1045 SAFETY AND ANTIVIRAL EFFICACY OF 14 DAYS OF THE CYCOPHILIN INHIBITOR NIM811 IN COMBINATION WITH PEGYLATED INTERFERON α2a IN RELAPSED GENOTYPE 1 HCV INFECTED PATIENTS

Läwitz, E.; Rouzier, Roman; Nguyen, Thai Minh; Huang, Minda; Ke, June; Præstgaard, Jens; Serra, Denise; Koziel, Margaret James; Evans, Thomas G.

doi:10.1016/s0168-8278(09)61047-3

Cited by 13 publications

(5 citation statements)

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“…114 No viral decline in genotype 1-infected patients treated with NIM811 alone was observed in a phase 1 study ( Figure 1D). 115 However, selection of cell lines conferring resistance to NIM811 without disclosure of the mutations observed was shown in the replicon system. 111 Taken together, cyclophilin inhibitors may have the potential of broad antiviral activity to different HCV genotypes.…”

Section: Cyclophilin Inhibitorsmentioning

confidence: 99%

Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection

2010

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Section: Cyclophilin Inhibitorsmentioning

confidence: 99%

Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection

2010

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“…Host-targeting antivirals (HTAs) may have a higher barrier to resistance than (most) DAA inhibitors. A number of cyclophilinbinding molecules such as alisporivir (DEB025), NIM811, and SCY-635 have proven to be potent inhibitors of HCV replication and have shown clinical efficacy (30,47).…”

mentioning

confidence: 99%

Comparative Study of the Genetic Barriers and Pathways towards Resistance of Selective Inhibitors of Hepatitis C Virus Replication

Delang

Vliegen

Froeyen

et al. 2011

Antimicrob Agents Chemother

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Hepatitis C virus (HCV) inhibitors include direct-acting antivirals (DAAs) such as NS3 serine protease inhibitors, nucleoside and nonnucleoside polymerase inhibitors, and host-targeting antivirals (HTAs) such as cyclophilin inhibitors that have been developed in recent years. Drug-resistant HCV variants have been reported both in vitro and in the clinical setting for most classes of drugs. We report a comparative study in which the genetic barrier to drug resistance of a representative selection of these inhibitors is evaluated employing a number of resistance selection protocols. The NS3 protease inhibitors VX-950 and BILN 2061, the nucleoside polymerase inhibitor 2-C-methylcytidine, three nonnucleoside polymerase inhibitors (thiophene carboxylic acid, benzimidazole, and benzothiadiazine), and DEB025 were included. For each drug and passage in the selection process, the phenotype and genotype of the drug-resistant replicon were determined. For a number of molecules (BILN 2061 and nonnucleoside inhibitors), drug-resistant variants were readily selected when wild-type replicon-containing cells were directly cultured in the presence of high concentrations of the inhibitor. Resistance to DEB025 could be selected only following a lengthy stepwise selection procedure. For some DAAs, the signature mutations that emerged under inhibitor pressure differed depending on the selection protocol that was employed. Replication fitness of resistant mutants revealed that the C445F mutation in the RNA-dependent RNA polymerase can restore loss of fitness caused by a number of unfit resistance mutations. These data provide important insights into the various pathways leading to drug resistance and allow a direct comparison of the genetic barriers of various HCV drugs.Hepatitis C virus (HCV) is a positive single-stranded RNA virus and the only member of the Hepacivirus genus within the Flaviviridae family. An estimated 170 million people are chronically infected worldwide. Three million to four million people become newly infected each year (57). Chronically infected patients are at increased risk of developing liver cirrhosis and hepatocellular carcinoma. In Western countries, infection with HCV is the most common reason for liver transplantation. The current standard of care for the management of chronic hepatitis C virus infection consists of the combination of pegylated alpha interferon (pegIFN-␣) and ribavirin. This therapy is effective in only 50 to 60% of infected patients and is associated with serious side effects (44). Therefore, more tolerable, highly potent inhibitors of HCV replication are urgently needed and are currently also being developed. Antivirals that specifically target viral proteins are referred to as "direct-acting antivirals" (DAAs) for HCV. A number of NS3/NS4A protease inhibitors are currently in clinical development. The first HCV NS3/4A serine protease inhibitor to enter clinical trials was ciluprevir (BILN 2061) (54), but clinical development was halted because of cardiotoxicity. Other protease inhib...

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“…[62] In patients with relapse after SOC, NIM811+PegIFN achieved an HCV-VL decrease of 2.78 log after 14 days, as compared to a decrease of 0.58 log with PegIFN monotherapy. [63] Decrease in platelets was more pronounced in the NIM811+PegIFN arm than in the PegIFN arm.…”

Section: Potential Cocktail Componentsmentioning

confidence: 99%

Mixing the right hepatitis C inhibitor cocktail

Gelman

Glenn

2011

Trends in Molecular Medicine

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Therapy for hepatitis C virus (HCV) infection is on the cusp of a new era. Until now, standard of care (SOC) therapy has involved interferon (IFN) and ribavirin. With the first successful phase 3 trials of specific targeted antiviral therapy for HCV (STAT-C) compounds, as well as three trials in progress giving the first glimpse of IFN-free combinations of STAT-C agents, this review looks ahead to the new classes of anti-HCV agents currently in clinical development. Successful pharmacologic control of HIV and TB frames the discussion, as well as consideration of the mutation frequency of HCV replication. Maximizing synergy between agents and minimizing cumulative toxicity will be critical to the design of future IFN-free STAT-C regimens.

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1045 SAFETY AND ANTIVIRAL EFFICACY OF 14 DAYS OF THE CYCOPHILIN INHIBITOR NIM811 IN COMBINATION WITH PEGYLATED INTERFERON α2a IN RELAPSED GENOTYPE 1 HCV INFECTED PATIENTS

Cited by 13 publications

References 0 publications

Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection

Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection

Comparative Study of the Genetic Barriers and Pathways towards Resistance of Selective Inhibitors of Hepatitis C Virus Replication

Mixing the right hepatitis C inhibitor cocktail

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