731 Interim results of a multiple ascending dose study of R1626, a novel nucleoside analog targeting hcv polymerase in chronic HCV patients

Roberts, S.; Cooksley, Graham; Shaw, David R.; Berns, Heather; Brandl, Michael; Fettner, Scott; Hill, George; Ipe, David; Klumpp, Klaus; Mannino, Maurizio; O’Mara, Edward; Tuo, Ya; Washington, Carla

doi:10.1016/s0168-8278(06)80731-2

Cited by 52 publications

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“…In a multiple ascending dose phase I study, R1626 showed dose proportional pharmacokinetics and robust antiviral effects in HCV-infected persons. When administered for 14 days, R1626 achieved mean HCV viral load reductions of 1.2, 2.6, and 3.7 log IU/ml at dose levels of 1500, 3000, and 4500 mg, twice a day, respectively (8). R1626 therefore provided clinical proof-of-concept for 4Ј-modified ribonucleoside analogs as inhibitors of HCV replication.…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 93%

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

Klumpp

Kalayanov

et al. 2008

Journal of Biological Chemistry

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RNA polymerases effectively discriminate against deoxyribonucleotides and specifically recognize ribonucleotide substrates most likely through direct hydrogen bonding interaction with the 2-␣-hydroxy moieties of ribonucleosides. Therefore, ribonucleoside analogs as inhibitors of viral RNA polymerases have mostly been designed to retain hydrogen bonding potential at this site for optimal inhibitory potency. Here, two novel nucleoside triphosphate analogs are described, which are efficiently incorporated into nascent RNA by the RNA-dependent RNA polymerase NS5B of hepatitis C virus (HCV), causing chain termination, despite the lack of ␣-hydroxy moieties. 2-Deoxy-2-␤-fluoro-4-azidocytidine (RO-0622) and 2-deoxy-2-␤-hydroxy-4-azidocytidine (RO-9187) were excellent substrates for deoxycytidine kinase and were phosphorylated with efficiencies up to 3-fold higher than deoxycytidine. As compared with previous reports on ribonucleosides, higher levels of triphosphate were formed from RO-9187 in primary human hepatocytes, and both compounds were potent inhibitors of HCV virus replication in the replicon system (IC 50 ‫؍‬ 171 ؎ 12 nM and 24 ؎ 3 nM for RO-9187 and RO-0622, respectively; CC 50 >1 mM for both). Both compounds inhibited RNA synthesis by HCV polymerases from either HCV genotypes 1a and 1b or containing S96T or S282T point mutations with similar potencies, suggesting no cross-resistance with either R1479 (4-azidocytidine) or 2-C-methyl nucleosides. Pharmacokinetic studies with RO-9187 in rats and dogs showed that plasma concentrations exceeding HCV replicon IC 50 values 8 -150-fold could be achieved by low dose (10 mg/kg) oral administration. Therefore, 2-␣-deoxy-4-azido nucleosides are a new class of antiviral nucleosides with promising preclinical properties as potential medicines for the treatment of HCV infection. Hepatitis C virus (HCV)3 infection is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma and is the leading cause of liver transplantation. Current treatment options available to HCV-infected persons have limitations with regard to efficacy and tolerability. Only about 50% of individuals infected with HCV genotype 1 achieve sustained virological response when treated with a combination of pegylated interferon ␣ and ribavirin (1, 2). In addition, high viral load, age, body weight, co-infection with human immunodeficiency virus, and cirrhosis negatively affect the probability of achieving sustained virological response (3, 4). Therefore, there is an urgent need to develop new and more effective therapies for the treatment of HCV infection. A number of new antiviral candidates are currently being evaluated in clinical studies, the majority targeting either the HCV protease or HCV polymerase enzymes, which are essential for viral replication (5). The HCV RNA-dependent RNA polymerase, NS5B, contains the active site responsible for viral RNA synthesis and functions as part of a membrane-associated replicase complex. Nucleoside and non-nucleoside inhibitors of HCV polymerase h...

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Section: Hepatitis C Virus (Hcv)mentioning

confidence: 93%

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

Klumpp

Kalayanov

et al. 2008

Journal of Biological Chemistry

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“…In phase I trials, R1626 has been shown to induce the greatest viral load reduction in genotype 1 HCV-infected patients, so far reported among this class of antiviral agents. It was a 3.7 log mean HCV RNA decline for 4500 mg q12h at d 14, and a 2.6 log decline for the lower dose of 3000 mg q12h, but with better tolerability [47] . In vitro analysis of the antiviral effects exerted by combinations of R1479 with interferon or ribavirin have demonstrated synergistic effects, whereas with other direct antivirals the effects were additive [48] .…”

Section: Polymerase Inhibitorsmentioning

confidence: 94%

Specifically targeted antiviral therapy for hepatitis C virus

Parfieniuk¹

2007

WJG

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Hepatitis C virus (HCV) infection affects 180 million people worldwide with the predominant prevalence being infection with genotype 1, followed by genotypes 2 and 3. Standard anti-HCV therapy currently aims to enhance natural immune responses to the virus, whereas new therapeutic concepts directly target HCV RNA and viral enzymes or influence host-virus interactions. Novel treatment options now in development are focused on inhibitors of HCVspecific enzymes, NS3 protease and NS5B polymerase. These agents acting in concert represent the concept of specifically targeted antiviral therapy for HCV (STAT-C). STAT-C is an attractive strategy in which the main goal is to increase the effectiveness of antiviral responses across all genotypes, with shorter treatment duration and better tolerability. However, the emergence of resistant mutations that limit the use of these compounds in monotherapy complicates the regimens. Thus, a predictable scenario for HCV treatment in the future will be combinations of drugs with distinct mechanisms of action. For now, it seems that interferon will remain a fundamental component of any new anti-HCV therapeutic regimens in the near future; therefore, there is pressure to develop forms of interferon that are more effective, less toxic, and more convenient than pegylated interferon.

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“…Two have been withdrawn due to toxicity. R1626 (Roche Products) induces a dose-dependent HCV RNA level reduction [28]. At very high doses, HCV RNA level decrease reaches more than 3 logs, but side-effects are frequent.…”

Section: Inhibitors Of Hcv Replicationmentioning

confidence: 99%

“…Other drugs are still being developed in spite of serious side-effects. R1626 has been shown to induce a dose-dependent reduction of blood cell counts and hemoglobin levels after two weeks of administration at high doses [28], and the outcome of these effects is unknown if therapy is prolonged or if ribavirin is used in combination. Apparent safety during short-term administration does not guarantee that no serious adverse effects will occur when the drug is given for several weeks or months.…”

Section: Tolerabilitymentioning

confidence: 99%

Therapeutic perspectives for hepatitis C

2007

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OverviewHepatitis C virus (HCV) is represented by a single open reading frame of single-stranded RNA comprising approximately 3000 AA, positioned between 3' and 5' noncoding extremities. Transcription from the 5' end results in a compound polyprotein, generated by structural proteins in the amino-terminal region extremity and by nonstructural proteins in the opposing terminal region. Post-transcription cleavage by viral and host cell proteases generates 10 individual HCV proteins [1]. The HCV cDNA clone was first described in 1989. Subsequently, counter to the expectations of an enormous breakthrough, there was a hiatus in the growth of knowledge regarding the molecular virology of this virus. Only in 1997 was the first functioning and complete HCV cDNA clone described and used in animal models (chimpanzees) for preliminary analyses of the viral expression using biotechnological tools. A milestone in the study of viral molecular biology was the description, in 1999, of a viral culture model in tumor cells (Huh 7) using a HCV 1b subgenomic replicon. Based on this model, despite strict limitations, other viral fragments were used in order to evaluate the dynamics of viral replication in different settings and with exposure to antiviral agents. Nevertheless, the inability to obtain a complete HCV sequence remains an obstacle to be overcome [1].One characteristic of HCV is that is has minimal cytopathic effects, with immunomediated hepatotropic injury. However, it is also found in extrahepatic sites, where it has a short halflife (approximately 3 hours) and high serum turnover [2]. Standard treatment involves the administration of pegylated interferon alpha together with ribavirin. This treatment regimen has had modest success, a little over 50% [3], reaching 71% in cases of dose optimization and full compliance [4]. However, it could be much less, if we consider real life data, as well as characteristics of the host (race, comorbidities, immune state), of the liver disease (level of fibrosis and steatosis), of the medication (dose, interferon type) and of the virus itself. In addition, it is well known that genotype 1 has a lower response rate, and certain viral proteins can subvert the stimulus induced by interferon and ribavirin [3]. Viral kinetics, the evaluation of the decay pattern of the viremia -in terms of intensity and speed -after the initiation of the therapy, has proven to be a useful tool in the management of patients. It demonstrates the interaction among virus, drug, and host, in a relatively simple way: intense, rapid decay indicates a favorable case; insignificant, slow decay indicates cases that are unfavorable, moderate or intermediate. Such kinetic patterns allow patients to be characterized as rapid responders, slow responders, or nonresponders. This approach allows the treatment to be individualized, with ideal doses per weight and shorter, standard, or extended duration. In addition, it allows early prediction of treatment response. Therefore, individualized therapy constitutes the best thera...

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731 Interim results of a multiple ascending dose study of R1626, a novel nucleoside analog targeting hcv polymerase in chronic HCV patients

Cited by 52 publications

References 0 publications

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

2′-Deoxy-4′-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2′-α-Hydroxyl Groups

Specifically targeted antiviral therapy for hepatitis C virus

Therapeutic perspectives for hepatitis C

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