2008 Dose-Ranging, Three-Day Monotherapy Study of the HCV Ns3 Protease Inhibitor Gs-9256

Lawitz, E.J.; Marbury, T.; Vince, Bradley; Grunenberg, Nicole; Rodrı́guez-Torres, Maribel; Micco, M.P. De; Tarro, J.N.; Shelton, Mark J.; West, Sophie; Zong, Jiang; Bae, Andrew; Wong, Kelly A.; Mo, Hongmei; Oldach, David; Delaney, William E.; Rousseau, Franck

doi:10.1016/s0168-8278(10)61199-3

Cited by 17 publications

(21 citation statements)

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“…These results are consistent with the antiviral activity observed in a recent phase 1b monotherapy study (42). In addition, GS-9451 has an orthogonal resistance profile, as well as an additive to synergistic in vitro antiviral activity with respect to other classes of HCV in- hibitors.…”

Section: Discussionsupporting

confidence: 89%

Preclinical Characterization of the Novel Hepatitis C Virus NS3 Protease Inhibitor GS-9451

Yang

Robinson

Corsa

et al. 2014

Antimicrob Agents Chemother

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GS-9451 is a selective hepatitis C virus (HCV) NS3 protease inhibitor in development for the treatment of genotype 1 (GT1) HCV infection. Key preclinical properties of GS-9451, including in vitro antiviral activity, selectivity, cross-resistance, and combination activity, as well as pharmacokinetic properties, were determined. In multiple GT1a and GT1b replicon cell lines, GS-9451 had mean 50% effective concentrations (EC 50 s) of 13 and 5.4 nM, respectively, with minimal cytotoxicity; similar potency was observed in chimeric replicons encoding the NS3 protease gene of GT1 clinical isolates. GS-9451 was less active in GT2a replicon cells (EC 50 ‫؍‬ 316 nM). Additive to synergistic in vitro antiviral activity was observed when GS-9451 was combined with other agents, including alpha interferon, ribavirin, and the polymerase inhibitors GS-6620 and tegobuvir (GS-9190), as well as the NS5A inhibitor ledipasvir (GS-5885). GS-9451 retained wild-type activity against multiple classes of NS5B and NS5A inhibitor resistance mutations. GS-9451 was stable in hepatic microsomes and hepatocytes from human and three other tested species. Systemic clearance was low in dogs and monkeys but high in rats. GS-9451 showed good oral bioavailability in all three species tested. In rats, GS-9451 levels were ϳ40-fold higher in liver than plasma after intravenous dosing, and elimination of GS-9451 was primarily through biliary excretion. Together, these results are consistent with the antiviral activity observed in a recent phase 1b study. The results of in vitro cross-resistance and combination antiviral assays support the ongoing development of GS-9451 in combination with other agents for the treatment of chronic HCV infection.T he NS3 serine protease of hepatitis C virus (HCV), which liberates essential nonstructural proteins from the HCV polyprotein, is required for viral replication (1) and may promote infection by blunting host innate immunity (2). Inhibitors of the HCV NS3/4A serine protease can induce rapid and substantial reductions in viral load. The NS3 protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are separately indicated for use in triple therapy combinations with pegylated alpha interferon (PEG-IFN) and ribavirin (RBV) for treating chronic genotype 1 (GT1) HCV infection. When added to PEG-IFN and RBV, telaprevir and boceprevir independently have increased rates of sustained virologic response (SVR) in GT1 HCV-infected patients (3-13). However, the standard of care still has many limitations, including a complex treatment regimen, significant drug-drug interaction potential, and adverse effects that can limit tolerability.There is continued need for novel NS3 protease inhibitors that are well tolerated, have minimal potential for drug-drug interactions, and provide more favorable treatment regimens to improve compliance. GS-9451 is a novel acyclic HCV protease inhibitor being developed for the treatment of GT1 HCV infection. GS-9451 inhibits NS3 protease by binding the active site of the enzyme in a reve...

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Section: Discussionsupporting

confidence: 89%

Preclinical Characterization of the Novel Hepatitis C Virus NS3 Protease Inhibitor GS-9451

Yang

Robinson

Corsa

et al. 2014

Antimicrob Agents Chemother

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“…10 VDV dosed at 200 or 400 mg for 3 days suppressed HCV RNA levels by a median of 3.2-3.6 log 10 IU/mL from baseline in treatment-na€ ıve patients infected with HCV genotype 1a or 1b. 8 In another study, 8 days of TGV treatment resulted in a mean maximal decline in HCV RNA of >1.5 log 10 IU/mL in patients with HCV genotype 1. 9 Resistance mutations detected in these studies did not confer cross-resistance to other classes of DAAs.…”

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confidence: 96%

“…From the 1 University of California, San Diego, La Jolla, CA; 2 Fundacion de Investigacion de Diego, Santurce, Puerto Rico; 3 Texas Liver Institute, San Antonio, TX; 4 Liver Institute of Virginia, Richmond, VA; 5 Hôpital Cochin, Paris, France; 6 Quality Medical Research, PLLC, Nashville, TN; 7 Gilead Sciences, Inc., Foster City, CA; 8 Inserm 1110, Universite de Strasbourg, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; and 9 Johns Hopkins University School of Medicine, Baltimore, MD.…”

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confidence: 99%

“…Individually, these agents have demonstrated antiviral activity against genotype 1 HCV. [7][8][9] In a 3-day monotherapy study, LDV dosed at 90 mg demonstrated significant antiviral activity within the first 12 hours of therapy. At doses of 3 mg or greater, the median maximal reduction in HCV RNA from baseline was >3 log 10 IU/mL in patients infected with HCV genotype 1a; LDV dosed at 30 mg or higher provided >95% of maximal antiviral response.…”

mentioning

confidence: 99%

“…9 Resistance mutations detected in these studies did not confer cross-resistance to other classes of DAAs. [7][8][9] Given the positive results of combining two DAAs with RBV in previous trials, we hypothesized that the addition of a third DAA with a distinct mechanism of action might result in improved response with a shortened treatment duration. Although the results from the 3-day monotherapy study with LDV suggested that the 30-mg dose or higher resulted in robust viral suppression, the optimal dose of LDV given for a longer period has not been determined.…”

mentioning

confidence: 99%

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All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with genotype 1 HCV infection

et al. 2014

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This phase II trial assessed the efficacy and safety of a combination regimen of the nonstructural protein (NS)5A inhibitor ledipasvir (LDV), NS3 protease inhibitor vedroprevir (VDV), non-nucleoside NS5B inhibitor tegobuvir (TGV), and ribavirin (RBV) in treatment-na€ ıve patients with chronic hepatitis C virus (HCV) genotype 1 without cirrhosis. Patients were randomized 1:2 to LDV 30 mg once daily (QD; Arm 1; n 5 46) or LDV 90 mg QD (Arm 2; n 5 94); patients in both arms also received VDV 200 mg QD, TGV 30 mg twice-daily, and RBV 1,000-1,200 mg/day. Patients in Arm 2 with vRVR, defined as HCV RNA below the lower limit of quantification (LLOQ) from treatment weeks 2 to 10, were randomized 1:1 to stop treatment at 12 weeks or continue for 24 weeks. Sustained virologic response 12 weeks after treatment (SVR12) was higher in patients receiving 90 mg of LDV for 24 weeks (63%), compared with LDV 90 mg for 12 weeks (54%) and LDV 30 mg for 24 weeks (48%). In patients with very rapid virologic response (vRVR) in Arm 2, SVR12 was achieved by 68% and 81% of patients treated for 12 and 24 weeks, respectively. Virologic breakthrough was more common in patients with HCV genotype 1a and was associated with resistance-associated variants for all three direct-acting antiviral agents (DAAs); however, in all but 1 patient who relapsed, resistance-associated variants directed against only one or two of the DAAs were detected. The most common adverse events were fatigue, headache, nausea, rash, and diarrhea. Conclusion: In patients with HCV genotype 1, an interferon-free regimen containing LDV/VDV/TGV/RBV was well tolerated and led to SVR12 in up to 63% of patients. LDV 90 mg is currently being investigated in combination with the nucleotide polymerase inhibitor, sofosbuvir. (HEPATOLOGY 2014;60:56-64)

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Direct-acting antivirals for chronic hepatitis C

Jakobsen

Nielsen

Feinberg

et al. 2017

Cochrane Database of Systematic Reviews

103

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Overall, DAAs on the market or under development do not seem to have any effects on risk of serious adverse events. Simeprevir may have beneficial effects on risk of serious adverse event. In all remaining analyses, we could neither confirm nor reject that DAAs had any clinical effects. DAAs seemed to reduce the risk of no sustained virological response. The clinical relevance of the effects of DAAs on no sustained virological response is questionable, as it is a non-validated surrogate outcome. All trials and outcome results were at high risk of bias, so our results presumably overestimate benefit and underestimate harm. The quality of the evidence was very low.

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2008 Dose-Ranging, Three-Day Monotherapy Study of the HCV Ns3 Protease Inhibitor Gs-9256

Cited by 17 publications

References 0 publications

Preclinical Characterization of the Novel Hepatitis C Virus NS3 Protease Inhibitor GS-9451

Preclinical Characterization of the Novel Hepatitis C Virus NS3 Protease Inhibitor GS-9451

All-oral combination of ledipasvir, vedroprevir, tegobuvir, and ribavirin in treatment-naïve patients with genotype 1 HCV infection

Direct-acting antivirals for chronic hepatitis C

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