mk-7009 and Hepatitis-C--Chronic

The current standard of care for patients with chronic hepatitis C virus (HCV) infection is pegylated interferon alfa in combination with ribavirin. Treatment duration and efficacy depend heavily on HCV genotype. A sustained virologic response (SVR) is achieved only in approximately 40% of patients. Side effects of the current standard of care often make adherence to therapy difficult, further reducing the chance for an SVR. Numerous patient-related and virus-related factors can determine response to treatment. Nonresponders are a large proportion of the current HCV-infected population, and the number of patients with HCV infection is growing, necessitating newer therapies with higher efficacy and potentially fewer side effects. A new era of direct acting antiviral (DAA) compounds has emerged. The first 2 protease inhibitors for HCV infection, telaprevir and boceprevir, are coming to market in 2011. Other protease compounds in development include TMC-435, vaniprevir, BI-201335, BMS-650032, and danoprevir. The numerous other therapies that have potential in the treatment of HCV infection include nucleoside inhibitors, non-nucleoside inhibitors, NS5A inhibitors, DAA combinations, therapeutic vaccines, human monoclonal antibodies, immune modifiers, and interferon lambda.

Topics: Aminoisobutyric Acids; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Indoles; Isoindoles; Lactams; Lactams, Macrocyclic; Leucine; Oligopeptides; Proline; Quinolines; Simeprevir; Sulfonamides; Thiazoles; Treatment Outcome; Viral Load; Virus Replication

Fine-needle aspiration (FNA) for serial hepatic sampling may be an efficient and less invasive alternative to core needle biopsy (CNB), the current standard for liver tissue sampling. In this randomized, open-label trial in 31 participants with hepatitis C virus genotype 1 infection (NCT01678131/Merck protocol PN048), we evaluated the feasibility of using FNA to obtain human liver tissue samples appropriate for measuring hepatic pharmacokinetics (PK), using vaniprevir as a tool compound. The primary end point was successful retrieval of liver tissue specimens with measurable vaniprevir concentrations at two of three specified FNA time points. Twenty-nine patients met the primary end point and, therefore, were included in the PK analyses. Hepatic vaniprevir concentrations obtained with FNA were consistent with known vaniprevir PK properties. The shape of liver FNA and CNB concentration-time profiles were comparable. In conclusion, FNA may be effective for serial tissue sampling to assess hepatic drug exposure in patients with liver disease.

Topics: Adult; Antiviral Agents; Biopsy, Fine-Needle; Cyclopropanes; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Isoindoles; Lactams, Macrocyclic; Leucine; Liver; Male; Middle Aged; Proline; Sulfonamides; Tissue Distribution; Young Adult

Vaniprevir is a potent macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. This phase III study evaluated the safety and efficacy of vaniprevir in combination with peginterferon alfa-2b and ribavirin (PR) for 24 weeks compared with PR alone for 48 weeks in treatment-naive Japanese patients with HCV genotype 1 infection.. Treatment-naive Japanese patients with HCV genotype 1 infection were randomly assigned to receive vaniprevir (300 mg twice daily) plus PR for 12 weeks then PR alone for 12 weeks, vaniprevir (300 mg twice daily) plus PR for 24 weeks, or PR alone for 48 weeks. The primary end point was sustained virologic response 24 weeks after completion of treatment (SVR24).. In total, 294 patients were randomly assigned to receive treatment. Most patients had HCV genotype 1b infection (98 %, 288 of 294 patients). SVR24 was achieved in 83.7, 84.5, and 55.1 % of the patients in the vaniprevir 12-week, vaniprevir 24-week, and control arms, respectively. The difference in SVR24 rates between each vaniprevir arm and the control arm was statistically significant (p < 0.001 for both). Relapse was commoner in the control arm (29.5 %) than in the vaniprevir arms (8.6 % and 10.5 % for the 12-week and 24-week arms, respectively). Commonly reported adverse events were generally similar across treatment arms, with the exception of an increase in the incidence of gastrointestinal adverse events such as nausea, diarrhea, and vomiting in patients receiving vaniprevir. These events were considered manageable.. Vaniprevir is a valuable addition to the therapeutic options available to Japanese patients with HCV genotype 1 infection who are eligible for interferon-based treatment. CLINICALTRIALS.. NCT01370642.

Topics: Adult; Aged; Antiviral Agents; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Interferon alpha-2; Interferon-alpha; Isoindoles; Japan; Lactams, Macrocyclic; Leucine; Male; Middle Aged; Polyethylene Glycols; Proline; Recombinant Proteins; Recurrence; Ribavirin; Sulfonamides; Treatment Outcome; Young Adult

Vaniprevir is a macrocyclic hepatitis C virus (HCV) non-structural (NS)3/4A protease inhibitor. The objective of these phase 3 multicenter, open-label trials was to evaluate the safety and efficacy of vaniprevir + peginterferon alfa-2b + ribavirin (PR) in Japanese patients with HCV genotype (GT)1 infection who had previously failed treatment with interferon-based regimens.. Japanese patients with chronic HCV GT1 were enrolled. In PN044, patients with previous relapse or virologic breakthrough were randomized to vaniprevir (300 mg twice daily) + PR for 12 weeks followed by PR for another 12 weeks (12-week arm) or vaniprevir + PR for 24 weeks (24-week arm). In PN045, patients with previous partial/null response received vaniprevir + PR for 24 weeks. The primary endpoint was sustained virologic response at 24 weeks after completing treatment (SVR. Vaniprevir + PR is an effective, well-tolerated treatment for Japanese patients with HCV GT1 infection who failed previous interferon-based treatment. ClinicalTrials.gov Identifier NCT01405937 and NCT01405560 (Protocols PN044 and PN045).

Topics: Adult; Aged; Antiviral Agents; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Interferon alpha-2; Interferon-alpha; Isoindoles; Lactams, Macrocyclic; Leucine; Male; Medication Adherence; Middle Aged; Polyethylene Glycols; Proline; Recombinant Proteins; Recurrence; Ribavirin; RNA, Viral; Sulfonamides; Viral Load; Young Adult

The restoration of innate immune responses has potential as a novel therapeutic strategy for chronic hepatitis C (CHC). We compared the efficacy and safety of induction therapy (IT) with natural interferon-β (n-IFN-β) followed by pegylated-IFN-α/ribavirin (PR) alone (group A, n = 30) and IT with a protease inhibitor (PI) (simeprevir or vaniprevir)/PR (group B, n = 13) in CHC patients with genotype 1b and high viral loads. During IT with nIFN-β, virologic response rates in group A and group B were 10% and 8% (p = 0.6792) at week 4, 30% and 16% (p = 0.6989) at week 12 and 47% and 20% (p = 0.0887) at week 24 respectively. During and after the treatment with PR alone or PI/PR, virologic response rates in groups A and B were 50% and 82% (p = 0.01535) at week 4, 53% and 91% (p = 0.006745) at week 8, 57% and 91% (p = 0.001126) at week 12, 57% and 100% (p < 0.001845) at the end of the treatment and 57% and 80% (p < 0.005166) after treatment cessation. IT with PI/PR linked to the restoration of innate immune response was tolerated well, overcame virological breakthrough, enhanced early virologic responses, and resulted in a sustained virologic response in difficult-to-treat CHC patients. IT with PI/PR is beneficial for treating difficult-to-treat CHC patients.

Topics: Aged; Antiviral Agents; Cyclopropanes; Drug Administration Schedule; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Interferon-beta; Isoindoles; Lactams, Macrocyclic; Leucine; Male; Middle Aged; Polyethylene Glycols; Proline; Protease Inhibitors; Ribavirin; Simeprevir; Sulfonamides

Vaniprevir (MK-7009) is a hepatitis C virus (HCV) non-structural 3/4a protease inhibitor which significantly increases virologic response rates in HCV genotype (GT) 1-infected patients when added to peginterferon and ribavirin (PR).. This was a phase II, multicenter, double-blind, randomized, dose-ranging study in Japanese patients with HCV GT1 infection and previous relapse. Patients received twice daily vaniprevir 100, 300, or 600 mg, or placebo plus PR for 4 weeks then PR alone for 2 weeks. Further treatment with PR was continued up to a maximum of 72 weeks. The primary endpoint was rapid virologic response (RVR; undetectable HCV RNA at treatment week 4).. Ninety patients completed 4 weeks of vaniprevir/placebo plus PR. Rates of RVR were significantly higher with vaniprevir compared with placebo (86, 95, and 76 % in the vaniprevir 100-, 300-, and 600-mg arms versus 20 % with control; p<0.001 for all comparisons). Rates of SVR, an exploratory analysis, in the vaniprevir 100-, 300-, 600-mg, and control arms were 95, 100, 100, and 72 %, respectively. No patient had virologic breakthrough or non-response while receiving vaniprevir. There were no serious adverse events (AEs) or discontinuations due to an AE during vaniprevir treatment. Diarrhea and nausea were more common with vaniprevir 600 mg than control or lower vaniprevir doses.. The addition of vaniprevir to PR was associated with an increase in RVR and SVR. Combined with a generally safe and well-tolerated profile, these data supported the further evaluation of vaniprevir in Japanese patients with HCV GT1 infection (#NCT00880763).

Topics: Adult; Antiviral Agents; Cyclopropanes; Dose-Response Relationship, Drug; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Interferon-alpha; Isoindoles; Lactams, Macrocyclic; Leucine; Male; Middle Aged; Polyethylene Glycols; Proline; Recombinant Proteins; Ribavirin; RNA, Viral; Sulfonamides; Viral Load; Young Adult

Some drugs that are actively taken up into the liver exhibit greater than dose proportional increases in plasma exposure, although human liver-to-plasma concentration ratios have rarely been evaluated. Understanding these relationships has implications for drug concentrations at the target site for certain classes of compounds, such as direct-acting antivirals, targeted towards HCV.. Treatment-experienced, chronic HCV non-cirrhotic patients (n=3) received vaniprevir (600 mg or 300 mg twice daily) on days 1-3 and (600 mg or 300 mg single dose) on day 4. Core needle biopsy was performed at 6 or 12 h post-dose on day 4. Blood samples were collected pre-dose on days 1 and 4, and for 24 h post-dose on day 4. The primary study objective was the hepatic concentration of vaniprevir at 6 and 12 h post-dose.. Vaniprevir plasma pharmacokinetic parameters increased in a greater than dose-proportional manner between the 300 mg and 600 mg doses, with approximately fivefold increases in AUC0-12 and Cmax associated with a twofold increase in dose (AUC0-12, 10.6 μM/h to 59.5 μM/h; Cmax, 2.60 μM to 13.5 μM). In the 300 mg and 600 mg dose groups, mean liver concentrations of vaniprevir were 84.6 μM and 169 μM at 6 h post-dose, and 29.4 μM and 53.7 μM at 12 h post-dose. Liver concentrations were higher than plasma with liver-to-plasma concentration ratios of approximately 20-280.. These data confirm higher vaniprevir concentrations in human liver compared with plasma and demonstrate that measurement of human liver drug concentration using needle biopsy is feasible.

Topics: Administration, Oral; Adult; Aged; Antiviral Agents; Biopsy; Cyclopropanes; Drug Monitoring; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Isoindoles; Lactams, Macrocyclic; Leucine; Liver; Liver Cirrhosis; Male; Middle Aged; Proline; Sulfonamides

The combination of vaniprevir (a NS3/4A protease inhibitor) with peginterferon and ribavirin was shown to increase rates of sustained virologic response (SVR) significantly, compared with peginterferon and ribavirin alone, in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection without cirrhosis. We performed a blinded, randomized, controlled trial of the effects of vaniprevir with peginterferon and ribavirin in patients with cirrhosis who did not respond to prior therapy with peginterferon and ribavirin.. Treatment-experienced patients (88% white and 35% prior null responders) with HCV genotype 1 infection and compensated cirrhosis were assigned randomly to groups given vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 24 weeks (n = 16), vaniprevir (600 mg twice daily) for 24 weeks with peginterferon and ribavirin for 48 weeks (n = 14), vaniprevir (300 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), vaniprevir (600 mg twice daily) with peginterferon and ribavirin for 48 weeks (n = 15), or placebo with peginterferon and ribavirin for 48 weeks (n = 14, control). Cirrhosis was documented by liver biopsy (84%) or noninvasive methods (16%). Before randomization, participants were stratified based on their historical response to peginterferon and ribavirin.. In the primary analysis, SVR rates among patients in the respective vaniprevir groups were 9 of 15 (60.0%), 9 of 13 (69.2%), 8 of 15 (53.3%), and 10 of 13 (76.9%), compared with 2 of 14 (14.3%) in the control group (pairwise P values ≤ .016). Cirrhotic patients with null or partial responses to prior therapy achieved SVR less often than patients with prior breakthrough or relapse, although 42.1% of prior null responders in the vaniprevir groups achieved SVRs. Patients in the vaniprevir groups more frequently experienced mild-moderate nausea, vomiting, and diarrhea than controls; 5% developed grade 2 anemia compared with none in the control group (no patient developed grade 3 or 4 anemia). Among patients in the vaniprevir groups who experienced virologic failure, resistance-associated variants were detected predominantly at positions 155, 156, and 168 in the HCV protease gene.. In a controlled phase 2B trial, vaniprevir with peginterferon and ribavirin significantly increased rates of SVR among treatment-experienced patients with chronic HCV genotype 1 infection, compared with re-treatment with peginterferon and ribavirin alone. Vaniprevir generally was well tolerated for up to 48 weeks in patients with compensated cirrhosis. ClinicalTrials.gov number, NCT00704405.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Interferon-alpha; Isoindoles; Lactams, Macrocyclic; Leucine; Liver Cirrhosis; Male; Middle Aged; Placebos; Proline; Ribavirin; Sulfonamides; Treatment Outcome; Viral Load; Young Adult

MK-7009 (vaniprevir) is a non-covalent competitive inhibitor of the hepatitis C virus (HCV) NS3/4A protease. This report presents the primary analysis results (safety and sustained viral response) of a phase 2b study of MK-7009 given in combination with peginterferon (PegIFN) alfa2a 180 μg weekly and ribavirin (RBV) 1000-1200 mg/day, for 24-48 weeks to non-cirrhotic patients who have failed previous PegIFN and RBV treatment.. We present results of a randomized, placebo-controlled, double-blind study of MK-7009 administered for 24-48 weeks in combination with PegIFN and RBV in 4 regimens to at least 40 patients per arm. Stratification by prior response to PegIFN and RBV was as follows: null response, partial response, breakthrough and relapse. HCV RNA was determined by Roche Cobas Taqman with a lower limit of detection (LLoD) of 10 IU/ml and a lower limit of quantification (LLoQ) of 25 IU/ml.. SVR24 in patients on MK-7009+PegIFN and ribavirin (P/R) was statistically superior to placebo+P/R in all treatment groups (p<0.001). MK-7009 at 300 mg b.i.d. and 600 mg b.i.d. is generally well tolerated for use for up to 48 weeks of therapy. Patients in MK-7009 regimens had higher rates of gastrointestinal adverse events as compared to control (mostly mild to moderate). There were no significant differences in rates of anemia and rash between the MK-7009 regimens and control.. In conclusion, patients treated with MK-7009 plus P/R experienced significant improvement in SVR compared to P/R control in a population of GT 1 experienced patients.

Topics: Adult; Aged; Antiviral Agents; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Interferon-alpha; Isoindoles; Lactams, Macrocyclic; Leucine; Male; Middle Aged; Polyethylene Glycols; Proline; Protease Inhibitors; Recombinant Proteins; Ribavirin; Sulfonamides; Viral Load; Viral Nonstructural Proteins; Young Adult

Vaniprevir with P/R improved SVR rates over P/R alone in treatment-experienced patients with chronic HCV-genotype 1 infection, but treatment failure presents therapeutic challenges. We identified RAVs from non-cirrhotic patients failing to achieve SVR on vaniprevir-containing regimens from a dose/duration-ranging trial of triple-combination therapy.. Using population analysis, resistance sequencing was performed on all baseline samples and on samples at virologic failure in the vaniprevir arms. Longitudinal clonal analyses were performed on viral isolates from six vaniprevir recipients experiencing breakthrough viremia.. Baseline RAVs were detected in two patients subsequently experiencing virologic failure. At virologic failure, the majority of RAVs had substitutions at R155, A156, or D168. Clonal analyses identified novel double/triple variants emerging with continuing vaniprevir dosing.. RAVs were predominantly observed at R155, A156, and/or D168 during virologic failure on vaniprevir/P/R. Double/triple RAVs were identified in patients remaining viremic on triple therapy, suggesting evolution of resistance under selective pressure.

Topics: Adolescent; Adult; Aged; Amino Acid Substitution; Antiviral Agents; Cyclopropanes; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; Genetic Variation; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Indoles; Isoindoles; Lactams, Macrocyclic; Leucine; Male; Middle Aged; Peptide Hydrolases; Polyethylene Glycols; Proline; Ribavirin; RNA, Viral; Sulfonamides; Treatment Failure; Treatment Outcome; Viremia; Young Adult

Vaniprevir (MK-7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha-2a (Peg-IFN-α-2a) plus ribavirin (RBV). In this double-blind, placebo-controlled, dose-ranging study, treatment-naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open-label Peg-IFN-α-2a (180 μg/week) and RBV (1,000-1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice-daily [BID], 600 mg BID, 600 mg once-daily [QD], or 800 mg QD) for 28 days, then open-label Peg-IFN-α-2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two-phase decline in viral load, with HCV RNA levels approximately 3 log(10) IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%-83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin-28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses.. Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration.

Topics: Adult; Aged; Antiviral Agents; Cyclopropanes; Double-Blind Method; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Indoles; Interferon-alpha; Isoindoles; Lactams, Macrocyclic; Leucine; Middle Aged; Polyethylene Glycols; Proline; Recombinant Proteins; Ribavirin; Sulfonamides; Young Adult

Topics: Clinical Trials as Topic; Cyclopropanes; Drug Combinations; Drug Resistance, Viral; Hepatitis C, Chronic; Humans; Indoles; Interferons; Isoindoles; Lactams, Macrocyclic; Leucine; Proline; Ribavirin; Sulfonamides

Efforts to develop novel, interferon-sparing therapies for treatment of chronic hepatitis C (HCV) infection are contingent on the ability of combination therapies consisting of direct antiviral inhibitors to achieve a sustained virologic response. This work demonstrates a proof of concept that coadministration of the nucleoside analogue MK-0608 with the protease inhibitor MK-7009, both of which produced robust viral load declines as monotherapy, to an HCV-infected chimpanzee can achieve a cure of infection.

Topics: Animals; Antiviral Agents; Cyclopropanes; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Indoles; Isoindoles; Lactams, Macrocyclic; Leucine; Pan troglodytes; Proline; Protease Inhibitors; Sulfonamides; Treatment Outcome; Tubercidin; Viral Load; Viral Nonstructural Proteins