The Experts below are selected from a list of 72 Experts worldwide ranked by ideXlab platform
H W Reesink - One of the best experts on this subject based on the ideXlab platform.
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Miravirsen dosing in chronic hepatitis c patients results in decreased microrna 122 levels without affecting other micrornas in plasma
Alimentary Pharmacology & Therapeutics, 2016Co-Authors: M H Van Der Ree, Harry L.a. Janssen, A J Van Der Meer, A C Van Nuenen, J De Bruijne, S Ottosen, N A Kootstra, H W ReesinkAbstract:Summary Background MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus replication. Administration of Miravirsen, an anti-miR-122 oligonucleotide, resulted in a dose dependent and prolonged decrease in HCV RNA levels in chronic hepatitis C patients. Aim To assess the plasma level of various miRNAs in patients dosed with Miravirsen. Methods We included 16 of 36 chronic hepatitis C patients who received five injections of either 3 mg/kg (n = 4), 5 mg/kg (n = 4), 7 mg/kg (n = 4) Miravirsen or placebo (n = 4) over a 4-week period in a double-blind, randomised phase 2a study. Plasma levels of 179 miRNAs were determined by qPCR and compared between patients dosed with Miravirsen or placebo. Results Median plasma miR-122 level at baseline in patients receiving Miravirsen was 3.9 × 103 compared to 1.3 × 104 copies/4 μL in placebo-dosed patients (P = 0.68). At week 1, 4, 6 and 10/12, patients dosed with Miravirsen had respectively a median 72-fold, 174-fold, 1109-fold and 552-fold lower expression of miR-122 than at baseline (P = 0.001, as compared to patients receiving placebo). At week 4 of dosing, miRNA-profiling demonstrated a significant lower expression of miR-210 and miR-532-5p compared to baseline (3.0 and 4.7-fold lower respectively). However, subsequent longitudinal analysis showed no significant differences in miR-210 and miR-532-5p plasma levels throughout the study period. Conclusions We demonstrated a substantial and prolonged decrease in plasma miR-122 levels in patients dosed with Miravirsen. Plasma levels of other miRNAs were not significantly affected by antagonising miR-122.
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treatment of hcv infection by targeting microrna
The New England Journal of Medicine, 2013Co-Authors: Harry L.a. Janssen, H W Reesink, S Zeuzem, E Lawitz, M Rodrigueztorres, Keyur Patel, Adriaan J. Van Der Meer, Amy K Patick, Alice Chen, Yi ZhouAbstract:Background The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid–modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function. Methods In this phase 2a study at seven international sites, we evaluated the safety and efficacy of Miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of Miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization. Results Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the Miravirsen groups, the mean maximum reduction in HCV RNA level (log10 IU per milliliter) from baseline was 1.2 (P=...
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58 final results randomized double blind placebo controlled safety anti viral proof of concept study of Miravirsen an oligonucleotide targeting mir 122 in treatment naive patients with genotype 1 chronic hcv infection
Journal of Hepatology, 2012Co-Authors: H W Reesink, H L A Janssen, S Zeuzem, E Lawitz, M Rodrigueztorres, Keyur Patel, A Chen, C Davis, B King, Arthur A LevinAbstract:58 FINAL RESULTS – RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED SAFETY, ANTI-VIRAL PROOF-OF-CONCEPT STUDY OF Miravirsen, AN OLIGONUCLEOTIDE TARGETING MIR-122, IN TREATMENT-NAIVE PATIENTS WITH GENOTYPE 1 CHRONIC HCV INFECTION H.W. Reesink, H.L.A. Janssen, S. Zeuzem, E. Lawitz, M. Rodriguez-Torres, K. Patel, A. Chen, C. Davis, B. King, A. Levin, M.R. Hodges. Department of Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Medicine, J.W. Goethe University Hospital, Frankfurt/Main, Germany; Alamo Medical Research, San Antonio, TX, Fundacion de Investigacion, San Juan, PR, Duke University, Durham, NC, Santaris Pharma, San Diego, CA, USA E-mail: h.w.reesink@amc.nl
Harry L.a. Janssen - One of the best experts on this subject based on the ideXlab platform.
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inducing hepatitis c virus resistance after pig liver transplantation a proof of concept of liver graft modification using warm ex vivo perfusion
American Journal of Transplantation, 2017Co-Authors: Nicolas Goldaracena, Robert Persson, Harry L.a. Janssen, Vinzent N Spetzler, Juan Echeverri, Johan Moritz Kaths, Vera Cherepanov, Michael G Hodges, Nazia Selzner, David R GrantAbstract:Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering Miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with Miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of Miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved Miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed Miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, Miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide "proof of concept" for using NEVLP to modify and optimize liver grafts for transplantation.
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Miravirsen dosing in chronic hepatitis c patients results in decreased microrna 122 levels without affecting other micrornas in plasma
Alimentary Pharmacology & Therapeutics, 2016Co-Authors: M H Van Der Ree, Harry L.a. Janssen, A J Van Der Meer, A C Van Nuenen, J De Bruijne, S Ottosen, N A Kootstra, H W ReesinkAbstract:Summary Background MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus replication. Administration of Miravirsen, an anti-miR-122 oligonucleotide, resulted in a dose dependent and prolonged decrease in HCV RNA levels in chronic hepatitis C patients. Aim To assess the plasma level of various miRNAs in patients dosed with Miravirsen. Methods We included 16 of 36 chronic hepatitis C patients who received five injections of either 3 mg/kg (n = 4), 5 mg/kg (n = 4), 7 mg/kg (n = 4) Miravirsen or placebo (n = 4) over a 4-week period in a double-blind, randomised phase 2a study. Plasma levels of 179 miRNAs were determined by qPCR and compared between patients dosed with Miravirsen or placebo. Results Median plasma miR-122 level at baseline in patients receiving Miravirsen was 3.9 × 103 compared to 1.3 × 104 copies/4 μL in placebo-dosed patients (P = 0.68). At week 1, 4, 6 and 10/12, patients dosed with Miravirsen had respectively a median 72-fold, 174-fold, 1109-fold and 552-fold lower expression of miR-122 than at baseline (P = 0.001, as compared to patients receiving placebo). At week 4 of dosing, miRNA-profiling demonstrated a significant lower expression of miR-210 and miR-532-5p compared to baseline (3.0 and 4.7-fold lower respectively). However, subsequent longitudinal analysis showed no significant differences in miR-210 and miR-532-5p plasma levels throughout the study period. Conclusions We demonstrated a substantial and prolonged decrease in plasma miR-122 levels in patients dosed with Miravirsen. Plasma levels of other miRNAs were not significantly affected by antagonising miR-122.
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treatment of hcv infection by targeting microrna
The New England Journal of Medicine, 2013Co-Authors: Harry L.a. Janssen, H W Reesink, S Zeuzem, E Lawitz, M Rodrigueztorres, Keyur Patel, Adriaan J. Van Der Meer, Amy K Patick, Alice Chen, Yi ZhouAbstract:Background The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid–modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function. Methods In this phase 2a study at seven international sites, we evaluated the safety and efficacy of Miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive five weekly subcutaneous injections of Miravirsen at doses of 3 mg, 5 mg, or 7 mg per kilogram of body weight or placebo over a 29-day period. They were followed until 18 weeks after randomization. Results Miravirsen resulted in a dose-dependent reduction in HCV RNA levels that endured beyond the end of active therapy. In the Miravirsen groups, the mean maximum reduction in HCV RNA level (log10 IU per milliliter) from baseline was 1.2 (P=...
Robert Persson - One of the best experts on this subject based on the ideXlab platform.
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inducing hepatitis c virus resistance after pig liver transplantation a proof of concept of liver graft modification using warm ex vivo perfusion
American Journal of Transplantation, 2017Co-Authors: Nicolas Goldaracena, Robert Persson, Harry L.a. Janssen, Vinzent N Spetzler, Juan Echeverri, Johan Moritz Kaths, Vera Cherepanov, Michael G Hodges, Nazia Selzner, David R GrantAbstract:Normothermic ex vivo liver perfusion (NEVLP) offers the potential to optimize graft function prior to liver transplantation (LT). Hepatitis C virus (HCV) is dependent on the presence of miRNA(microRNA)-122. Miravirsen, a locked-nucleic acid oligonucleotide, sequesters miR-122 and inhibits HCV replication. The aim of this study was to assess the efficacy of delivering Miravirsen during NEVLP to inhibit miR-122 function in a pig LT model. Pig livers were treated with Miravirsen during NEVLP or cold storage (CS). Miravirsen absorption, miR-122 sequestration, and miR-122 target gene derepression were determined before and after LT. The effect of Miravirsen treatment on HCV infection of hepatoma cells was also assessed. NEVLP improved Miravirsen uptake versus CS. Significant miR-122 sequestration and miR-122 target gene derepression were seen with NEVLP but not with CS. In vitro data confirmed Miravirsen suppression of HCV replication after established infection and prevented HCV infection with pretreatment of cells, analogous to the pretreatment of grafts in the transplant setting. In conclusion, Miravirsen delivery during NEVLP is a potential strategy to prevent HCV reinfection after LT. This is the first large-animal study to provide "proof of concept" for using NEVLP to modify and optimize liver grafts for transplantation.
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P12: Miravirsen does not interact with telaprevir
Journal of Viral Hepatitis, 2013Co-Authors: Robert Persson, Arthur A Levin, A Chen, B King, A Karim, J Rodriguez-orengo, K. Zeh, Michael R. HodgesAbstract:BACKGROUND: Miravirsen sodium is a b-D-oxy-Locked Nucleic Acid (LNA)-modified phosphorothioate anti-sense oligonucleotide inhibitor of the liver-expressed microRNA122 (miR-122). Miravirsen reduces HCV RNA levels indirectly, by targeting the critical host factor miR-122 rather than by directly targeting the virus. Prior clinical and nonclinical studies have demonstrated Miravirsen activity against all HCV genotypes (GT) and long-lasting suppression of HCV viremia without evidence of viral resistance. Miravirsen is not metabolized by CYP450 enzymes suggesting it has a low propensity for drug-drug interactions. METHOD: An open-label drug interaction study was performed in healthy subjects to assess the effect of Miravirsen on telaprevir plasma PK. Five subjects received telaprevir every day during a week (Days 1–7). The subjects subsequently received five single doses of Miravirsen (7 mg/kg, on Days 8, 15, 22, 29 and 36). In the period from Day 30 to Day 36, the subjects once more received telaprevir daily. The plasma PK for telaprevir were followed on Days 1, 7, 30 and 36 and those for Miravirsen on Days 15 and 36. The plasma PK of telaprevir before and after Miravirsen treatment were compared, as well as those after a singleand multiple dosing with telaprevir. The effect of telaprevir on Miravirsen plasma PK was also studied. RESULTS: The study showed that repeated dosing with Miravirsen (five doses over 29 days) had no effect on exposure (expressed as AUC values) of the subsequently administered telaprevir, Day 36 versus Day 7 (A). Neither had repeated dosing with telaprevir during 1 week any effect on subsequently administered Miravirsen, Day 36 versus Day 15 (B). There was no statistically or clinically significant difference on systemic exposure of telaprevir at steady state or Miravirsen when these compounds were co administered as compared with administration alone. CONCLUSION: There is no meaningful drug interaction between Miravirsen and telaprevir upon co-administration in healthy subjects. P13 Plasma TIMP-1/MMP-2 ratio dynamics in patients with chronic hepatitis C treated with PegIFN and ribavirin H Fota-Markowska, E Kobylecka and A Przybyla Medical University of Lublin, Lublin, Poland
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p11 Miravirsen does not interact with pegylated interferon alpha or ribavirin
Journal of Viral Hepatitis, 2013Co-Authors: Robert Persson, Arthur A Levin, B King, K. Zeh, C Wynne, T Boyea, Michael R. HodgesAbstract:cialist tests, requested following referral to secondary care services for investigation and management. METHODS: All HCV testing undertaken between 2002 and 2011 were extracted from laboratory information systems of 23 participating centres in England, capturing an estimated 2/3 of all HCV testing. Duplicate records, infants under 1 year, and people tested through renal units were excluded. An algorithm based on frequency of HCV RNA testing within a defined time period was designed to identify treated patients. Findings for one centre were validated by comparison with treatment data recorded in a local clinical database managed by the Trent HCV study group. RESULTS: Between January 2002 and December 2011 267,887 PCR test results from 100,640 individuals were extracted. Of these, 78.9% (79,360) tested positive for viral RNA, indicating an active infection, 20.8% (16,538) of whom had a repeat pattern of HCV-RNA testing suggestive of treatment-monitoring. The number of individuals estimated to have started treatment annually increased significantly (p < 0.001) from 468 in 2002 to 3295 in 2009, decreasing to 3110 by 2010. An estimated 16% of HCV infected individuals with an active infection were treated within 2 years of their diagnosis, and 20% were ever treated. Approximately two-thirds (63.3; 10,468) of those treated had results consistent with a sustained virological response, including 55.3% and 67.1% of those with a genotype-one and non-one virus, respectively. Being younger, of Asian/Asian British ethnicity and infected with a non-genotype 1 virus, were independent predictors of being treated and achieving a sustained virological response. On validation, the algorithm was 95% sensitive and 93% specific in detecting treatment, and 100% sensitive and 93% specific for detecting treatment outcome. CONCLUSIONS: For the majority of individuals HCV can be cured, but it is essential that opportunities for treatment exits, and can be monitored. Laboratory testing activity, collected through a sentinel surveillance programme has enabled the first country-wide analysis of treatment and response among HCV-infected individuals. Our approach provides a sensitive, robust, and sustainable method by which service provision across England can be monitored.
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A Locked Nucleic Acid Oligonucleotide Targeting MicroRNA 122 Is Well-Tolerated in Cynomolgus Monkeys
Nucleic acid therapeutics, 2012Co-Authors: Elisabeth S. Hildebrandt-eriksen, Robert Persson, Vibeke Aarup, Henrik Frydenlund Hansen, Martin E. Munk, Henrik OrumAbstract:MicroRNA 122 (miR-122) is liver specific, fine-tunes lipid metabolism, and is required for hepatitis C virus (HCV) abundance. Miravirsen, an oligonucleotide with locked nucleic acid, binds to miR-122, potently inhibiting its activity. We aimed at determining the safety of the miR-122 antagonism in vivo in 6 to 10 cynomolgus monkeys/group intravenously treated with a range of dose levels twice weekly for 4 weeks. Survival, body weights, clinical signs, and cardiovascular and ophthalmologic parameters were unaffected. Anticipated hypolipidemia due to the inhibition of miR-122 was observed in all treated animals. Only the highest dose level produced distinct transient prolongations of clotting times, slight alternative complement pathway activation, and a reversible increase of hepatic transaminases. Distribution half-life was 10–20 minutes, and accumulation was mainly in the kidney and liver with slow elimination. Microscopic examinations revealed granulated Kupffer cells and lymph node macrophages, cytopla...
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1204 PHARMACOKINETICS OF Miravirsen, A MIR-122 INHIBITOR, PREDICT THE PROLONGED VIRAL LOAD REDUCTION IN TREATMENT NAIVE GENOTYPE 1 HCV INFECTED PATIENTS
Journal of Hepatology, 2012Co-Authors: Robert Persson, A Chen, B King, K. Zeh, Michael R. Hodges, A.a. LevineAbstract:(6/6), respectively in arm C and 88% (7/8), 94%, (15/16) and 83% (5/6), respectively, in arm D. Conclusions: There was an association between IL28B genotype and undetectable HCVRNA at Week 2 in arms C and D, however this association disappears by Week 4 due to high RVR rates across all IL28B genotypes. Patients from all IL28B genotypes achieved high SVR rates, thus IL28B may not be predictive of response to QUAD therapy in treatment-naive patients with genotype 1 chronic HCV.
Michael R. Hodges - One of the best experts on this subject based on the ideXlab platform.
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In Vitro Antiviral Activity and Preclinical and Clinical Resistance Profile of Miravirsen, a Novel Anti-Hepatitis C Virus Therapeutic Targeting the Human Factor miR-122
2016Co-Authors: Michael R. Hodges, Amy C K. PatickcAbstract:Miravirsen is a-D-oxy-locked nucleic acid-modified phosphorothioate antisense oligonucleotide targeting the liver-specific microRNA-122 (miR-122). Miravirsen demonstrated antiviral activity against hepatitis C virus (HCV) genotype 1b replicons with a mean 50 % effective concentration (EC50) of 0.67M. No cytotoxicity was observed up to the highest concentration tested (>320M) in different cell culture models, yielding a therapeutic index of>297. Combination studies of Miravirsen with inter-feron2b, ribavirin, and nonnucleoside (VX-222) and nucleoside (2=-methylcytidine) inhibitors of NS5B, NS5A (BMS-790052), or NS3 (telaprevir) indicated additive interactions. Miravirsen demonstrated broad antiviral activity when tested against HCV replicons resistant to NS3, NS5A, and NS5B inhibitors with less than 2-fold reductions in susceptibility. In serial passage studies, an A4C nucleotide change was observed in the HCV 5 = untranslated region (UTR) from cells passaged in the presence of up to 20 M (40-fold the Miravirsen EC50 concentration) at day 72 of passage but not at earlier time points (up to 39 days of passage). Likewise, a C3U nucleotide change was observed in the HCV 5=UTR from subjects with viral rebound after the completion of therapy in a Miravirsen phase 2 clinical trial. An HCV variant constructed to contain the A4C change was fully susceptible to Miravirsen. A C3UHCV variant demonstrated overall reductions in susceptibility to Miravirsen but was fully susceptible to all other anti-HCV agents tested. In summary, Miravirsen has demonstrated broad antiviral activity and a relatively high genetic barrier to resistance. The identification of nucleotide changes associated with Miravirsen resistance should help further elucidate the biology of miR-122 interactions with HCV. (The clinical trial study has been registered at ClinicalTrials.gov under registra
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P12: Miravirsen does not interact with telaprevir
Journal of Viral Hepatitis, 2013Co-Authors: Robert Persson, Arthur A Levin, A Chen, B King, A Karim, J Rodriguez-orengo, K. Zeh, Michael R. HodgesAbstract:BACKGROUND: Miravirsen sodium is a b-D-oxy-Locked Nucleic Acid (LNA)-modified phosphorothioate anti-sense oligonucleotide inhibitor of the liver-expressed microRNA122 (miR-122). Miravirsen reduces HCV RNA levels indirectly, by targeting the critical host factor miR-122 rather than by directly targeting the virus. Prior clinical and nonclinical studies have demonstrated Miravirsen activity against all HCV genotypes (GT) and long-lasting suppression of HCV viremia without evidence of viral resistance. Miravirsen is not metabolized by CYP450 enzymes suggesting it has a low propensity for drug-drug interactions. METHOD: An open-label drug interaction study was performed in healthy subjects to assess the effect of Miravirsen on telaprevir plasma PK. Five subjects received telaprevir every day during a week (Days 1–7). The subjects subsequently received five single doses of Miravirsen (7 mg/kg, on Days 8, 15, 22, 29 and 36). In the period from Day 30 to Day 36, the subjects once more received telaprevir daily. The plasma PK for telaprevir were followed on Days 1, 7, 30 and 36 and those for Miravirsen on Days 15 and 36. The plasma PK of telaprevir before and after Miravirsen treatment were compared, as well as those after a singleand multiple dosing with telaprevir. The effect of telaprevir on Miravirsen plasma PK was also studied. RESULTS: The study showed that repeated dosing with Miravirsen (five doses over 29 days) had no effect on exposure (expressed as AUC values) of the subsequently administered telaprevir, Day 36 versus Day 7 (A). Neither had repeated dosing with telaprevir during 1 week any effect on subsequently administered Miravirsen, Day 36 versus Day 15 (B). There was no statistically or clinically significant difference on systemic exposure of telaprevir at steady state or Miravirsen when these compounds were co administered as compared with administration alone. CONCLUSION: There is no meaningful drug interaction between Miravirsen and telaprevir upon co-administration in healthy subjects. P13 Plasma TIMP-1/MMP-2 ratio dynamics in patients with chronic hepatitis C treated with PegIFN and ribavirin H Fota-Markowska, E Kobylecka and A Przybyla Medical University of Lublin, Lublin, Poland
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p11 Miravirsen does not interact with pegylated interferon alpha or ribavirin
Journal of Viral Hepatitis, 2013Co-Authors: Robert Persson, Arthur A Levin, B King, K. Zeh, C Wynne, T Boyea, Michael R. HodgesAbstract:cialist tests, requested following referral to secondary care services for investigation and management. METHODS: All HCV testing undertaken between 2002 and 2011 were extracted from laboratory information systems of 23 participating centres in England, capturing an estimated 2/3 of all HCV testing. Duplicate records, infants under 1 year, and people tested through renal units were excluded. An algorithm based on frequency of HCV RNA testing within a defined time period was designed to identify treated patients. Findings for one centre were validated by comparison with treatment data recorded in a local clinical database managed by the Trent HCV study group. RESULTS: Between January 2002 and December 2011 267,887 PCR test results from 100,640 individuals were extracted. Of these, 78.9% (79,360) tested positive for viral RNA, indicating an active infection, 20.8% (16,538) of whom had a repeat pattern of HCV-RNA testing suggestive of treatment-monitoring. The number of individuals estimated to have started treatment annually increased significantly (p < 0.001) from 468 in 2002 to 3295 in 2009, decreasing to 3110 by 2010. An estimated 16% of HCV infected individuals with an active infection were treated within 2 years of their diagnosis, and 20% were ever treated. Approximately two-thirds (63.3; 10,468) of those treated had results consistent with a sustained virological response, including 55.3% and 67.1% of those with a genotype-one and non-one virus, respectively. Being younger, of Asian/Asian British ethnicity and infected with a non-genotype 1 virus, were independent predictors of being treated and achieving a sustained virological response. On validation, the algorithm was 95% sensitive and 93% specific in detecting treatment, and 100% sensitive and 93% specific for detecting treatment outcome. CONCLUSIONS: For the majority of individuals HCV can be cured, but it is essential that opportunities for treatment exits, and can be monitored. Laboratory testing activity, collected through a sentinel surveillance programme has enabled the first country-wide analysis of treatment and response among HCV-infected individuals. Our approach provides a sensitive, robust, and sustainable method by which service provision across England can be monitored.
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1204 PHARMACOKINETICS OF Miravirsen, A MIR-122 INHIBITOR, PREDICT THE PROLONGED VIRAL LOAD REDUCTION IN TREATMENT NAIVE GENOTYPE 1 HCV INFECTED PATIENTS
Journal of Hepatology, 2012Co-Authors: Robert Persson, A Chen, B King, K. Zeh, Michael R. Hodges, A.a. LevineAbstract:(6/6), respectively in arm C and 88% (7/8), 94%, (15/16) and 83% (5/6), respectively, in arm D. Conclusions: There was an association between IL28B genotype and undetectable HCVRNA at Week 2 in arms C and D, however this association disappears by Week 4 due to high RVR rates across all IL28B genotypes. Patients from all IL28B genotypes achieved high SVR rates, thus IL28B may not be predictive of response to QUAD therapy in treatment-naive patients with genotype 1 chronic HCV.
B King - One of the best experts on this subject based on the ideXlab platform.
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P12: Miravirsen does not interact with telaprevir
Journal of Viral Hepatitis, 2013Co-Authors: Robert Persson, Arthur A Levin, A Chen, B King, A Karim, J Rodriguez-orengo, K. Zeh, Michael R. HodgesAbstract:BACKGROUND: Miravirsen sodium is a b-D-oxy-Locked Nucleic Acid (LNA)-modified phosphorothioate anti-sense oligonucleotide inhibitor of the liver-expressed microRNA122 (miR-122). Miravirsen reduces HCV RNA levels indirectly, by targeting the critical host factor miR-122 rather than by directly targeting the virus. Prior clinical and nonclinical studies have demonstrated Miravirsen activity against all HCV genotypes (GT) and long-lasting suppression of HCV viremia without evidence of viral resistance. Miravirsen is not metabolized by CYP450 enzymes suggesting it has a low propensity for drug-drug interactions. METHOD: An open-label drug interaction study was performed in healthy subjects to assess the effect of Miravirsen on telaprevir plasma PK. Five subjects received telaprevir every day during a week (Days 1–7). The subjects subsequently received five single doses of Miravirsen (7 mg/kg, on Days 8, 15, 22, 29 and 36). In the period from Day 30 to Day 36, the subjects once more received telaprevir daily. The plasma PK for telaprevir were followed on Days 1, 7, 30 and 36 and those for Miravirsen on Days 15 and 36. The plasma PK of telaprevir before and after Miravirsen treatment were compared, as well as those after a singleand multiple dosing with telaprevir. The effect of telaprevir on Miravirsen plasma PK was also studied. RESULTS: The study showed that repeated dosing with Miravirsen (five doses over 29 days) had no effect on exposure (expressed as AUC values) of the subsequently administered telaprevir, Day 36 versus Day 7 (A). Neither had repeated dosing with telaprevir during 1 week any effect on subsequently administered Miravirsen, Day 36 versus Day 15 (B). There was no statistically or clinically significant difference on systemic exposure of telaprevir at steady state or Miravirsen when these compounds were co administered as compared with administration alone. CONCLUSION: There is no meaningful drug interaction between Miravirsen and telaprevir upon co-administration in healthy subjects. P13 Plasma TIMP-1/MMP-2 ratio dynamics in patients with chronic hepatitis C treated with PegIFN and ribavirin H Fota-Markowska, E Kobylecka and A Przybyla Medical University of Lublin, Lublin, Poland
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p11 Miravirsen does not interact with pegylated interferon alpha or ribavirin
Journal of Viral Hepatitis, 2013Co-Authors: Robert Persson, Arthur A Levin, B King, K. Zeh, C Wynne, T Boyea, Michael R. HodgesAbstract:cialist tests, requested following referral to secondary care services for investigation and management. METHODS: All HCV testing undertaken between 2002 and 2011 were extracted from laboratory information systems of 23 participating centres in England, capturing an estimated 2/3 of all HCV testing. Duplicate records, infants under 1 year, and people tested through renal units were excluded. An algorithm based on frequency of HCV RNA testing within a defined time period was designed to identify treated patients. Findings for one centre were validated by comparison with treatment data recorded in a local clinical database managed by the Trent HCV study group. RESULTS: Between January 2002 and December 2011 267,887 PCR test results from 100,640 individuals were extracted. Of these, 78.9% (79,360) tested positive for viral RNA, indicating an active infection, 20.8% (16,538) of whom had a repeat pattern of HCV-RNA testing suggestive of treatment-monitoring. The number of individuals estimated to have started treatment annually increased significantly (p < 0.001) from 468 in 2002 to 3295 in 2009, decreasing to 3110 by 2010. An estimated 16% of HCV infected individuals with an active infection were treated within 2 years of their diagnosis, and 20% were ever treated. Approximately two-thirds (63.3; 10,468) of those treated had results consistent with a sustained virological response, including 55.3% and 67.1% of those with a genotype-one and non-one virus, respectively. Being younger, of Asian/Asian British ethnicity and infected with a non-genotype 1 virus, were independent predictors of being treated and achieving a sustained virological response. On validation, the algorithm was 95% sensitive and 93% specific in detecting treatment, and 100% sensitive and 93% specific for detecting treatment outcome. CONCLUSIONS: For the majority of individuals HCV can be cured, but it is essential that opportunities for treatment exits, and can be monitored. Laboratory testing activity, collected through a sentinel surveillance programme has enabled the first country-wide analysis of treatment and response among HCV-infected individuals. Our approach provides a sensitive, robust, and sustainable method by which service provision across England can be monitored.
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58 final results randomized double blind placebo controlled safety anti viral proof of concept study of Miravirsen an oligonucleotide targeting mir 122 in treatment naive patients with genotype 1 chronic hcv infection
Journal of Hepatology, 2012Co-Authors: H W Reesink, H L A Janssen, S Zeuzem, E Lawitz, M Rodrigueztorres, Keyur Patel, A Chen, C Davis, B King, Arthur A LevinAbstract:58 FINAL RESULTS – RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED SAFETY, ANTI-VIRAL PROOF-OF-CONCEPT STUDY OF Miravirsen, AN OLIGONUCLEOTIDE TARGETING MIR-122, IN TREATMENT-NAIVE PATIENTS WITH GENOTYPE 1 CHRONIC HCV INFECTION H.W. Reesink, H.L.A. Janssen, S. Zeuzem, E. Lawitz, M. Rodriguez-Torres, K. Patel, A. Chen, C. Davis, B. King, A. Levin, M.R. Hodges. Department of Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Medicine, J.W. Goethe University Hospital, Frankfurt/Main, Germany; Alamo Medical Research, San Antonio, TX, Fundacion de Investigacion, San Juan, PR, Duke University, Durham, NC, Santaris Pharma, San Diego, CA, USA E-mail: h.w.reesink@amc.nl
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1204 PHARMACOKINETICS OF Miravirsen, A MIR-122 INHIBITOR, PREDICT THE PROLONGED VIRAL LOAD REDUCTION IN TREATMENT NAIVE GENOTYPE 1 HCV INFECTED PATIENTS
Journal of Hepatology, 2012Co-Authors: Robert Persson, A Chen, B King, K. Zeh, Michael R. Hodges, A.a. LevineAbstract:(6/6), respectively in arm C and 88% (7/8), 94%, (15/16) and 83% (5/6), respectively, in arm D. Conclusions: There was an association between IL28B genotype and undetectable HCVRNA at Week 2 in arms C and D, however this association disappears by Week 4 due to high RVR rates across all IL28B genotypes. Patients from all IL28B genotypes achieved high SVR rates, thus IL28B may not be predictive of response to QUAD therapy in treatment-naive patients with genotype 1 chronic HCV.