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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.

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EASL 2011 31 March 2011 - Berlin, Germany

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  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.

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