1 / 18

Disclosure Information

Ef ficacy and Safety of TMC435 in Combination With Peginterferon a -2a and Ribavirin in Treatment-naïve Genotype-1 HCV Patients: 24-Week Interim Results from the PILLAR Study.

zach
Download Presentation

Disclosure Information

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Efficacy and Safety of TMC435 in Combination With Peginterferon a-2a and Ribavirin in Treatment-naïve Genotype-1 HCV Patients: 24-Week Interim Results from the PILLAR Study M.W. Fried,1 M. Buti,2 G.J. Dore,3 P. Ferenci,4I. Jacobson,5 P. Marcellin,6S. Zeuzem,7O. Lenz,8 M. Peeters,8 V. Sekar,9G. De Smedt8 1University of North Carolina at Chapel Hill, North Carolina, USA;2Hospital Vall d'Hebron and Ciberehd, Barcelona, Spain; 3St Vincent's Hospital, Sydney, Australia and National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; 4Allgemeines Krankenhaus der Stadt Wien, Wien, Austria ; 5Weill Cornell Medical College, New York, USA; 6Hopital Beaujon, Clichy, Paris, France; 7Klinikum der Johann-Wolfgang-Goethe-Universität - Med. Klinik I, Frankfurt, Germany; 8Tibotec, Beerse, Belgium; 9Tibotec Inc., Titusville, New Jersey, USA

  2. Disclosure Information • Michael Fried Grants/Research Support, Consultant (Roche, Merck, Human Genome Sciences, Vertex, Tibotec, Bristol Myers Squibb, Anadys, Conatus, Schering, Pharmasset, Glaxo, Novartis), Stock/Shareholder (Pharmasset) • Maria Buti Advisory Board and Speaker (MSD, Gilead, BMS) • Greg Dore Advisory Committee, Grant/Research Support, Teaching and Speaking, Travel Scholarship (Roche, Merck, Bristol-Myer Squibb, Gilead) • Peter Ferenci Advisory Committee and Review Panels, Unrestricted Grant/Research Support, Teaching and Speaking, Consulting, Patent Held (Roche, Vertex/Tibotec, Madaus-Rottapharm, Boehringer Ingelheim, MSD/previously SPI) • Ira Jacobson Grant/Research Support, Member of Speaker’s Bureau, Consultant/Advisor (Schering/Merck, Tibotec, Roche/Genentech, Pharmasset, Anadys, Boehringer Ingelheim, Novartis, Gilead, Vertex, GlobeImmune, Human Genome Sciences, Bristol Myers Squibb, Pfizer, Zymogenetics, Abbott, sanofi-aventis) • Patrick Marcellin Grant, Investigator, Speaker, and Expert (Roche, Schering Plough, Gilead, BMS, Vertex, Novartis, Pharmasset, Tibotec, MSD, Boehringer Ingelheim, Biolex, Intermune, Zymogenetics) • Stefan Zeuzem Consultancy, Member of Speaker’s Bureau (Abbott, BMS, Gilead, Merck, Pfizer, Roche, Tibotec, Vertex) • Oliver Lenz Employed by Tibotec • Monika Peeters Employed by Tibotec • Vanitha Sekar Employed by Tibotec • Goedele De Smedt Employed by Tibotec

  3. PILLAR (Study TMC435-C205): Objectives & Endpoints • Objective • To assess efficacy and safety of protease inhibitor TMC435 once-daily in combination with PegIFN/RBV* in treatment-naïvepatientsinfectedwith HCV genotype-1 • Study design • Ongoing international, Phase IIb, randomized, double-blind, placebo-controlled clinical trial • Primary endpoint • Sustained virologic response at Week 72 • Key secondary endpoints • Antiviral activity throughout study • Viral breakthrough and relapse rates • Safety and tolerability • Pharmacokinetics Results of a planned Week 24 interim analysis are reported today *PegIFN/RBV, peginterferon -2a (180 g/wk) + ribavirin (1000–1200 mg/day); HCV, hepatitis C virus

  4. PILLAR: Study Design Planned interim analysis All available data included N=ITT Pbo & PegIFN/RBV TMC435 75 mg & PegIFN/RBV TMC12/PR24 75 mg N=78 Post-therapy FU TMC24/PR24 75 mg N=75 TMC435 75 mg & PegIFN/RBV Post-therapy FU Pbo & PegIFN/RBV TMC435 150 mg & PegIFN/RBV TMC12/PR24 150 mg N=77 Post-therapy FU TMC24/PR24 150 mg N=79 Post-therapy FU TMC435 150 mg & PegIFN/RBV Pbo24/PR48 N=77 Post-therapy FU PegIFN/RBV Pbo & PegIFN/RBV Week 0 12 72 24 48 • Response-guided treatment duration in TMC435 arms • End treatment at Week 24, if • HCV RNA <25 IU/mL detectable or undetectable at Week 4, and • HCV RNA <25 IU/mL undetectable at Weeks 12, 16, and 20 • All other patients continued Peg/RBV for up to 48 weeks TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; FU, follow-up; ITT, intent to treat; Pbo, placebo; RNA, ribonucleic acid; TMC, TMC435

  5. PILLAR: Demographics and Baseline Disease Characteristics *As determined by NS5B sequence-based assay † Patients with cirrhosis (F4) were not eligible ‡ Polymorphism on chromosome 19 s12979860, data available for patients who consented only (67.9%) TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; no. of subjects completing therapy at Week 24 was according to response-guided treatment algorithm

  6. TMC12/PR24 75 mg TMC24/PR24 75 mg TMC12/PR24 150 mg TMC24/PR24 150 mg Pbo24/PR48 • PILLAR Week 24 Analysis: Mean Change in Plasma HCV RNA From Baseline 0 -1 -2 -3 Mean (+/- SE) change in plasma HCV RNA (log10 IU/mL) from baseline -4 -5 -6 -7 0 4 8 12 16 20 24 Week TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; SE, standard error

  7. PILLAR Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Weeks 4 and 12 Week 12 Week 4 100 *** *** *** *** *** *** *** *** 80 60 Proportion of patients (%) 40 20 0 Pbo24/PR48 (n=74) TMC12/PR24 75 mg (n=77) TMC24/PR24 75 mg (n=75) TMC12/PR24 150 mg (n=76) TMC24/PR24 150 mg (n=75) Pbo24/PR48 (n=75) TMC12/PR24 75 mg (n=78) TMC24/PR24 75 mg (n=73) TMC12/PR24 150 mg (n=77) TMC24/PR24 150 mg (n=77) >25 IU/mL <25 IU/mL undetectable <25 IU/mLdetectable HCVRNA ***TMC435 vs placebo: p≤0.001; TMC12/PR24, TMC435 for 12 weeks in addition to Peg/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to Peg/RBV for 24 weeks; HCV RNA determined using Roche TaqMan v2

  8. PILLAR Week 24 Analysis: Proportion of Patients Achieving Virologic Response at Week 24 Week 24 100 80 60 Proportion of patients (%) 40 20 0 TMC12/PR24 75 mg (n=77) TMC24/PR24 75 mg (n=72) TMC12/PR24 150 mg (n=69) TMC24/PR24 150 mg (n=73) Pbo24/PR48 (n=73) >25 IU/mL <25 IU/mL undetectable <25 IU/mLdetectable HCVRNA TMC12/PR24, TMC435 for 12 weeks in addition to Peg/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to Peg/RBV for 24 weeks; HCV RNA determined using Roche TaqMan v2

  9. PILLAR Week 24 Analysis: Proportion of Patients Achieving Undetectable HCV RNA After Planned End of Treatment • Between 79% and 86% of patients in TMC435 arms ended therapy at Week 24 as per protocol-defined response criteria * Denominator based on number of patients that stopped treatment for any reason by Week 24 and reached specified timepoint TMC12/PR24, TMC435 for 12 weeks in addition to PegIFN/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to PegIFN/RBV for 24 weeks; SVR, sustained virologic response; †not yet defined in the placebo group in this Week 24 analysis as planned end of treatment has not been reached

  10. PILLAR Week 24 Analysis: Viral Breakthrough 50 40 30 Proportion of patients with viral breakthrough,* cumulative (%) 20 7.8% 6.4% 10 3.9% 2.7% 2.5% 0 TMC24/PR24 75 mg TMC12/PR24 150 mg TMC24/PR24 150 mg Pbo24/PR48 TMC12/PR24 75 mg Weeks 1-12 Weeks 1-4 Weeks 1-24 *Viral breakthrough: confirmed increase of >1 log from nadir or >100 IU/mL if undetectable; TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks

  11. PILLAR Week 24 Analysis: Mean Change in HCV RNA from Baseline According to IL28B Genotype* Placebo 0 -2 CC CT TT -4 -6 Mean (+/- SE) change in plasma HCV RNA (log10 IU/mL) from baseline 0 4 8 12 16 20 24 Week All TMC435 75 mg All TMC435 150 mg 0 0 -2 -2 -4 -4 -6 -6 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Week Week *Data shown for patients who consented only (67.9%); CC/TT/CT, polymorphism on chromosome 19 s12979860

  12. PILLAR Week 24 Analysis: Adverse Events *Reported in ≥25% of subjects in the ‘All TMC435’ group (all dose groups combined) † Rash (any type) combines all reported types of rash ‡ Reported as an adverse event by study investigator if laboratory abnormalities considered clinically relevant TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks

  13. PILLAR Week 24 Analysis: Laboratory • Parameters, Bilirubin Over Time • Mild and reversible increases in bilirubin (direct and indirect) were noted in TMC435 150 mg dose arms Pbo24/PR48 TMC 75 mg TMC 150 mg 30 25 Upper limit of normal 20 Mean (+/- SE) values of bilirubin (μmol/L) 15 10 Lower limit of normal 5 0 0 1 2 4 6 8 12 16 20 24 Week TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; SE, standard error; to convert from bilirubin mol/L to mg/dL, divide by 17.1

  14. PILLAR Week 24 Analysis: Laboratory • Parameters, Bilirubin Over Time • Mild and reversible increases in bilirubin (direct and indirect) were noted in TMC435 150 mg dose arms TMC12/PR24 75 mg TMC24/PR24 75 mg TMC12/PR24 150 mg TMC24/PR24 150 mg Pbo24/PR48 TMC 75 mg TMC 150 mg 30 25 Upper limit of normal 20 Mean (+/- SE) values of bilirubin (μmol/L) 15 10 Lower limit of normal 5 0 0 1 2 4 6 8 12 16 20 24 Week TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks;all TMC435 doses were administered once-daily;Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; SE, standard error; to convert from bilirubin mol/L to mg/dL, divide by 17.1

  15. PILLAR Week 24 Analysis: Laboratory Parameters, Bilirubin, ALT, and ALP Over Time (TMC12/PR24 150 mg) Upper limit of normal Mean (+/- SE) values of bilirubin (μmol/L) 20 10 90 Mean (+/- SE) values of ALT (IU/mL) 60 Upper limit of normal 30 Upper limit of normal 140 120 100 Mean (+/- SE) values of ALP (IU/mL) 80 60 40 20 0 1 2 4 6 8 12 16 20 24 Week TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -2a [180 g/wk] + ribavirin [1000–1200 mg/day]); ALT, alanine aminotransferase; ALP, alkaline phosphatase ; SE, standard error; to convert from bilirubin mol/L to mg/dL, divide by 17.1

  16. PILLAR Week 24 Analysis: Efficacy Summary • TMC435 administered once-dailywith PegIFN/RBV over 12 or 24 weeks demonstrated potent antiviral activity • At Weeks 4 and 12, HCV RNA was <25 IU/mL (undetectable) for the majority of patients in TMC435 groups • The majority of patients in TMC435 groups met the criteria to stop treatment at Week 24 • In patients who completed therapy at or before Week 24, response rates remained high 12 weeks after planned end of therapy • Addition of TMC435 to PegIFN/RBV increased response rates in all IL28B genotypes

  17. PILLAR Week 24 Analysis: Safety Summary • No clinically relevant difference in safety and tolerability between TMC435 and placebo groups • Frequency of rash, gastrointestinal events, and anemia were similar to placebo group • Mild and reversible increases in bilirubin concentration observed with 150 mg dose • ALT concentration decreased in all treatment groups • Discontinuation in TMC435 groups was low and similar to placebo group • Planning of Phase III studies of TMC435 is underway

  18. Acknowledgements Gregory Fanning, Richard Hoetelmans, Ronald Kalmeijer,Eric Lefebvre, Karen Manson, Gaston Picchio, Setareh Seyedkazemi, and Brian Woodfall (Tibotec) have also contributed to development of the presentation, and editorial assistance was provided by Bethan Lowder at Complete Medical Communications. • The patients and their families • The PILLAR investigators and their study staff • New Zealand • Ed Gane, Auckland • Catherine Stedman, Christchurch • Graeme Dickson, Hamilton • Norway • Trond Bruun, Bergen • Bent von der Lippe, Kirkeveien • Zbigniev Konopski, Trondheimsveien • Kjell Block Hellum, Sykehusveien • Jon Florholmen, Tromso • Poland • Robert Flisiak, Bialystok • Andrzej Horban, Warszawa • Waldemar Halota, Bydgoszcz • Wieslaw Kryczka, Kielce • Maciej Jablkowski, Lodz • Ewa Janczewska-Kazek, Czeladz • Russia • Alexey A. Yakovlev, Saint-Petersburg • Vladimir V. Rafalskiy, Smolensk • Evgeny E. Voronin, Saint-Petersburg • N Zakharova, Saint-Petersburg • Igor G. Nikitin, Moscow • Pavel O. Bogomolov, Moscow • Vladimir T. Ivashkin, Moscow • Vyacheslav G. Morozov, Samara • Olga V. Korochkina, Nizhny • Novgorod • Spain • Maria Buti, Barcelona • Moises Diago, Valencia • Ricardo Moreno-Otero, Madrid • Manuel Romero, Sevilla • Jose Luis Calleja, Madrid • Germany • Keikawus Arasteh, Berlin • Thomas Berg. Berlin • Peter Buggisch, Hamburg • Hartwig Klinker, Würzburg • Andreas Trein, Stuttgart • Tobias Goeser, Köln • Stefan Mauss, Düsseldorf • Dr. Jens Rasenack, Freiburg • Stefan Zeuzem, Frankfurt • Hans-Jürgen Stellbrink, Hamburg • USA • Daniel Pambianco, Charlottesville • Edwin DeJesus, Orlando • Kyle Etzkron, Jacksonville • Michael Fried, Chapel Hill • Andrei Gasic, Longview • Nigel Girgrah, New Orleans • Ira M. Jacobson, New York • Donald M. Jensen, Chicago • Mark E. Jonas, Cincinnati • Fred Poordad, Los Angeles • Coleman Smith, Plymouth • Jawahar Taunk, Palm Harbor • Lawrence Wruble, Germantown • Ziad Younes, Germantown • Canada • Pierre Cote, Montreal • Gideon Hirschfield, Toronto • Maged Peter Ghali, Montreal • Sam Lee, Calgary • Morris Sherman, Toronto • Australia • Greg Dore, Darlinghurst • Paul Desmond, Fitzroy • Stuart Roberts, Melbourne • Jacob George, Westmead • Graeme Macdonald, Woolloongabba • Alice Lee, Concord • Austria • Peter Ferenci, Wien • Hermann Laferl, Wien • Michael Gschwantler, Wien • Belgium • F. Nevens, Leuven • Y. Horsmans, Bruxelles • C. Moreno, Bruxelles • H. Van Vlierberghe, Ghent • P. Michielsen, Edegem • H. Orlent, Brugge • H. Reynaert, Bruxelles • J. Decaestecker, Roeselare • Denmark • Jan Gerstoft, Copenhagen • Alex Lund Laursen, Aarhus • Lars Mathiesen, Hvidovre • Axel Møller, Kolding • Peer Brehm Christensen, Odense • France • Yves Benhamou, Paris • Christian Trepo, Lyon • Jean Pierre Bronowicki, Vandoeuvre Les Nancy • Christophe Hezode, Creteil • Patrick Marcellin , Clichy • Jean-didier Grange, Paris • Jean Pierre Zarski, Grenoble • Albert Tran, Nice

More Related