rg-7128 and danoprevir

Setrobuvir is a direct-acting antiviral (DAA) non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study examined interferon-free combinations containing setrobuvir, a ritonavir-boosted protease inhibitor (danoprevir/r) and ribavirin, with/without the nucleoside inhibitor mericitabine in HCV genotype (G)1 patients.. Non-cirrhotic treatment-naïve patients (N = 110) were randomized to five groups. Three groups received a 14-day mericitabine/ribavirin lead-in followed by treatment with 3 DAAs (setrobuvir, danoprevir/r, mericitabine) plus ribavirin for 12 weeks (Group A: G1a; D: G1b) or 24 weeks (B: G1a), and two groups received 2 DAAs (setrobuvir, danoprevir/r) plus ribavirin for 12 weeks (E: G1b) or 24 weeks (C: G1a). Efficacy was defined as sustained virological response (HCV RNA <25 IU/ml after 12 weeks' follow-up, SVR12).. Two groups met predefined futility criteria for breakthrough (C) or relapse (A) and were discontinued. SVR12 rates were 42.9% (3/7) and 74.1% (20/27) in G1a patients in Groups A and B, respectively, and 95.7% (22/23) and 68.2% (15/22) in G1b patients in Groups D and E respectively. All G1a patients assigned to 24 weeks of treatment who experienced a decrease in HCV RNA of ≥2.3 log10 IU by the end of the lead-in period (n = 28) achieved SVR12. Overall, treatment was well tolerated and most adverse events were mild to moderate. No major safety signals were identified.. An interferon-free setrobuvir-based regimen (3 DAAs plus ribavirin) is safe and effective in treatment-naïve G1 patients.

Topics: Adult; Antiviral Agents; Australia; Benzothiadiazines; Cyclopropanes; Deoxycytidine; Drug Therapy, Combination; Europe; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Isoindoles; Lactams; Lactams, Macrocyclic; Male; Middle Aged; New Zealand; Phenotype; Proline; Quinolones; Remission Induction; Ribavirin; RNA, Viral; Sulfonamides; Time Factors; Treatment Outcome; United States; Viral Load

Modelling HCV RNA decline kinetics under therapy has proven useful for characterizing treatment effectiveness.. Here we model HCV viral kinetics (VK) in 72 patients given a combination of danoprevir, a protease inhibitor, and mericitabine, a nucleoside polymerase inhibitor, for 14 days in the INFORM-1 trial. A biphasic VK model with time-varying danoprevir and mericitabine effectiveness and Bliss independence for characterizing the interaction between both drugs provided the best fit to the VK data.. The average final antiviral effectiveness of the drug combination varied between 0.998 for 100 mg three times daily of danoprevir and 500 mg twice daily of mericitabine and 0.9998 for 600 mg twice daily of danoprevir and 1,000 mg twice daily of mericitabine. Using the individual parameters estimated from the VK data collected over 2 weeks, we were not able to reproduce the low sustained virological response rates obtained in a more recent study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir for 24 weeks.. This suggests that drug-resistant viruses emerge after 2 weeks of treatment and that longer studies are necessary to provide accurate predictions of longer treatment outcomes.

Topics: Antiviral Agents; Cyclopropanes; Deoxycytidine; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Isoindoles; Lactams; Lactams, Macrocyclic; Models, Biological; Proline; RNA, Viral; Sulfonamides; Viral Load

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

Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct-acting antivirals.. We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a Phase I study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naive and 8 were non-responders to prior pegylated IFN-α/ribavirin treatment.. In all patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg twice daily) and 0.99 at the highest dose (200 mg three times daily). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg twice daily). The second phase decline showed two different behaviours, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 day(-1)), whereas the viral decline was slower in the other patients.. Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.

Topics: Antiviral Agents; Cyclopropanes; Deoxycytidine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon-alpha; Isoindoles; Lactams; Lactams, Macrocyclic; Models, Theoretical; Polyethylene Glycols; Proline; Protease Inhibitors; Recombinant Proteins; Ribavirin; Sulfonamides; Treatment Outcome; Viral Load; Viral Nonstructural Proteins

Baseline and posttreatment samples from hepatitis C virus (HCV) genotype (GT) 1-infected patients who received a combination of danoprevir and mericitabine from a phase II clinical study (INFORM-SVR) were analyzed. In addition to resistance monitoring, sequencing and phenotypic assays were combined with statistical analysis to identify potential novel amino acid substitutions associated with treatment outcome. The NS5B S282T substitution associated with mericitabine resistance was identified in 2/30 viral breakthrough patients and was replaced by wild-type viruses after cessation of drug treatment (during follow-up). The NS3 R155K substitution associated with danoprevir resistance was also observed in these 2 patients. All 69 GT 1a-infected patients who experienced viral breakthrough on treatment or relapsed during follow-up (relapsers) developed NS3 R155K. Among GT 1b-infected patients, substitutions at the danoprevir resistance locus NS3 D168 were observed in 15/20 subjects, whereas substitutions at the danoprevir resistance locus NS3 R155 were observed in 5/20 subjects. Interestingly, the baseline polymorphism NS5B Q47H was more prevalent in GT 1a-infected patients who achieved a sustained virologic response at follow-up week 24 (SVR24) than in non-SVR24 patients (2/13 versus 0/72), and a postbaseline NS3 S122G substitution was more prevalent in GT 1a-infected patients with viral breakthrough than in relapsers (4/22 versus 0/47). Neither substitution conferred resistance to danoprevir or mericitabine, but the substitutions reduced (NS5B Q47H) or improved (NS3 S122G) replication capacity by 2- to 4-fold. The NS5B S282T mericitabine-resistant variant was rare and did not persist once drug was discontinued. NS5B Q47H and NS3 S122G are two newly identified substitutions that affected replication capacity and were enriched in distinct treatment response groups. (This study has been registered at ClinicalTrials.gov under registration no. NCT01278134.).

Topics: Adult; Amino Acid Substitution; Antiviral Agents; Base Sequence; Cyclopropanes; Deoxycytidine; DNA Replication; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Isoindoles; Lactams; Lactams, Macrocyclic; Male; Middle Aged; Molecular Sequence Data; Mutation; Phenotype; Proline; RNA, Viral; Sequence Analysis, DNA; Sulfonamides; Viral Nonstructural Proteins

Although interleukin 28B (interferon, lambda 3) (IL28B) genotype affects the response of patients with chronic hepatitis C to peginterferon and ribavirin, little is known regarding its effect on response to direct-acting antivirals in interferon-free combinations. We analyzed the effects of IL28B genotype on the viral kinetic (VK) response to an interferon-free combination of the nucleoside polymerase inhibitor mericitabine (RG7128) and the hepatitis C virus (HCV) protease inhibitor danoprevir.. We performed a double-blind, dose-escalation study of patients with chronic HCV genotype 1 infection who were interferon treatment naive or had not responded to previous therapy with peginterferon and ribavirin. Patients were sequentially assigned to 1 of 7 cohorts then randomly assigned to groups that received up to 13 days of treatment with mericitabine (500 or 1000 mg, twice daily) plus danoprevir (100 or 200 mg, every 8 hours, or 600 or 900 mg, twice daily) or placebo. Eighty-three of 87 patients were genotyped for the IL28B single-nucleotide polymorphism rs12979860. VKs were analyzed only in patients who received 13 days of treatment, at optimal doses, using a biphasic model to describe first- and second-phase slopes of viral decay during therapy.. At day 14 (the end of interferon-free treatment), the mean reduction in the serum level of HCV RNA was slightly greater in patients with the CC polymorphism (5.01 log(10) IU/mL) than those without (4.59 log(10) IU/mL). Modeling revealed that patients with the CC polymorphism had slightly better early VKs, most apparent in the β-phase of viral decay. A mixed effect on the α-phase was observed, which was reduced in magnitude but prolonged in patients with CC, who also had better on-treatment response to peginterferon and ribavirin during follow up.. IL28B genotype appears to affect early VKs in patients with chronic hepatitis C receiving interferon-free treatment.

Topics: Antiviral Agents; Australia; Cyclopropanes; Deoxycytidine; Double-Blind Method; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Interleukins; Isoindoles; Kinetics; Lactams; Lactams, Macrocyclic; Models, Biological; Models, Statistical; New Zealand; Phenotype; Polymorphism, Single Nucleotide; Proline; RNA, Viral; Sulfonamides; Treatment Outcome; Viral Load; Virus Replication

In the INFORM-1 study, 73 patients with chronic hepatitis C virus infection received mericitabine plus danoprevir for up to 13 days. Seventy-two patients experienced a continuous decline in HCV RNA levels during treatment, and of these patients, 14 had viral loads that remained >1,000 IU/ml by day 13 and 1 met the definition for viral breakthrough. In-depth NS5B and NS3/4A population and clonal sequencing studies and mericitabine and danoprevir drug susceptibility testing were performed to assess the variability and quasispecies dynamics before and upon monotherapy or dual therapy. Sequence analysis of the viral quasispecies indicated that the mericitabine resistance mutation S282T was not present at baseline, nor was it selected (even at a low level) during treatment. Protease inhibitor resistance mutations, either as predominant or as minority species, were detected in 18 patients at baseline. No enrichment of minority protease inhibitor-resistant variants present at baseline was observed during treatment; viral population samples were fully susceptible to mericitabine and/or danoprevir, despite the presence within their quasispecies of minority variants confirmed to have reduced susceptibility to danoprevir or other protease inhibitors. It was also observed that certain NS3 amino acid substitutions affected protease inhibitor drug susceptibility in a compound-specific manner and varied with the genetic context. In summary, the slower kinetics of viral load decline observed in some patients was not due to the selection of danoprevir or mericitabine resistance during treatment. Over 2 weeks' therapy, mericitabine suppressed the selection of danoprevir resistance, results that could differ upon longer treatment periods.

Topics: Adult; Antiviral Agents; Cyclopropanes; Deoxycytidine; Double-Blind Method; Drug Administration Schedule; Drug Resistance, Viral; Drug Therapy, Combination; Enzyme Inhibitors; Hepacivirus; Hepatitis C, Chronic; Humans; Isoindoles; Lactams; Lactams, Macrocyclic; Mutation; Placebos; Proline; RNA, Viral; Sulfonamides; Viral Load; Viral Nonstructural Proteins

Present interferon-based standard of care treatment for chronic hepatitis C virus (HCV) infection is limited by both efficacy and tolerability. We assessed the safety, tolerability, and antiviral activity of an all-oral combination treatment with two experimental anti-HCV drugs-RG7128, a nucleoside polymerase inhibitor; and danoprevir, an NS3/4A protease inhibitor-in patients with chronic HCV infection.. Patients from six centres in New Zealand and Australia who were chronically infected with HCV genotype 1 received up to 13 days oral combination treatment with RG7128 (500 mg or 1000 mg twice daily) and danoprevir (100 mg or 200 mg every 8 h or 600 mg or 900 mg twice daily) or placebo. Eligible patients were sequentially enrolled into one of seven treatment cohorts and were randomly assigned by interactive voice or web response system to either active treatment or placebo. Patients were separately randomly assigned within each cohort with a block size that reflected the number of patients in the cohort and the ratio of treatment to placebo. The random allocation schedule was computer generated. Dose escalation was started in HCV treatment-naive patients; standard of care treatment-experienced patients, including previous null responders, were enrolled in higher-dose danoprevir cohorts. Investigators, personnel at the study centre, and patients were masked to treatment allocation. However, the pharmacist who prepared the doses, personnel involved in pharmacokinetic sample analyses, statisticians who prepared data summaries, and the clinical pharmacologists who reviewed the data before deciding to initiate dosing in the next cohort were not masked to treatment allocation. The primary outcome was change in HCV RNA concentration from baseline to day 14 in patients who received 13 days of combination treatment. All patients who completed treatment with the study drugs were included in the analyses. This study is registered with ClinicalTrials.gov, NCT00801255.. 88 patients were randomly assigned to a study drug treatment regimen (n=74 over seven treatment groups; 73 received at least one dose of study drug) or to placebo (n=14, all of whom received at least one dose). The median change in HCV RNA concentration from baseline to day 14 ranged from -3·7 to -5·2 log(10) IU/mL in the cohorts that received 13 days of combination treatment. At the highest combination doses tested (1000 mg RG7128 and 900 mg danoprevir twice daily), the median change in HCV RNA concentration from baseline to day 14 was -5·1 log(10) IU/mL (IQR -5·6 to -4·7) in treatment-naive patients and -4·9 log(10) IU/mL in previous standard of care null responders (-5·2 to -4·5) compared with an increase of 0·1 log(10) IU/mL in the placebo group. The combination of RG7128 and danoprevir was well tolerated with no treatment-related serious or severe adverse events, no grade 3 or 4 changes in laboratory parameters, and no safety-related treatment discontinuations.. This oral combination of a nucleoside analogue polymerase inhibitor and protease inhibitor holds promise as an interferon-free treatment for chronic HCV.. Roche Palo Alto.

Topics: Administration, Oral; Adult; Antiviral Agents; Cyclopropanes; Deoxycytidine; Double-Blind Method; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Isoindoles; Lactams; Lactams, Macrocyclic; Male; Middle Aged; Polyethylene Glycols; Proline; Recombinant Proteins; RNA, Viral; Sulfonamides; Viral Nonstructural Proteins

Topics: Administration, Oral; Antiviral Agents; Cyclopropanes; Deoxycytidine; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Humans; Isoindoles; Lactams; Lactams, Macrocyclic; Proline; Sulfonamides; Viral Nonstructural Proteins