MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

Summa, Vincenzo; Ludmerer, Steven W.; McCauley, John A.; Fandozzi, Christine; Burlein, Christine; Claudio, Giuliano; Coleman, Paul J.; DiMuzio, Jillian; Marco, Fernando; Filippo, Marcello Di; Gates, Adam; Graham, Donald J.; Harper, Steven J.; Hazuda, Daria J.; Huang, Qian; McHale, Carolyn; Monteagudo, Edith; Pucci, Vincenzo; Rowley, Michael; Rudd, Michael T.; Soriano, Aileen; Stahlhut, Mark W.; Vacca, Joseph P.; Olsen, David B.; Liverton, Nigel J.; Carroll, Steven S.

doi:10.1128/aac.03565-14

Cited by 17 publications

(18 citation statements)

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“…Simeprevir was least active against GT2a (strain J6) and GT3a. These data are consistent with previously published in vitro protease assay data Liverton, 2010;Summa et al, 2012). Telaprevir displayed similar activity against GT1a, GT1b, GT2a, GT2b, and GT6a, but significantly reduced activity against GT3a, GT4a, and GT5a.…”

Section: Drug Resistance Profiles Of Hcv Infected Patientssupporting

confidence: 92%

“…For GT1a, single mutations at position R155 (R155G, R155K, R155S, and R155T) resulted in 85-390-fold changes in IC 50 relative to wild-type for the protease inhibitors GS-9451 and GS-9256, with the greatest reduction in susceptibility to GS-9451 and GS-9256 observed with the R155K and R155S mutations, respectively. Consistent with previously published data from mutant replicons (Summa et al, 2012), mutations at position R155 resulted in moderate shifts in susceptibility to the PIs simeprevir and telaprevir (14-59-fold), while only minor reductions in susceptibility were observed with MK-5172 (<8.2-fold). The D168E GT1a mutation resulted in moderate reductions in susceptibility to GS-9451, GS-9256, and simeprevir, but no significant change in susceptibility to telaprevir or MK-5172.…”

Section: Ic 50 Determination In Gt1a and Gt1b Ns3 Mutantssupporting

confidence: 91%

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Development and application of a fast, reproducible assay to measure HCV NS3 protease activity using Escherichia coli lysate

Han

Dvory‐Sobol

Greenstein

et al. 2015

Journal of Virological Methods

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Section: Drug Resistance Profiles Of Hcv Infected Patientssupporting

confidence: 92%

Section: Ic 50 Determination In Gt1a and Gt1b Ns3 Mutantssupporting

confidence: 91%

Development and application of a fast, reproducible assay to measure HCV NS3 protease activity using Escherichia coli lysate

Han

Dvory‐Sobol

Greenstein

et al. 2015

Journal of Virological Methods

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“…(6,7) The combination of elbasvir (EBR), an NS5A inhibitor, and grazoprevir (GZR), an NS3/4a inhibitor, is approved in many Western countries and in Japan for treatment of HCV GT1 and 4 infection. (8)(9)(10) This combination has broad and potent antiviral activity in vitro (11)(12)(13)(14) and has shown high efficacy in phase 2 and 3 studies when administered for 12 weeks across a wide spectrum of people, including those with cirrhosis, chronic kidney disease, or human immunodeficiency virus coinfection, and in previously treated people in whom IFN-based therapy failed. (15)(16)(17)(18)(19)(20)(21)(22)(23) Rates of sustained virologic response 12 weeks after completion of treatment (SVR12) in these predominantly Western populations generally exceeded 90%, and high rates of SVR12 have also been reported in Japanese individuals.…”

mentioning

confidence: 99%

Elbasvir/grazoprevir in Asia‐Pacific/Russian participants with chronic hepatitis C virus genotype 1, 4, or 6 infection

George

Бурневич

Sheen

et al. 2018

Hepatology Communications

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The prevalence of hepatitis C virus (HCV) infection in Asian countries is high. This study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from Asia‐Pacific countries and Russia. In this phase 3, randomized, placebo‐controlled, double‐blind study, treatment‐naive participants with HCV genotype (GT) 1, 4, or 6 infection were randomized to EBR 50 mg/GZR 100 mg (immediate‐treatment group [ITG]) or placebo (deferred‐treatment group [DTG]) once daily for 12 weeks (Protocol PN‐5172‐067, NCT02251990). The primary efficacy variable was a nonrandomized comparison of sustained virologic response at 12 weeks after the end of therapy (SVR12) for the ITG with a historical control. The primary safety outcome was a randomized comparison between the ITG and DTG. Three hundred thirty‐seven participants were randomized to the ITG (n = 251) or DTG (n = 86); 199 (59.2%) participants were Asian, and 250 (74.4%) had HCV GT1b infection. Overall, 232/250 (92.8%) participants in the ITG achieved SVR12 (97.5% confidence interval, 89.1, 96.5). Of the 18 participants who failed to attain SVR12, 1 was lost to follow‐up and 17 had virologic failure, 13 of whom had HCV GT6 infection. The incidence of adverse events was similar between participants receiving EBR/GZR and placebo (50.8% versus 51.2%; difference, −0.3%; 95% confidence interval, −12.3, 11.9). Conclusion: EBR/GZR for 12 weeks provides an effective and well‐tolerated regimen for chronic HCV GT1 infection in treatment‐naive people from Asia‐Pacific countries and Russia, particularly for the large population with GT1b infection. EBR/GZR is not recommended for the treatment of individuals with HCV GT6 infection. (Hepatology Communications 2018;2:595‐606)

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“…Data from Refs. [22][23][24] Retreatment in DAA Failures they are T54A/S, V55A, A156S, and I/V170A. 22 These RAVs have impaired production of the virus and viral proteins, and others increase replicative fitness of the virus.…”

Section: Viral Factorsmentioning

confidence: 99%

Mechanisms of Virologic Failure with Direct-Acting Antivirals in Hepatitis C and Strategies for Retreatment

Costilla

Mathur

Gutiérrez

2015

Clinics in Liver Disease

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MK-5172, a Selective Inhibitor of Hepatitis C Virus NS3/4a Protease with Broad Activity across Genotypes and Resistant Variants

Cited by 17 publications

References 0 publications

Development and application of a fast, reproducible assay to measure HCV NS3 protease activity using Escherichia coli lysate

Development and application of a fast, reproducible assay to measure HCV NS3 protease activity using Escherichia coli lysate

Elbasvir/grazoprevir in Asia‐Pacific/Russian participants with chronic hepatitis C virus genotype 1, 4, or 6 infection

Mechanisms of Virologic Failure with Direct-Acting Antivirals in Hepatitis C and Strategies for Retreatment

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