rg-7128 and Hepatitis-C

Mathematical modeling of hepatitis C viral kinetics has been an important tool in understanding hepatitis C virus (HCV) infection dynamics and in estimating crucial in vivo parameters characterizing the effectiveness of HCV therapy. Because of the introduction of direct-acting antiviral agents, there is a need to extend previous models so as to understand, characterize, and compare various new HCV treatment regimens. Here we review recent modeling efforts in this direction.

Topics: Antiviral Agents; Carbamates; Deoxycytidine; Hepacivirus; Hepatitis C; Humans; Imidazoles; Models, Biological; Oligopeptides; Protease Inhibitors; Pyrrolidines; Silybin; Silymarin; Valine

Nucleoside/nucleotide analogue polymerase inhibitors (NPIs) are analogues of natural substrates that bind the active site of NS5B and terminate viral RNA chain generation and generally provide a high genetic barrier to resistance and are effective in all genotypes. NPIs such as sofosbuvir (GS-7977) show high antiviral activities that, together with their high genetic barrier to resistance, suggest that they are optimal backbone candidates for all-oral combination therapies. Several trials are ongoing to further define the potential of all-oral regimens with sofosbuvir (GS-7977). Recent interim analyses indicate that many patients treated with only 2 direct-acting antiviral agents experience viral breakthrough, which can be significantly reduced by the addition of ribavirin without pegylated interferon α.

Topics: Cytidine; Deoxycytidine; Drugs, Investigational; Enzyme Inhibitors; Hepacivirus; Hepatitis C; Humans; Protein Conformation; RNA-Dependent RNA Polymerase; Sofosbuvir; Uridine Monophosphate; Viral Nonstructural Proteins

This article introduces one of the most diverse classes of direct-acting antivirals for hepatitis C, the nucleoside and non-nucleoside NS5B polymerase inhibitors. Through a systematic review of the published literature, we describe their structure, mechanism of action, issues with resistance, and clinical effectiveness shown in the latest clinical trials. Direct-acting antiviral combination trials that have already shown some early promising results even in the setting of interferon-sparing antiviral regimens are discussed.

Topics: Antiviral Agents; Clinical Trials as Topic; Deoxycytidine; Guanosine Monophosphate; Hepatitis C; Humans; Sofosbuvir; Uridine Monophosphate; Viral Nonstructural Proteins

Safety and tolerability of peginterferon-based hepatitis C virus (HCV) infection therapy remains suboptimal, even when direct-acting antiviral agents are added. This study assessed the efficacy, safety and tolerability of mericitabine combined with ritonavir-boosted danoprevir (danoprevir/r) ± ribavirin for up to 24 weeks in treatment-naïve HCV genotype (G)1 infected patients.. Patients received twice daily mericitabine (1000 mg) and danoprevir/r (100 mg/100 mg) plus either ribavirin (1000/1200 mg/day; Arm A) or placebo (Arm B) for 12 or 24 weeks. Patients with HCV RNA <43 IU/ml between Weeks 2 and 8 and HCV RNA <15 IU/ml at Week 10 were rerandomized (1:1) at Week 12 to discontinue/continue assigned regimens until Week 24. Because of unacceptable relapse rates in both 12-week arms and in ribavirin-free Arm B, treatment was extended to 24 weeks and patients in Arm B received peginterferon alfa-2a/ribavirin. The primary outcome was sustained virological response 24 weeks after end of treatment (SVR24).. In Arm A, the SVR24 rate in patients receiving 24 weeks of therapy was 37.9% (25/66); 63.6% (14/22) in G1b and 25.0% (11/44) in G1a patients. Virologic breakthrough and relapse were associated with danoprevir-resistant virus in most cases. The mericitabine-resistance mutation (NS5BS282T) was detected in two patients bearing dual resistant virus NS3 R155K/NS5B S282T and dual resistance mutation L159F/L320F in one patient. Treatment was safe and well tolerated.. Mericitabine, danoprevir/r plus ribavirin for 24 weeks were safe and well tolerated. However, SVR rates were poor, achieving rates of only 25.0% in G1a and 63.6% in G1b patients.

Topics: Adult; Aged; Cyclopropanes; Deoxycytidine; Electrocardiography; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Isoindoles; Lactams; Lactams, Macrocyclic; Male; Middle Aged; Proline; Ribavirin; Ritonavir; RNA, Viral; Sulfonamides

Mericitabine (RG7128) is a nucleoside polymerase inhibitor (NPI), which requires intracellular uptake and phosphorylation to two active triphosphates. Mathematical modeling has provided important insights for characterizing hepatitis C virus (HCV) RNA decline and estimating in vivo effectiveness of antiviral agents; however, it has not been used to characterize viral kinetics with NPIs. HCV RNA was frequently measured in 32 treatment-experienced patients infected with HCV genotype 1 during and after mericitabine monotherapy for 14 days with 750 mg or 1500 mg administered once (qd) or twice daily (bid). The initial decline of HCV RNA was typically slower than with interferon-α or protease inhibitors, and 12 patients presented a novel pattern of HCV RNA kinetics characterized by a monophasic viral decline. Viral kinetics could be well fitted by assuming that the effectiveness in blocking viral production gradually increased over time to reach its final value, ε(2), consistent with previous accumulation time estimates of intracellular triphosphates. ε(2) was high with bid dosing (mean 750 mg and 1500 mg: 98.0% and 99.8%, respectively; P = 0.018) and significantly higher than in patients treated qd (mean qd versus bid: 90% versus 99%, P < 10(-7)). Virus rebounded rapidly upon drug discontinuation, which was attributed to the elimination of active drug and the subsequent decline of drug effectiveness, with mean t(1/2) = 13.9 hours in the bid regimens.. The observed slower initial decline likely represents the time needed to accumulate intracellular triphosphates and is consistent with in vitro data. When administered bid, mericitabine reached a high, dose-dependent, final effectiveness in blocking viral production that rapidly dropped upon treatment cessation. Understanding HCV RNA kinetics with mericitabine could provide valuable insights for combining it with other direct-acting antiviral agents.

Topics: Antiviral Agents; Deoxycytidine; Dideoxynucleotides; Dose-Response Relationship, Drug; Enzyme Inhibitors; Genotype; Hepacivirus; Hepatitis C; Humans; Models, Theoretical; RNA, Viral; Time Factors; Treatment Outcome; Viral Load; Virus Replication

Two isomeric series of new thieno-fused 7-deazapurine ribonucleosides (derived from 4-substituted thieno[2',3':4,5]pyrrolo[2,3-d]pyrimidines and thieno[3',2':4,5]pyrrolo[2,3-d]pyrimidines) were synthesized by a sequence involving Negishi coupling of 4,6-dichloropyrimidine with iodothiophenes, nucleophilic azidation, and cyclization of tetrazolopyrimidines, followed by glycosylation and cross-couplings or nucleophilic substitutions at position 4. Most nucleosides (from both isomeric series) exerted low micromolar or submicromolar in vitro cytostatic activities against a broad panel of cancer and leukemia cell lines and some antiviral activity against HCV. The most active were the 6-methoxy, 6-methylsulfanyl, and 6-methyl derivatives, which were highly active to cancer cells and less toxic or nontoxic to fibroblasts.

Topics: Antineoplastic Agents; Antiviral Agents; Cell Line, Tumor; Hepacivirus; Hepatitis C; Humans; Neoplasms; Purines; Ribonucleosides

RG7128 is a di-ester prodrug of a cytidine analog for the treatment of hepatitis C virus (HCV) infection. The structures of nine low level impurities (0.05-0.10%) in RG7128 drug substance were elucidated. The majority of the impurities were formed during the synthesis of the prodrug from the parent drug. Structural elucidations of the impurities were achieved either by enrichment of the impurities using preparative chromatography followed by spectroscopic techniques or by confirmation with a reference sample. Heart-cut and recycle chromatographic techniques were applied to purify closely eluting isomers of RG7128.

Topics: Antiviral Agents; Chromatography, High Pressure Liquid; Deoxycytidine; Drug Contamination; Esters; Hepatitis C; Magnetic Resonance Spectroscopy; RNA-Dependent RNA Polymerase; Spectrometry, Mass, Electrospray Ionization

The application of a phosphoramidate prodrug approach to 2'-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2'-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2'-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.

Topics: Amides; Animals; Antiviral Agents; Cell Line; Cytidine; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Phosphoric Acids; Polyphosphates; Prodrugs; Structure-Activity Relationship; Virus Replication