Interferon-Combination Strategies for the Treatment of Chronic Hepatitis C
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
Faldaprevir, Pegylated Interferon, and Ribavirin for Treatment-Naïve HCV Genotype-1: Pooled Analysis of Two Phase 3 Trials
Faldaprevir, pegylated interferon and ribavirin. , 2016; 15 (3): 333-349 333 ORIGINAL ARTICLE May-June, Vol. 15 No. 3, 2016: 333-349 The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for Study of the Liver and the Canadian Association for the Study of the Liver Faldaprevir, pegylated interferon, and ribavirin for treatment-naïve HCV genotype-1: pooled analysis of two phase 3 trials Donald M. Jensen,1 Tarik Asselah,2 Douglas Dieterich,3 Graham R. Foster,4 Mark S. Sulkowski,5 Stefan Zeuzem,6 Parvez Mantry,7 Eric M. Yoshida,8 Christophe Moreno,9 Denis Ouzan,10 Mark Wright,11 Luis E. Morano,12 Robert Buynak,13 Marc Bourlière,14 Tarek Hassanein,15 Shuhei Nishiguchi,16 Jia-Horng Kao,17 Masao Omata,18 Seung W. Paik,19 David K. Wong,20 Edward Tam,21 Kelly Kaita,22 S. Victor Feinman,23 Jerry O. Stern,24 Joseph Scherer,24 Anne-Marie Quinson,24 Florian Voss,25 John-Paul Gallivan,25 Wulf O. Böcher,25 Peter Ferenci26 1 University of Chicago Medicine, Chicago, IL, USA. 2 Hôpital Beaujon, APHP, University Paris-Diderot and INSERM CRB3, Clichy, France. 3 Icahn School of Medicine at Mount Sinai, New York, NY, USA. 4 Queen Mary University of London, London, UK. 5 Johns Hopkins University School of Medicine, Baltimore, MD, USA. 6 J.W.Goethe University Hospital, Frankfurt, Germany. 7 The Liver Institute at Methodist Dallas Medical Center, Dallas, TX, USA. 8 University of British Columbia, Vancouver, BC, Canada. 9 CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. 10 Institut Arnault Tzanck, St. -
Faldaprevir Combined with Peginterferon Alfa2a and Ribavirin In
Faldaprevir Combined With Peginterferon Alfa-2a and Ribavirin in Chronic Hepatitis C Virus Genotype-1 Patients With Prior Nonresponse: SILEN-C2 Trial Mark S. Sulkowski,1 Marc Bourlie`re,2 Jean-Pierre Bronowicki,3 Tarik Asselah,4 Jean-Michel Pawlotsky,5 Stephen D. Shafran,6 Stanislas Pol,7 Stefan Mauss,8 Dominique Larrey,9 Yakov Datsenko,10 Jerry O. Stern,11 George Kukolj,12 Joseph Scherer,11 Gerhard Nehmiz,10 Gerhard G. Steinmann,10 and Wulf O. B€ocher13 Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor. In all, 290 noncirrhotic HCV genotype (GT)-1 patients with prior null (<1log10 viral load [VL] drop at any time on treatment) or partial response (1log10 VL drop but never undetectable on treatment) were randomized 2:1:1 to receive 48 weeks of peginterferon alfa-2a and ribavirin (PegIFN/RBV) in combination with faldaprevir 240 mg once daily (QD) with 3 days PegIFN/RBV lead-in (LI), 240 mg QD without LI, or 240 mg twice daily (BID) with LI. Patients in the 240 mg QD/LI group achieving maintained rapid virologic response (mRVR; VL <25 IU/mL [Roche TaqMan] at week 4 and undetectable at weeks 8 to 20) were rerandomized to cease all treatment at week 24 or continue PegIFN/RBV up to week 48. Sustained virologic response (SVR) rates were 32%, 50%, and 42% in prior partial responders, and 21%, 35%, and 29% in prior null responders in the faldaprevir 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. -
Hepatitis-C-Virus-Induced Micrornas Dampen Interferon-Mediated
LETTERS Hepatitis-C-virus-induced microRNAs dampen interferon-mediated antiviral signaling Abigail Jarret1, Adelle P McFarland1,6,7, Stacy M Horner1,6,7, Alison Kell1, Johannes Schwerk1, MeeAe Hong1, Samantha Badil1, Rochelle C Joslyn1, Darren P Baker2,6, Mary Carrington3,4, Curt H Hagedorn5, Michael Gale Jr1 & Ram Savan1 Hepatitis C virus (HCV) infects 200 million people globally, currently in clinical trials6,10. More recently, interferon-free com- and 60–80% of cases persist as a chronic infection that will binations of HCV protease and RNA polymerase inhibitors, some- progress to cirrhosis and liver cancer in 2–10% of patients1–3. times with ribavirin, have produced dramatic results in a subset of We recently demonstrated that HCV induces aberrant expression patients10. However, the emergence of resistant HCV variants and of two host microRNAs (miRNAs), miR-208b and miR-499a-5p, the high cost of DAA treatments might limit the availability of these encoded by myosin genes in infected hepatocytes4. These therapies worldwide11–13. The usefulness of DAA-based therapies for miRNAs, along with AU-rich-element-mediated decay, suppress some patients—such as those with advanced infection, who are at IFNL2 and IFNL3, members of the type III interferon (IFN) the highest risk for hepatic decompensation, liver failure, hepato- gene family, to support viral persistence. In this study, we cellular carcinoma and/or death—also remains to be fully proven13. show that miR-208b and miR-499a-5p also dampen type I Hence, it is critical to identify the mechanisms that HCV employs IFN signaling in HCV-infected hepatocytes by directly which lead to the failure of type I IFN therapy. -
Hepatitis C Agents Therapeutic Class Review
Hepatitis C Agents Therapeutic Class Review (TCR) November 2, 2018 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland 21046 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to [email protected]. Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004–2018 Magellan Rx Management. All Rights Reserved. FDA-APPROVED INDICATIONS Drug Mfr FDA-Approved Indications Interferons peginterferon alfa-2a Genentech Chronic hepatitis C (CHC) 1 (Pegasys®) . -
Sofosbuvir-Velpatasvir (Epclusa)
© Hepatitis C Online PDF created September 29, 2021, 4:07 am Sofosbuvir-Velpatasvir (Epclusa) Table of Contents Sofosbuvir-Velpatasvir Epclusa Summary Drug Summary Adverse Effects Class and Mechanism Manufacturer for United States Indications Contraindications Dosing Clinical Use Cost and Medication Access Resistance Key Drug Interactions Full Prescribing Information Figures Drug Summary Sofosbuvir-velpatasvir is a pangenotypic NS5A-NS5B inhibitor single-pill combination regimen that has potent activity against hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5, and 6. It provides a much-needed option for patients with HCV genotype 3 infection, including those with compensated cirrhosis. Notably, an abbreviated duration of 8 weeks has not been studied with sofosbuvir-velpatasvir for any of the genotypes, except in conjunction with a third agent (voxilaprevir). Sofosbuvir-velpatasvir, like ledipasvir-sofosbuvir, may have have levels significantly reduced with acid-reducing agents, particularly proton-pump inhibitors. Adverse Effects The most common adverse effects, observed in at least 10% of phase 3 trial participants, were headache and fatigue. Class and Mechanism Sofosbuvir-Velpatasvir is an oral fixed-dose combination of sofosbuvir, a nucleotide analog NS5B polymerase inhibitor and velapatasvir, an NS5A replication complex inhibitor. Sofosbuvir is currently approved in the Page 1/4 United States for the treatment of genotype 1, 2, 3 and 4 HCV infection with different regimens and durations dependent on the HCV genotype. Velpatasvir (formerly GS-5816) is a novel NS5A inhibitor that has potent in vitro anti-HCV activity across all genotypes at the picomolar level. The combination of sofosbuvir-velpatasvir is the first once-daily single-tablet regimen with pangenotypic activity. -
Interferon-Based and Interferon-Free New Treatment Options
Interferon-based and interferon-free new treatment options White Nights of Hepatology St. Petersburg, 7. June 2013 Christoph Sarrazin Klinikum der J. W. Goethe-Universität Medizinische Klinik I Frankfurt am Main Mode of action of Interferons natural immunomodulatory effects IFN-stimulated gene activation Antiviral Apoptotic Immunomodulatory activity activity activity B-cell proliferation Reduced transcription Elevates apoptosis by CTL proliferation Reduced translation multiple mechanisms MHC upregulation Reduced RNA stability Augments NK activity Host-mediated effects are important for DAA combination therapy • Potency and additive effects • Prevention of resistance and viral breakthrough Different types of Interferons Type I Interferons Type III Interferons Broad receptor Receptors distribution distributed throughout various primarily in body tissues epithelial cells and hepatocytes Antiviral effects Antiviral effects Adverse events of Type I IFNs treatment Peg‐Intron • Flu-like symptoms PegIFN‐2a Type III IFNs Potentially fewer • Haematologic IFN omega Peg‐IFN‐ adverse events disorders IFN‐alfa‐2b XL lambda than with type I • Psychiatric Belerofon (Peg‐rIL‐29) interferons symptoms Albuferon Locteron Adapted from 1. Marcello T et al. Gastroenterology 2006;131:1887–98; 2. Muir AJ et al. 2009 AASLD. Abstract 1591; 3. O'Brien TR. Nat Genet. 2009;41:1048–50. PEG-Interferon alfa / Ribavirin Approval studies: efficacy Approval study (n=1530) Approval study (n=1121) Therapy: IFN vs. PEG-IFN alfa 2b Therapy: IFN vs. PEG-IFN alfa 2a 1,0/1,5µg/kgKG -
UNO Template
26 November 2013 Americas/United States Equity Research Biotechnology Global Biotech & Pharma: The HCV Revolution - Edition 2 Research Analysts COMMENT Ravi Mehrotra PhD 212 325 3487 [email protected] What Is The N Number: Keeping An Eye On Vamil Divan, MD 212 538 5394 Potential Longer Term Pricing Disruption [email protected] Koon Ching PhD ■ No pricing disruption expected in the near-term, but potential exists in 212 325 6286 the medium- to long-term. OK this is somewhat obvious, but bear with us: [email protected] Value/NPV = Price x Mkt Share x Mkt Size x Mkt Longevity. This is the Bruce Nudell PhD second note in our "The HCV Revolution" series. HCV is clearly a highly 212 325 9122 competitive therapeutic area with many players vying for their share of the [email protected] potentially >$15B/year HCV market. We previously addressed immediate- European Pharma Team 44 207 888 0304 term pricing of next-generation regimens, specifically for Sofosbuvir (LINK). [email protected] In this note, we simply highlight the potential number of competing all-oral, Ronak H. Shah, Pharm.D., CFA IFN-free regimens, and timing of key data, in HCV (Exhibits 1-7). The 212 325 9799 number of ultimate competitors has important implications for the HCV [email protected] market. In our view, in a HCV market with up to 4−5 players, we expect Lee Kalowski "normal drug rules" to apply: i.e. the order to market, overall clinical profile of 212 325 9683 drug, and commercial prowess will primarily dictate market share, with price [email protected] used as a tool but not in a "disruptive" way. -
Startverso4 PHASE III TRIAL of FALDAPREVIR PLUS PEGYLATED INTERFERON Α-2A and RIBAVIRIN in PATIENTS with HIV and HCV GENOTYPE-1 CO-INFECTION
STARTVerso4 PHASE III TRIAL OF FALDAPREVIR PLUS PEGYLATED INTERFERON α-2a AND RIBAVIRIN IN PATIENTS WITH HIV AND HCV GENOTYPE-1 CO-INFECTION JK Rockstroh1, M Nelson2, V Soriano3, K Arastéh4, J Guardiola5, S Bhagani6, J Mallolas7, C Tural8, M Puoti9, P Ingiliz10, M Battegay11, MK Jain12, M Núñez13, K Marks14, J Kort15, JO Stern15, R Vinisko15, M Manero16, D Dieterich17, on behalf of the STARTVerso4 Study Group 1University of Bonn, Bonn, Germany; 2Chelsea and Westminster Hospital, London, UK; 3Hospital Carlos III, Madrid, Spain; 4EPIMED, Vivantes Auguste-Viktoria Hospital, Berlin, Germany; 5Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 6Royal Free Hospital, London, UK; 7Hospital Clínic, Barcelona, Spain; Jürgen K. Rockstroh 1099 8Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 9AO Ospedale Niguarda Cà Granda, Milan, Italy; 10Medizinisches Infektiologiezentrum Berlin (MIB), Berlin, Germany; 11Division of Infectious Diseases and Hospital Epidemiology, Basel, Switzerland; 12UT Southwestern Medical Center, Dallas, TX, USA; 13Wake Forest University, Winston-Salem, NC, USA; 14Weill Cornell Medical College, New York, NY, USA; 15Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 16Boehringer Ingelheim España S.A., Barcelona, Spain; 17Mount Sinai School of Medicine, New York, NY, USA [email protected] BACKGROUND RESULTS EFFICACY FIGURE 4e. SVR4 by ART (total population) TABLE 5. AE summary ●● SVR4 was achieved by 74% of patients overall (Figure 3). FDV 120 mg FDV 240 mg + PR + PR Total ●● Faldaprevir (FDV) is a potent inhibitor of HCV NS3/4A.1 PATIENTS - SVR4 rates were comparable across FDV doses and durations of treatment. 24 weeks Total FDV + PR a ●● 1 n (%) (N=123) (N=185) (N=308) FDV has antiviral activity against HCV genotypes (GT) 1, 4, 5, and 6 in vitro. -
Interplay Between Hepatitis D Virus and the Interferon Response
viruses Review Interplay between Hepatitis D Virus and the Interferon Response Zhenfeng Zhang 1 and Stephan Urban 1,2,* 1 Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany; [email protected] 2 German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany * Correspondence: [email protected]; Tel.: +49-6221-564-902 Received: 27 October 2020; Accepted: 18 November 2020; Published: 20 November 2020 Abstract: Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, with rapid progression of liver-related diseases and high rates of development of hepatocellular carcinoma. The causative agent, hepatitis D virus (HDV), contains a small (approximately 1.7 kb) highly self-pairing single-strand circular RNA genome that assembles with the HDV antigen to form a ribonucleoprotein (RNP) complex. HDV depends on hepatitis B virus (HBV) envelope proteins for envelopment and de novo hepatocyte entry; however, its intracellular RNA replication is autonomous. In addition, HDV can amplify HBV independently through cell division. Cellular innate immune responses, mainly interferon (IFN) response, are crucial for controlling invading viruses, while viruses counteract these responses to favor their propagation. In contrast to HBV, HDV activates profound IFN response through the melanoma differentiation antigen 5 (MDA5) pathway. This cellular response efficiently suppresses cell-division-mediated HDV spread and, to some extent, early stages of HDV de novo infection, but only marginally impairs RNA replication in resting hepatocytes. In this review, we summarize the current knowledge on HDV structure, replication, and persistence and subsequently focus on the interplay between HDV and IFN response, including IFN activation, sensing, antiviral effects, and viral countermeasures. -
Assessment Report
21 November 2013 EMA/CHMP/688774/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Sovaldi International non-proprietary name: sofosbuvir Procedure No. EMEA/H/C/002798/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2014. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure ............................................ 7 1.1. Submission of the dossier .................................................................................... 7 1.2. Manufacturers .................................................................................................... 8 1.3. Steps taken for the assessment of the product ....................................................... 8 2. Scientific discussion .............................................................................. 9 2.1. Introduction ....................................................................................................... 9 2.2. Quality aspects ................................................................................................ 14 2.2.1. Introduction .................................................................................................. 14 2.2.2. -
HCV Eradication with Direct Acting Antivirals (Daas)?
HCV eradication with direct acting antivirals (DAAs)? Emilie Estrabaud Service d’Hépatologie et INSERM UMR1149, AP-HP Hôpital Beaujon, Paris, France. [email protected] HCV eradication with direct acting antivirals (DAAs)? HCV replication HCV genome and DAAs targets NS3 inhibitors NS5A inhibitors NS5B inhibitors Take home messages HCV viral cycle Asselah et al. Liver Int. 2015;35 S1:56-64. Direct acting antivirals 5’NTR Structural proteins Nonstructural proteins 3’NTR Metalloprotease Envelope Serine protease Glycoproteins RNA Capsid RNA helicase Cofactors Polymerase C E1 E2 NS1 NS2 NS3 NS4A NS4B NS5A NS5B Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors Telaprevir Daclatasvir Nucs Non-Nucs Boceprevir Ledipasvir Simeprevir ABT-267 Sofosbuvir ABT-333 Faldaprevir GS-5816 VX-135 Deleobuvir Asunaprevir Direct Acting Antivirals: 2015 Asselah et al. Liver Int. 2015;35 S1:56-64. Genetic barrier for HCV direct acting antivirals High Nucleos(t)ide 1 mutation= high cost to Analog Inhibitors fitness, 2-3 additional mutations to increase fitness 2 st generation Protease Inhibitors n Non Nucleos(t)ide Analog Inhibitors : NS5 A Inhibitors 1 st generation Protease Inhibitors 1 mutation= low cost to fitness Low Halfon et al. J Hepatol 2011. Vol 55(1):192-206. HCV protease inhibitors (PI) Inhibit NS3/NS4A serine protease responsible for the processing of the polyprotein 1st generation 1st generation, 2nd wave 2nd generation Resistance low low high barrier Genotype activity 1: 1 a< 1b All except 3 all Drug drug Important Less Less interaction Drugs Boceprevir Simeprevir (Janssen) MK-5172 Telaprevir Faldaprevir (BI) ACH-2684 Paritaprevir (ABT-450)/r (AbbVie) Vedroprevir (Gilead) Vaniprevir (Merck) Sovaprevir (Achillion) Asunaprevir (BMS) NS3/NS4A structure Repositioning of helicase domain Self cleavage Lipid Bilayer Inactive Insertion of the Active carboxy-terminal tail Bartenschlager et al. -
2019 Icar Program & Abstracts Book
Hosted by the International Society for Antiviral Research (ISAR) ND International Conference 32on Antiviral Research (ICAR) Baltimore MARYLAND PROGRAM and USA Hyatt Regency BALTIMORE ABSTRACTS May 12-15 2019 ND TABLE OF International Conference CONTENTS 32on Antiviral Research (ICAR) Daily Schedule . .3 Organization . 4 Contributors . 5 Keynotes & Networking . 6 Schedule at a Glance . 7 ISAR Awardees . 10 The 2019 Chu Family Foundation Scholarship Awardees . 15 Speaker Biographies . 17 Program Schedule . .25 Posters . 37 Abstracts . 53 Author Index . 130 PROGRAM and ABSTRACTS of the 32nd International Conference on Antiviral Research (ICAR) 2 ND DAILY International Conference SCHEDULE 32on Antiviral Research (ICAR) SUNDAY, MAY 12, 2019 › Women in Science Roundtable › Welcome and Keynote Lectures › Antonín Holý Memorial Award Lecture › Influenza Symposium › Opening Reception MONDAY, MAY 13, 2019 › Women in Science Award Lecture › Emerging Virus Symposium › Short Presentations 1 › Poster Session 1 › Retrovirus Symposium › ISAR Award of Excellence Presentation › PechaKucha Event with Introduction of First Time Attendees TUESDAY, MAY 14, 2019 › What’s New in Antiviral Research 1 › Short Presentations 2 & 3 › ISAR Award for Outstanding Contributions to the Society Presentation › Career Development Panel › William Prusoff Young Investigator Award Lecture › Medicinal Chemistry Symposium › Poster Session 2 › Networking Reception WEDNESDAY, MAY 15, 2019 › Gertrude Elion Memorial Award Lecture › What’s New in Antiviral Research 2 › Shotgun Oral