1 / 18

EASL 2011 31 March 2011 - Berlin, Germany

Impact of IL28B Genotype and Pre-treatment Serum IP-10 in Treatment-Naïve Genotype 1 HCV Patients Treated with TMC435 in Combination with Peginterferon a -2a and Ribavirin in the PILLAR Study.

waseem
Télécharger la présentation

EASL 2011 31 March 2011 - Berlin, Germany

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. Impact of IL28B Genotype and Pre-treatment Serum IP-10 in Treatment-Naïve Genotype 1 HCV Patients Treated with TMC435 in Combination with Peginterferon a-2a and Ribavirin in the PILLAR Study Jeroen AERSSENS,1 Greg FANNING,2 Annick SCHOLLIERS,3Oliver LENZ,4 Monika PEETERS,5 Goedele DE SMEDT,6Michael W FRIED7 1Department of Translational Genomics & Genetics; 2Department of Infectious Disease and Vaccines; 3Department of Enabling Biology; 4Department of Clinical Virology; 5Department of Statistics; 6Department of Clinical Development, Tibotec, Beerse, Belgium; 7University of North Carolina at Chapel Hill, Chapel Hill, NC, USA EASL 2011 31 March 2011 - Berlin, Germany

  2. Disclosures • Jeroen Aerssens • Greg Fanning • AnnickScholliers • Oliver Lenz • Monika Peeters • Goedele De Smedt • Michael W Fried • TMC435 is an investigational product for hepatitis C virus (HCV) treatment, under development by Tibotec (part of the Janssen Pharmaceutical Companies of Johnson & Johnson) Employed by Tibotec, stock/shareholder J&J Employed by Tibotec, stock/shareholder J&J Employed by Tibotec Employed by Tibotec, stock/shareholder J&J Employed by Tibotec, stock/shareholder J&J Employed by Tibotec, stock/shareholder J&J Grants/Research Support, Consultant (Roche, Merck, Human Genome Sciences, Vertex, Tibotec, Bristol-Myers Squibb, Anadys, Conatus, Schering, Pharmasset, Glaxo, Novartis), Stock/Shareholder (Pharmasset)

  3. Background: IL28B genotype and virologic response during treatment with PegIFN/RBV Treatment-naïve, HCV genotype 1, Caucasian patients (n=1171) PegIFN/RBV treatment RVR (week 4) cEVR (week 12) SVR p<0.0001 p<0.0001 p<0.0001 87% 69% Proportion of patients achieving virologic response (%) 38% 33% 28% 28% 27% 5% 5% TT CT CC TT CT CC TT CT CC Thompson et al. Gastroenterology 2010; 139:120-129 cEVR, complete early virologic response; IL28B CC/CT/TT, rs12979860 polymorphism; PegIFN, pegylated interferon α-2a; RBV, ribavirin; RVR, rapid virologic response; SVR, sustained virologic response

  4. Background: Pre-treatment serum IP-10 and virologic response during treatment with PegIFN/RBV Treatment-naïve, HCV genotype 1, European patients (n=173) PegIFN/RBV treatment p=0.0002 p=0.003 IP-10 (pg/mL) at baseline 68% Proportion of patients achieving virologic response (%): SVR 55% 21% n=47 n=102 n=24 IP-10 at baseline (pg/ml) Lagging et al. Hepatology 2006; 44:1617-1625 IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin; SVR, sustained virologic response, HCV RNA <25 IU/mL (undetectable)

  5. Background: Pre-treatment serum IP-10 improves predictive value of IL28B for PegIFN/RBV treatment response IL28B genotype and pre-treatment serum IP-10 are independent and additive factors to predict sustained virologic response (SVR) ViraHepC cohort (n=210) HCV genotype 1 Overall SVR = 59% 89% 79% 64% % patients with SVR 48% 24% 20% IL28B genotype Serum IP-10 concentration Likelihood ratio Chi2 = 55 p<0.0001 Darling et al. Hepatology 2011; 53:14-22 IL28B TT/CT/CC, rs12979860 polymorphism; IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin

  6. IL28B and IP-10 analyses: Objective • Evaluate the relationship of IL28B genotype and/or pre-treatment serum IP-10 level with on-treatment virologic response up to Week 24 in the TMC435 PILLAR study • TMC435 is a once-daily oral HCV NS3/4A protease inhibitor • PILLAR (TMC435-C205; NCT00882908) is a Phase IIb, randomised, double-blind, placebo-controlled study in treatment-naïve genotype 1 HCV patients treated with TMC435 in combination with PegIFN/RBV Fried et al. AASLD 2010 IL28B, rs12979860 polymorphism; IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin.

  7. PILLAR study design Consented for DNA research RGT* N=ITT PegIFN/RBV Pbo & PegIFN/RBV TMC435 75 mg & PegIFN/RBV TMC12/PR24 75 mg Post-therapy FU Post-therapy FU N=58 N=78 Post-therapy FU PegIFN/RBV TMC24/PR24 75 mg Post-therapy FU TMC435 75 mg & PegIFN/RBV Post-therapy FU N=51 Post-therapy FU N=75 Post-therapy FU PegIFN/RBV Pbo & PegIFN/RBV TMC435 150 mg & PegIFN/RBV Post-therapy FU TMC12/PR24 150 mg Post-therapy FU Post-therapy FU N=55 N=77 Post-therapy FU PegIFN/RBV TMC24/PR24150 mg Post-therapy FU N=79 N=52 Post-therapy FU TMC435 150 mg & PegIFN/RBV Post-therapy FU Post-therapy FU Pbo24/ PR48 PegIFN/RBV Pbo & PegIFN/RBV N=77 N=46 Week 72 4 24 48 0 12 * RGT: Response-guided treatment duration in TMC435 arms • For IL28B and IP-10 analyses, dose groups were pooled • 68% of patients (262 out of 386) consented for DNA research (including IL28B genotyping) Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 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 administered once-daily; FU, follow-up; IL28B, rs12979860 polymorphism; IP-10, interferon- inducible protein 10; ITT, intent to treat; Pbo, placebo; TMC, TMC435.

  8. PILLAR study: Demographics and baseline disease characteristics for patients who consented to DNA research #As determined by NS5B sequence-based assay; †patients with cirrhosis (F4) were not eligible; ‡no significant differences between treatment groups; *higher frequency of patients with high IP-10 in TMC435 150 mg group vs other groups (p<0.02) IL28B TT/CT/CC, rs12979860 polymorphism; IP-10, interferon- inducible protein 10.

  9. PILLAR: On-treatment virologic response up to Week 24 by IL28B genotype Virologic response: HCV RNA <25 IU/ml (detectable or undetectable) Placebo + PegIFN/RBV n=12 n=28 Proportion of patients (%) n=6 Pearson Chi2 test N.S. p<0.01 p<0.04 The data analysis excluded missing values. CC/CT/TT, rs12979860 polymorphism; N.S., not significant; PegIFN, pegylated interferon α-2a; RBV, ribavirin.

  10. PILLAR: On-treatment virologic response up to Week 24 by IL28B genotype Virologic response: HCV RNA <25 IU/ml (detectable or undetectable) TMC435 75 mg + PegIFN/RBV TMC435 150 mg + PegIFN/RBV Placebo + PegIFN/RBV n=31 n=12 n=35 n=64 n=60 n=12 n=28 n=14 Proportion of patients (%) n=6 Pearson Chi2 test N.S. p<0.003 p<0.003 N.S. N.S. N.S. N.S. p<0.01 p<0.04 The data analysis excluded missing values. CC/CT/TT, rs12979860 polymorphism; N.S., not significant; PegIFN, pegylated interferon α-2a; RBV, ribavirin.

  11. PILLAR: On-treatment virologic response up to Week 24 by baseline serum IP-10 Virologic response: HCV RNA <25 IU/ml (detectable or undetectable) Placebo + PegIFN/RBV Baseline IP-10 n=40 Low (<600 pg/mL) High (≥600 pg/mL) Proportion of patients (%) n=4 Pearson Chi2 test N.S. N.S. N.S. The data analysed excluded missing values. IP-10, interferon- inducible protein 10; N.S., not significant; PegIFN, pegylated interferon α-2a; RBV, ribavirin.

  12. PILLAR: On-treatment virologic response up to Week 24 by baseline serum IP-10 Virologic response: HCV RNA <25 IU/ml (detectable or undetectable) TMC435 75 mg + PegIFN/RBV TMC435 150 mg + PegIFN/RBV Placebo + PegIFN/RBV n=10 n=80 n=96 n=23 Baseline IP-10 n=40 Low (<600 pg/mL) High (≥600 pg/mL) Proportion of patients (%) n=4 Pearson Chi2 test N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. N.S. The data analysed excluded missing values. IP-10, interferon- inducible protein 10; N.S., not significant; PegIFN, pegylated interferon α-2a; RBV, ribavirin.

  13. PILLAR:On-treatmentvirologic response up to Week 24 by IL28B genotype/baseline serum IP-10 combined: Placebo + PegIFN/RBV Virologic response: HCV RNA <25 IU/ml (detectable or undetectable) Week 4 Week 12 Week 24 100% 100% 77% 57% Proportion of patients (%) 50% 17% 40% 40% 5% 25% 20% 0% IL28B IL28B IL28B IP-10 IP-10 IP-10 IL28B CC/CT/TT, rs12979860 polymorphism; IP-10, interferon- inducible protein 10;PegIFN, pegylated interferon α-2a; RBV, ribavirin

  14. PILLAR:On-treatmentvirologic response up to Week 24 by IL28B genotype/baseline serum IP-10 combined: TMC435 75 mg + PegIFN/RBV Virologic response: HCV RNA <25 IU/ml (detectable or undetectable) Week 4 Week 12 Week 24 100% 100% 100% 100% 100% 93% 100% 100% 100% 96% 96% 100% 86% 100% 100% 67% 67% 67% Proportion of patients (%) n=1 n=1 n=1 IL28B IL28B IL28B IP-10 IP-10 IP-10 IL28B CC/CT/TT, rs12979860 polymorphism; IP-10, interferon- inducible protein 10;PegIFN, pegylated interferon α-2a; RBV, ribavirin

  15. PILLAR:On-treatmentvirologic response up to Week 24 by IL28B genotype/baseline serum IP-10 combined: TMC435 150 mg + PegIFN/RBV Virologic response: HCV RNA <25 IU/ml (detectable or undetectable) Week 4 Week 12 Week 24 96% 100% 100% 100% 95% 100% 95% 100% 95% 100% 100% 100% 100% 100% 90% 77% 83% 77% Proportion of patients (%) IL28B IL28B IL28B IP-10 IP-10 IP-10 IL28B CC/CT/TT, rs12979860 polymorphism; IP-10, interferon- inducible protein 10;PegIFN, pegylated interferon α-2a; RBV, ribavirin

  16. Summary • During the first 24 weeks of treatment in the PILLAR study: • In the control group, treated with placebo and PegIFN/RBV, IL28B CC genotype and low baseline serum IP-10 levels were associated with the highest virologic response • In patients treated with TMC435 in combination with PegIFN/RBV, high virologic response rates were observed, regardless of IL28B genotype and/or baseline serum IP-10 • The highest response for IL28B TT genotype was observed in TMC435 150 mg group IL28B,rs12979860 polymorphism; IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin

  17. Conclusions • The addition of TMC435 to PegIFN/RBV reduces the impact of IL28B genotype and/or baseline serum IP-10 on virologic response up to 24 weeks of treatment • Evaluation of the potential impact of these markers on sustained virologic response (SVR) in triple combination therapy will be assessed in the Phase IIb and Phase III trials IL28B,rs12979860 polymorphism; IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin

  18. Acknowledgements • 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 • JawaharTaunk, Palm Harbor • Lawrence Wruble, Germantown • ZiadYounes, 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 • Editorial support was provided by Dr. BethanLowder at Complete Medical Communications, funded by Tibotec. • Maria Beumont-Mauviel, Joan Cannon, Ronald Kalmeijer, Eric Lefebvre, Karen Lindsay, Karen Manson, Gaston Picchio and VanithaSekarcontributed to development of the presentation.

More Related