37 Sustained Virologic Response (Svr) Following Rg7128 1500mg Bid/Peg-Ifn/RBV for 28 Days in HCV Genotype 2/3 Prior Non-Responders

Gane, Edward; Rodrı́guez-Torres, Maribel; Nelson, Donald E.; Jacobson, Ira M.; McHutchison, John G.; Duca, Ana; Hyland, R.; Hill, Graham; Albanis, Efsevia; Symonds, William T.; Berrey, M. Michelle

doi:10.1016/s0168-8278(10)60039-6

Cited by 15 publications

(21 citation statements)

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“…Subjects chronically infected with HCV-2 or -3 who did not achieve an SVR with standard therapy or non-responders achieved a mean 5.0 log 10 IU/ml decrease in HCV RNA, and 95% (19 of 20) subjects achieved RVR. Subjects receiving a placebo with PEG-IFN plus RBV achieved a mean 3.7 log 10 IU/ml decrease in HCV RNA, and 60% (3 of 5) achieved RVR (Gane et al, 2010e).…”

Section: R7128mentioning

confidence: 99%

“…Preclinical data demonstrated that danoprevir binds with high affinity and dissociates slowly from the HCV NS3 protease, allowing high liver drug exposure with only modest plasma drug exposure. A phase Ib, "IFN-free" clinical trial demonstrated that danoprevir, combined with the HCV polymerase inhibitor R7128, was effective in reducing HCV RNA levels in a large proportion of treatment-naive subjects with HCV infection and in approximately half of previously non-responsive subjects with HCV-1 infection, without resistance or safety concerns (Gane et al, 2010e). In a phase IIb trial in treatment-naive subjects with HCV-1 infection, danoprevir plus PEG-IFN α-2a and RBV resulted in undetectable levels of HCV RNA in the majority of subjects, showing no evidence of viral resistance.…”

Section: Danoprevir (Itmn-191/r7227)mentioning

confidence: 99%

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New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

Tong

Wang

2012

J. Zhejiang Univ. Sci. B

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Abstract:Infection with hepatitis C virus (HCV) affects approximately 170 million people worldwide. However, no vaccine or immunoglobulin is currently available for the prevention of HCV infection. The standard of care (SOC) involving pegylated interferon-α (PEG-IFN α) plus ribavirin (RBV) for 48 weeks results in a sustained virologic response in less than 50% of patients with chronic hepatitis C genotype 1, the most prevalent type of HCV in North America and Europe. Recently, reliable in vitro culture systems have been developed for accelerating antiviral therapy research, and many new specifically targeted antiviral therapies for hepatitis C (STAT-C) and treatment strategies are being evaluated in clinical trials. These new antiviral agents are expected to improve present treatment significantly and may potentially shorten treatment duration. The aim of this review is to summarize the current developments in new anti-HCV drugs.

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Section: R7128mentioning

confidence: 99%

Section: Danoprevir (Itmn-191/r7227)mentioning

confidence: 99%

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

Tong

Wang

2012

J. Zhejiang Univ. Sci. B

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“…In triple regimen with PR, mericitabine shows less antiviral activity for GT-1 patients compared to the triple regimen with PIs Pockros et al 2012]. However, it has high antiviral activity for GT-2 and À3 treatment-experienced patients and for GT-4 patients [Gane et al 2010b] (Table 2). If included in an IFN-free regimen with ritonavir-boosted danoprevir and ribavirin for treatment-experienced GT-1b patients or in quadruple therapy with boosted danoprevir and PR for treatment-experienced GT-1 patients, mericitabine leads to promising SVR rates [Feld et al 2012] (Table 3).…”

Section: Treatment Of Gt-1 Patients Beyond Boceprevir or Telaprevirmentioning

confidence: 99%

An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials

Wendt

Bourlière

2013

Therapeutic Advances in Infection

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The launch of first-generation protease inhibitors (PIs) was a major step forward in hepatitis C virus (HCV) treatment. However, this major advance is, up to now, restricted to genotype-1 (GT-1) patients. However, the ongoing development of new direct-acting antiviral agents (DAAs) allows new hope for the future. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors (NS5B.I) include nucleoside/nucleotide inhibitors (NIs) and nonnucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon (IFN) and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with PI can cure GT-1b null-responder patients in an IFN-free regimen. In addition, several studies demonstrate that IFN-free regimens with DAA combinations are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, a quadruple regimen with PR is able to cure almost all GT-1 null-responders. The development of pan-genotypic DAAs (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response (SVR) for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment in GT-1 patients.

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“…Among the nucleoside/nucleotide analogs, RG7128 (the prodrug of PSI-6130, ␤-D-2Ј-fluoro-2Ј-C-methylcytidine) is the most advanced anti-HCV nucleoside and is currently in phase IIb clinical studies. So far, results from the clinical studies showed that RG7128 is generally safe and effective in reducing the viral loads for genotype 1, 2, 3, and 4 HCV-infected patients when it is combined with SOC, with no resistance-related breakthrough (16,21,27,37).More recently, we reported results of in vitro studies characterizing PSI-7851 and PSI-7977 (the single Sp isomer of PSI-7851), phosphoramidate prodrugs of ␤-D-2Ј-fluoro-2Ј-Cmethyluridine 5Ј-monophosphate (30,45,48). While RG7128 was designed to improve the pharmacokinetic profile of PSI-6130, PSI-7851 and PSI-7977 were synthesized to bypass the nonproductive first phosphorylation step, as the corresponding nucleoside analog was incapable of being converted to the monophosphate form.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Inhibition of Hepatitis C Virus Replicon RNA Synthesis by PSI-352938, a Cyclic Phosphate Prodrug of β-d-2′-Deoxy-2′-α-Fluoro-2′-β-C-Methylguanosine

Lam¹,

Espiritu²,

Murakami³

et al. 2011

Antimicrob Agents Chemother

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PSI-352938 is a novel cyclic phosphate prodrug of ␤-D-2-deoxy-2-␣-fluoro-2-␤-C-methylguanosine 5-monophosphate that has potent activity against hepatitis C virus (HCV) in vitro. The studies described here characterize the in vitro anti-HCV activity of PSI-352938, alone and in combination with other inhibitors of HCV, and the cross-resistance profile of PSI-352938. The effective concentration required to achieve 50% inhibition for PSI-352938, determined using genotype 1a-, 1b-, and 2a-derived replicons stably expressed in the Lunet cell line, were 0.20, 0.13, and 0.14 M, respectively. The active 5-triphosphate metabolite, PSI-352666, inhibited recombinant NS5B polymerase from genotypes 1 to 4 with comparable 50% inhibitory concentrations. Hepatitis C virus (HCV), an important member of the Flaviviridae family of viruses, is a major health problem affecting approximately 170 million people worldwide. In the United States, where it is the leading cause of liver transplantation, nearly 2% of the U.S. population are HCV carriers (2). The current standard of care (SOC), which consists of pegylated alpha interferon (IFN-␣) and ribavirin, results in only about a 50% sustained virological response in patients infected with genotype 1 HCV, the predominant genotype in the United States and Europe (13, 18). The limited cure rate and potential side effects associated with interferon and ribavirin (10, 11) prompted the development of direct-acting antiviral agents (DAAs) in order to improve clinical efficacy and tolerability.Among the DAAs currently in clinical development, nucleoside/nucleotide analogs as inhibitors of HCV replication have the advantage of broad genotype coverage and a high barrier to resistance (14). The active 5Ј-triphosphates of nucleoside/ nucleotide analogs target the HCV NS5B RNA-dependent RNA polymerase (Pol) by serving as alternative substrate inhibitors during RNA synthesis (6). Both of the two resistance mutations identified so far, S96T and S282T, are highly conserved residues and unfit for HCV replicon replication (33). Among the nucleoside/nucleotide analogs, RG7128 (the prodrug of PSI-6130, ␤-D-2Ј-fluoro-2Ј-C-methylcytidine) is the most advanced anti-HCV nucleoside and is currently in phase IIb clinical studies. So far, results from the clinical studies showed that RG7128 is generally safe and effective in reducing the viral loads for genotype 1, 2, 3, and 4 HCV-infected patients when it is combined with SOC, with no resistance-related breakthrough (16,21,27,37).More recently, we reported results of in vitro studies characterizing PSI-7851 and PSI-7977 (the single Sp isomer of PSI-7851), phosphoramidate prodrugs of ␤-D-2Ј-fluoro-2Ј-Cmethyluridine 5Ј-monophosphate (30,45,48). While RG7128 was designed to improve the pharmacokinetic profile of PSI-6130, PSI-7851 and PSI-7977 were synthesized to bypass the nonproductive first phosphorylation step, as the corresponding nucleoside analog was incapable of being converted to the monophosphate form. In a 3-day phase I monotherapy study, a 1.95-log vira...

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37 Sustained Virologic Response (Svr) Following Rg7128 1500mg Bid/Peg-Ifn/RBV for 28 Days in HCV Genotype 2/3 Prior Non-Responders

Cited by 15 publications

References 0 publications

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

New developments in small molecular compounds for anti-hepatitis C virus (HCV) therapy

An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials

Inhibition of Hepatitis C Virus Replicon RNA Synthesis by PSI-352938, a Cyclic Phosphate Prodrug of β-d-2′-Deoxy-2′-α-Fluoro-2′-β-C-Methylguanosine

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