SILEN-C1: Early Antiviral Activity and Safety of BI 201335 ...

SILEN-C1: Early Antiviral Activity and Safety of BI 201335 ...

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. Bourlire,2 J.-P. Bronowicki,3 A. Streinu-Cercel,4 L. Preotescu,4 T. Asselah,5 J.-M. Pawlotsky,6 S. Shafran,7 S. Pol,8 F.A. Caruntu,4 S. Mauss,9 D. Larrey,10 C. Hfner,11 Y. Datsenko,11 J.O. Stern,12 R. Kubiak,11 W. Bcher,11 G. Steinmann11 On behalf of the SILEN-C2 study group Johns Hopkins University, Baltimore, MD, USA; 2Hpital Saint Joseph, Marseille, France; 3Hpital de Brabois, Vandoeuvre Cedex, France; 4Prof. Dr. Matei Bals Institute of Infectious Diseases, Bucharest, Romania; 5Hpital Beaujon, Clichy Cedex, France; 6Hpital Henri Mondor, Crteil, France; 7 University of Alberta, Edmonton, AB, Canada; 8Hpital Cochin, Paris, France; 9Center for HIV and Hepatogastroenterology, Dsseldorf, Germany; 10Hpital Saint-Eloi, Montpellier Cedex, France; 11Boehringer Ingelheim Pharma, Biberach, Germany; 12Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA 1 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 SILEN-C2 trial Double-blind, placebo-controlled, phase IIb study in HCV genotype-1 (GT-1) patients with nonresponse to previous PegIFN/RBV n = 142 * 240 mg QD LI BI 201335 + PegIFN/RBV PegIFN/RBV n = 76 240 mg QD BI 201335 + PegIFN/RBV PegIFN/RBV n = 70 * 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 g/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 weeks of PegIFN/RBV QD, once daily; BID, twice daily 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 Baseline characteristics 240 mg QD LI n = 142 48.7 240 mg QD n = 76 49.6 240 mg BID LI n = 70 50.1 71.1 65.8 58.6 Ethnicity (%) White Black Asian 92.3

3.5 4.2 84.2 9.2 6.6 92.9 4.3 2.9 Mean HCV RNA (log10) 6.60 6.56 6.55 Genotypea (%) 1a 1b 1, other subtypesb 54.9 43.0 2.1 55.3 43.4 1.3 38.6 60.0 1.4 Prior response to PegIFN/RBV (%) Null response Partial response Nonresponse Others 40.1 38.0 9.2 12.7 52.6 34.2 3.9 9.2

54.3 34.3 7.1 4.3 Mean age (years) Male gender (%) Based 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 a Virological response 240 mg QD LI Proportion of patients (%) Proportion 50 45 43 45 240 mg QD 240 mg BID LI 47 41 40 35 31 27 30 25 20 15 10 5 0 61/142 34/76 33/70

eRVR eRVR: HCV RNA < 25 IU/mL at Week 4 and undetected at Weeks 8 to 20 39/142 31/76 SVR 22/70 SVR in partial- and null-responders 240 mg QD LI 240 mg QD 240 mg BID LI Proportion Proportion of of patients patients (%) (%) 100 80 60 50 42 40 40 35 30 21 20 20 00 29 16/54 13/26 10/24

Partial-responders 12/57 14/40 11/38 Null-responders 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) SVR and relapse in eRVR patients by duration of PegIFN/RBV 240 mg QD LI 24 weeks Proportion patients(%) (%) Proportion of patients 100 100 P = 0.018 80 80 72 60 60 60 40 40 240 mg QD LI 48 weeks 40 21 20 20 00 12/30 21/29

SVR Relapse: rebound from undetectable at end of all treatment 18/30 6/29 Relapse Virological failures 240 mg QD LI 240 mg QD 240 mg BID LI Proportion of patients (%) 100 80 60 40 25 20 28 25 5 0 19 17 Breakthrougha on BI 201335 7 6 Breakthrougha on PegIFN/RBV 9 Relapseb 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 a Adverse eventsa 240 mg QD LI (%) 240 mg QD (%) 240 mg BID LI (%) All patients (nb) 141 76 69 Rashc Mild Moderate Severe 34.0 27.7 5.7 0.7 27.6 23.7 2.6 1.3 42.0 15.9 20.3 5.8 Jaundice Severe 19.0 0 21.1 0 41.4 0

Nausea 48.2 52.6 63.8 Diarrhoea 31.9 31.6 39.1 Vomiting 17.0 22.4 31.9 Adverse 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 a Adverse events: overall summary All patients (na) With severe adverse events Fatalities Discontinuations for adverse events Discontinuations for Rash Photosensitivity Jaundice Othersb 240 mg QD LI (%) 240 mg QD (%) 240 mg BID LI (%) 141

76 69 14.2 14.5 27.5 0 0 0 5.7 3.9 23.2 0 0 0.7 5.0 1.3 0 0 2.6 14.5 1.4 1.4 5.8 Number quoted is according to given treatment; bOther discontinuations mainly due to general disorders and administration site conditions, gastrointestinal and others a Effect of BI 201335 on bilirubin and haemoglobin 240 mg QD LI 240 mg QD 240 mg BID LI Total bilirubin mg/dL (normal range 0.1 1)

Mean total bilirubin (mg/dL) 4 3 2 1 0 Mean hemoglobin (g/dL) BL Day 4 Week 1 Week 2 Week 4 Week 8 Week 10 Week 12 Week 16 Week 20 Week 24 Week 28 Week 16 Week 20 Week 24 Week 28 Mean haemoglobin (g/dL) 20 18 16 14

12 10 BL BL, baseline Day 4 Week 1 Week 2 Week 4 Week 8 Week 10 Week 12 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 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 Jrg Reichen France Tarik Asselah Yves Benhamou Stanislas Pol Marc Bourlire Jean-Pierre Bronowicki Dominique Larrey Jean-Michel Pawlotsky Christophe Hezode Christian Trepo Germany Thomas Berg Dieter Hussinger Ansgar Lohse Marcus Schuchmann Johannes Wiegand Stefan Mauss Ulrich Spengler Wolfgang E. Schmidt Elmar Zehnter Portugal Armando Carvalho Fernando Ramalho Filipe Calinas Jos 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 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 Spain Jose Luis Calleja Javier Garca-Samaniego Mara Luisa Graca Buey Jaime Enriquez Vicente Soriano 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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