse²,

Lédinghen³

et al. 2012

Journal of Hepatology

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin

Larrey¹,

Lohse²,

Lédinghen³

et al. 2012

Journal of Hepatology

View full text Add to dashboard Cite

“…Based on the relationship observed for filibuvir dose and exposure (data not shown), doses in excess of 200 mg BID are expected to achieve 24‐hour exposures resulting in at least half the maximal response, whereas doses in excess of 600 mg BID are expected to achieve exposures approaching the maximal response. A phase 2a study evaluating the effect of filibuvir given at 200, 300, and 500 mg BID (given for 4 weeks in combination with pegIFN and RBV) on HCV RNA concentrations showed that a greater proportion of patients achieved rapid virological response (>60%) at all filibuvir doses tested compared with the standard of care (0%) 21. The exposure–response analysis, in conjunction with phase 2a combination study results, indicates that doses producing at least half the maximal response in monotherapy studies for filibuvir may be sufficient when used in combination with pegIFN and RBV to improve efficacy compared with current standard‐of‐care therapy.…”

Section: Discussionmentioning

confidence: 99%

Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1-infected patients

et al. 2011

View full text Add to dashboard Cite

More effective and better-tolerated therapies are needed for chronic hepatitis C virus (HCV) infection. Among the direct-acting anti-HCV agents in development is the nonstructural 5B protein (NS5B polymerase) non-nucleoside inhibitor filibuvir. We investigated the antiviral activity, pharmacokinetics, safety, and tolerability of multiple doses of filibuvir in treatment-naive and treatment-experienced patients who were chronically infected with HCV genotype 1 in two phase 1b clinical studies (study 1 was a randomized, placebo-controlled dose escalation study and study 2 was a nonrandomized, open-label study). The filibuvir doses evaluated ranged from 200-1400 mg daily, and the duration of dosing ranged from 3-10 days. Genotypic changes in the NS5B nucleotide sequence following short-term filibuvir therapy were also assessed. Filibuvir potently inhibited viral replication in a dose-dependent manner. Mean maximum HCV RNA change from baseline ranged from 20.97 log 10 IU/mL with filibuvir given at 100 mg twice daily to 22.30 log 10 IU/mL with filibuvir given at 700 mg twice daily in treatment-naive patients. In treatmentexperienced patients, an HCV RNA reduction of 2.20 log 10 IU/mL was achieved with filibuvir given at 450 mg twice daily. Filibuvir was well tolerated in both studies. Adverse events were mild or moderate in severity. No discontinuations, serious adverse events, or deaths were reported. NS5B sequencing identified residue 423 as the predominant site of mutation after filibuvir dosing. Conclusion: Filibuvir administration resulted in significant reductions in HCV RNA concentrations at doses that were well tolerated in patients infected with HCV genotype 1. Filibuvir is currently being evaluated in combination with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients. (HEPATOLOGY 2011;54:50-59) H epatitis C virus (HCV) infection affects approximately 180 million people worldwide 1 and is a leading cause of chronic liver disease. 2 The current standard of care for chronic HCV infection is a combination of pegylated interferon alfa (pegIFN) and ribavirin (RBV). 3 In treatment-naive patients who are infected with HCV genotype 1, administration of pegIFN and RBV results in a sustained virological response (SVR; defined as undetectable HCV RNA in the plasma 24 weeks after completion of therapy) in only 40%-50% of patients following 48 weeks of therapy. [4][5][6] In patients with genotype 1 infection who failed to achieve SVR with a prior 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,

show abstract

“…The development of HCV polymerase nonnucleoside inhibitors (NNIs) has been successfully validated in phase II clinical trials (21,24,41). From the extensive screening of NS5B inhibitors that has been performed to date, several chemotypes have emerged as promising scaffolds, namely, the indole, thiophene, benzothiadiazine, and benzofuran analogs.…”

mentioning

confidence: 99%

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

Nyanguile¹,

Devogelaere²,

Vijgen³

et al. 2010

J Virol

View full text Add to dashboard Cite

The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is an unusually attractive target for drug discovery since it contains five distinct drugable sites. The success of novel antiviral therapies will require nonnucleoside inhibitors to be active in at least patients infected with HCV of subtypes 1a and 1b. Therefore, the genotypic assessment of these agents against clinical isolates derived from genotype 1-infected patients is an important prerequisite for the selection of suitable candidates for clinical development. Here we report the 1a/1b subtype profiling of polymerase inhibitors that bind at each of the four known nonnucleoside binding sites. We show that inhibition of all of the clinical isolates tested is maintained, except for inhibitors that bind at the palm-1 binding site. Subtype coverage varies across chemotypes within this class of inhibitors, and inhibition of genotype 1a improves when hydrophobic contact with the polymerase is increased. We investigated if the polymorphism of the palm-1 binding site is the sole cause of the reduced susceptibility of subtype 1a to inhibition by 1,5-benzodiazepines by using reverse genetics, X-ray crystallography, and surface plasmon resonance studies. We showed Y415F to be a key determinant in conferring resistance on subtype 1a, with this effect being mediated through an inhibitor-and enzyme-bound water molecule. Binding studies revealed that the mechanism of subtype 1a resistance is faster dissociation of the inhibitor from the enzyme.

show abstract

1052 Antiviral Activity of Filibuvir in Combination With Pegylated Interferon Alfa-2a and Ribavirin for 28 Days in Treatment Naive Patients Chronically Infected With HCV Genotype 1

Cited by 39 publications

References 0 publications

Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin

Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin

Antiviral activity of the hepatitis C virus polymerase inhibitor filibuvir in genotype 1-infected patients

1a/1b Subtype Profiling of Nonnucleoside Polymerase Inhibitors of Hepatitis C Virus

Contact Info

Product

Resources

About