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SILEN-C2: sustained virological response (SVR) and safety of BI 201335 combined with peginterferon alfa 2a and ribavirin (PegIFN/RBV) in chronic HCV genotype-1 patients with nonresponse to PegIFN/RBV.

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  1. SILEN-C2: sustained virological response (SVR) and safety of BI 201335 combined with peginterferon alfa 2a and ribavirin (PegIFN/RBV) in chronic HCV genotype-1 patients with nonresponse to PegIFN/RBV M.S. Sulkowski,1 M. Bourlière,2 J.-P. Bronowicki,3 A. Streinu-Cercel,4 L. Preotescu,4T.Asselah,5 J.-M. Pawlotsky,6 S. Shafran,7 S. Pol,8 F.A. Caruntu,4 S. Mauss,9 D. Larrey,10C. Häfner,11 Y. Datsenko,11 J.O. Stern,12 R. Kubiak,11 W. Böcher,11 G. Steinmann11 On behalf of the SILEN-C2 study group 1Johns Hopkins University, Baltimore, MD, USA; 2Hôpital Saint Joseph, Marseille, France; 3Hôpital de Brabois, Vandoeuvre Cedex, France; 4“Prof. Dr. Matei Bals” Institute of Infectious Diseases, Bucharest, Romania; 5Hôpital Beaujon, Clichy Cedex, France; 6Hôpital Henri Mondor, Créteil, France; 7University of Alberta, Edmonton, AB, Canada; 8Hôpital Cochin, Paris, France; 9Center for HIV and Hepatogastroenterology, Düsseldorf, Germany; 10Hôpital Saint-Eloi, Montpellier Cedex, France; 11Boehringer Ingelheim Pharma, Biberach, Germany; 12Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA

  2. Speaker declaration I have financial relationships within the last 12 months relevant to my presentation with Boehringer Ingelheim Pharmaceuticals. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies and my presentation includes discussion of off-label or investigational use of: • BI 201335 • Peginterferon alfa 2a • Ribavirin

  3. Double-blind, placebo-controlled, phase IIb study in HCV genotype-1 (GT-1) patients with nonresponse to previous PegIFN/RBV * 240 mg QD LI BI 201335 + PegIFN/RBV PegIFN/RBV n = 142 n = 76 n = 70 PegIFN/RBV 240 mg QD BI 201335 + PegIFN/RBV * 240 mg BID LI BI 201335 + PegIFN/RBV PegIFN/RBV D1 D4 Week 24 Week 48 *3-day lead-in period (LI) of PegIFN alfa 2a (180 μg/week) plus ribavirin (1,000 mg or 1,200 mg/day); Re-randomisation 1:1 of patients with eRVR (extended rapid virological response) to 24 versus 48 weeksof PegIFN/RBV QD, once daily; BID, twice daily SILEN-C2 trial

  4. Main inclusion criteria • Age 18 to 65 years • Chronic hepatitis C GT-1 infection • Confirmed nonresponse during previous PegIFN/RBV treatment • ≥ 12 weeks of an approved dose of PegIFN/RBV • Null response: < 1 log10 maximum HCV RNA reduction any time during treatment • Partial response: > 1 log10 maximum HCV RNA reduction, but never undetectable (with a sensitive assay) • Relapsers were excluded • HCV RNA ≥ 100,000 IU/mL at screening • Liver biopsy within 2 years without evidence of cirrhosis

  5. Baseline characteristics aBased on NS3/4A sequencing; bOther genotypes were 1C (n=1), 1D (n=1) and 1G (n=1). 1 patient was GT-1 but subgenotype could not be determined

  6. Virological response Proportion of patients (%) 61/142 34/76 33/70 39/142 22/70 31/76 eRVR: HCV RNA < 25 IU/mL at Week 4 and undetected at Weeks 8 to 20

  7. SVR in partial- and null-responders 100 80 60 40 20 0 Proportion of patients (%) 16/54 13/26 10/24 12/57 11/38 14/40 Null response, <1 log10 maximum HCV RNA reduction any time during treatment; Partial response, > 1 log10 maximum HCV RNA reduction, but never undetectable (with a sensitive assay)

  8. SVR and relapse in eRVR patients by duration of PegIFN/RBV 100 80 60 40 20 0 P = 0.018 Proportion of patients (%) 12/30 21/29 18/30 6/29 Relapse: rebound from undetectable at end of all treatment

  9. Virological failures 240 mg QD LI 240 mg QD 240 mg BID LI 100 80 60 40 20 0 Proportion of patients (%) 28 25 25 19 17 9 7 6 5 Breakthrougha on Breakthrougha on Relapseb BI 201335 PegIFN/RBV a≥ 1 log10 rebound from nadir, or rebound to ≥ 100 IU/mL if nadir < lower limit of detection (LLOD) on treatment, confirmed in a second sample; bRebound after end of all treatment from nadir < LLOD after end of treatment

  10. Adverse eventsa aAdverse events > 10% compared with PegIFN/RBV; bNumber quoted is according to given treatment; cNo cases of Stevens-Johnson syndrome, erythema multiforme or drug rash with eosinophilia and systemic symptoms

  11. Adverse events: overall summary aNumber quoted is according to given treatment; bOther discontinuations mainly due to general disorders and administration site conditions, gastrointestinal and others

  12. 240 mg QD LI 240 mg QD 240 mg BID LI Mean total bilirubin (mg/dL) BL Day 4 Week 1 Week 2 Week 4 Week 8 Week Week Week Week Week Week 10 12 16 20 24 28 Effect of BI 201335 on bilirubin and haemoglobin Mean haemoglobin (g/dL) BL, baseline

  13. Discussion and conclusion • Virological response • robust SVR rates up to 41% at 240 mg QD • dose selected for phase III • response-guided therapy was not effective for nonresponsive patients achieving eRVR • 3-day PegIFN/RBV lead-in did not increase SVR • Safety and tolerability • most adverse events were those commonly related to PegIFN/RBV therapy • no excess effect on haemoglobin • mild-to-moderate jaundice and rash are the main BI 201335-related adverse events and are dose-dependent • jaundice is due to isolated indirect hyperbilirubinaemia • In treatment-experienced patients, BI 201335 240 mg QD appears to offer the best safety/efficacy balance • phase III trial in preparation

  14. Acknowledgements • Patients and study investigators at study centres in the following countries: Australia Jacob George William Sievert Barbara Leggett Graeme MacDonald Stephen Riordan Sally Bell Amany Zekry Austria Peter Ferenci Michael Gschwantler Andreas Maieron Canada Jenny Heathcote Stephen Shafran Bernard Willems Brian Conway Netherlands Henk Reesink Bart van Hoek Switzerland Enos Bernasconi Jürg Reichen France Tarik Asselah Yves Benhamou Stanislas Pol Marc Bourlière Jean-Pierre Bronowicki Dominique Larrey Jean-Michel Pawlotsky Christophe Hezode Christian Trepo Germany Thomas Berg Dieter Häussinger Ansgar Lohse Marcus Schuchmann Johannes Wiegand Stefan Mauss Ulrich Spengler Wolfgang E. Schmidt Elmar Zehnter Portugal Armando Carvalho Fernando Ramalho Filipe Calinas José Sarmento Rui Sarmento e Castro Republic of Korea Jeong Heo DoYoung Kim Young Oh Kweon SeungWoon Paik YounJae Lee Mong Cho Romania Adrian Streinu-Cercel Liliana Preotescu Florin Alexandru Caruntu Ceasu Emanoil Spain Jose Luis Calleja Javier García-Samaniego María Luisa Gracía Buey Jaime Enriquez Vicente Soriano United Kingdom Janice Main William Rosenberg Mark Wright Fiona Gordon Graham Foster Stephen Ryder Kosh Agarwal Mark Nelson United States Maurizio Bonacini Douglas Dieterich Ira Jacobson David Wright Donald Jensen Rajender Reddy Jacob Lalezari Ira Stein Lawrence Wruble • Boehringer Ingelheim for sponsoring the study and their clinical and statistical teams for study monitoring, data collection and analysis • Editorial support provided by StemScientific

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