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Introduction

EFFICACY AND SAFETY OF THE INTERFERON-FREE COMBINATION OF FALDAPREVIR (BI 201335) + BI 207127 ± RIBAVIRIN IN TREATMENT-NAÏVE PATIENTS WITH HCV GT-1 AND COMPENSATED LIVER CIRRHOSIS: RESULTS FROM THE SOUND-C2 STUDY.

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Introduction

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  1. EFFICACY AND SAFETY OF THE INTERFERON-FREE COMBINATION OF FALDAPREVIR (BI 201335) + BI 207127 ± RIBAVIRININ TREATMENT-NAÏVE PATIENTS WITH HCV GT-1 AND COMPENSATED LIVER CIRRHOSIS: RESULTS FROM THE SOUND-C2 STUDY Vicente Soriano1, Ed Gane2, Peter Angus3, Felix Stickel4, Jean-Pierre Bronowicki5, Stuart Roberts6, Michael Manns7, Stefan Zeuzem8, Richard Vinisko9, Ivona Herichova10, Wulf Böcher11, Jerry Stern9, and Federico Mensa9 1. Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain; 2. Auckland Clinical Studies, Auckland, New Zealand; 3. Austin Health, Liver Transplant Unit, Heidelberg, Australia; 4. Universitätsklinik für Viszerale Chirurgie und Medizin, Bern, Switzerland; 5. Hôpital de Brabois, Vandoeuvre, France; 6. Alfred Hospital, Dept Gastroenterology, Melbourne, Australia; 7. Medizinische Hochschule Hannover, Hannover, Germany; 8. Klinikum der J. W. Goethe-Universität, Frankfurt am Main, Germany; 9. BoehringerIngelheim Pharmaceuticals, Ridgefield, CT, USA; 10. Boehringer Ingelheim Pharma RCV GmbH & Co KG, Vienna, Austria; 11. Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany

  2. Introduction • Liver cirrhosis is an important risk factor for hepatic decompensation events, HCC1, liver transplantation, and death2 • There is urgent need for new treatments for patients with chronic HCV and cirrhosis: • Many patients are unable to receive PegIFN-based treatment due to contraindications or intolerance • In ‘real-world’ studies of patients with cirrhosis, the incidence of serious AEs with boceprevir or telaprevir + PegIFN/RBV were higher than in clinical trials3,4 • An IFN-free regimen may be particularly compelling for cirrhotic patients; however, so far most trials have excluded them • SOUND-C2 is the largest IFN-free trial performed to date; patients with compensated cirrhosis were included (9% of total) • We report the efficacy, safety, and PK data from patients with cirrhosis in SOUND-C2 1. McGivern DR, Lemon SM. Oncogene 2011; 30:1969–83; 2. Dienstag JL et al. Hepatology 2011; 54:396–405; 3. Hézode C et al. J Hepatol 2012; 56 (suppl 2): Abstract 8; 4. Martel-LaFerriere V et al. J Hepatol 2012;56 (suppl 2): Abstract 1137

  3. Phase IIb, multicenter, open-label, randomized (1:1:1:1:1) Treatment-naïve patients with chronic HCV GT-1 Compensated cirrhosis allowed, 18–75 years of age, HCV RNA >100 000 IU/mL Stopping rule: HCV RNA detectable between Weeks 6 and 8 Primary endpoint: SVR 12 weeks after treatment completion Methods No. with cirrhosis (n=9) (n=7) (n=5) (n=9) (n=3) (n=81) (n=80) (n=77) (n=78) (n=46) Faldaprevir 120 mg QD + BI 207127 600 mg TID+ RBV Follow-up Faldaprevir 120 mg QD + BI 207127 600 mg TID+ RBV Follow-up Faldaprevir 120 mg QD + BI 207127 600 mg TID+ RBV Follow-up Faldaprevir 120 mg QD + BI 207127 600 mg BID+ RBV Follow-up Faldaprevir 120 mg QD+ BI 207127 600 mgTID,no RBV Follow-up Day 1 Week 16 Week 28 Week 40 RBV dose, 1000 mg/day (<75 kg body weight) or 1200 mg/day (≥75 kg body weight)

  4. Analysis • Overall, 362 patients were randomized to treatment in the SOUND-C2 trial • 33 (9%) had liver cirrhosis (liver biopsy or Fibroscan) • This is a subanalysis to characterize the efficacy and safety of faldaprevir + BI 207127 +/- RBV in patients with compensated cirrhosis • Data from patients who received BI 207127 TID + RBV (TID16W, TID28W, and TID40W) were pooled for the safety and efficacy analyses due to the small number of cirrhotic patients in these arms

  5. Baseline characteristics in patients with cirrhosis

  6. SVR12: cirrhosis vs. no cirrhosis No cirrhosis Cirrhosis No cirrhosis Cirrhosis 48/69 11/21 6/9 124/217 1/3 17/43 No cirrhosis Cirrhosis BID 28 + TID 16, 28, & 40 + TID 28 - BI 207127 dosing Duration (weeks) RBV The presence of cirrhosis did not significantly influence the achievement of SVR12 in univariate regression analysis (odds ratio 0.84; p=0.66)

  7. SVR12 rates by HCV-1 subtype GT-1b GT-1a Cirrhosis No cirrhosis 3/7 8/14 2/4 4/5 0/0 1/3 40/93 84/124 11/26 37/43 2/18 15/25 BI 207127 dosingDuration (weeks)RBV TID16, 28, & 40+ BID28+ TID28- TID16, 28, & 40+ BID28+ TID28-

  8. On-treatment failure and relapse rates Cirrhosis No cirrhosis On-treatment failure On-treatment failure Relapse Relapse Failure rate (%) 4/21 1/16 3/9 0/6 2/3 0/1 45/217 18/69 0/49 19/43 2/20 12/156 BI 207127 dosingDuration (weeks)RBV TID16, 28, & 40+ BID28+ TID28- TID16, 28, & 40+ BID28+ TID28- On-treatment failure: breakthrough (increase in HCV RNA ≥1 log10 from nadir or HCV RNA ≥25 IU/mL after previous level <25 IU/mL, confirmed within 2 weeks), lack of response between Weeks 6 and 8, or lack of end of treatment response Relapse: HCV RNA <LLOD (~15 IU/mL) at treatment completion but >LLOD within 24 weeks of treatment completion

  9. Adverse event profile aOnecase each of: post-narcotic psychotic ideation; pulmonary embolism (underlying thrombophylia); nausea and vomiting; rash and photosensitivity; bOne case ofanemia;cOne patient discontinued due to rash and photosensitivity; dNo cases of erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrosis, or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); eBoth patients experienced isolated indirect hyperbilirubinemia which was not associated with liver dysfunction; fJaundice was reported post-treatment. Both patients discontinued for other reasons (vomiting and decreased appetite/fatigue).

  10. Laboratory parameters aBilirubin levels: 7.48, 7.38, 7.29, and 8.81 x ULN; bBilirubin levels: 7.14 and 5.57 x ULN

  11. Plasma faldaprevir and BI 207127trough concentrations at Week 8

  12. Conclusions • Interferon-free combination therapy with faldaprevir, BI 207127, and RBV provided 43–50% SVR12 in GT-1a and 57–80% in GT-1b patients with compensated liver cirrhosis • Plasma exposure of faldaprevir and BI 207127 was higher in cirrhotic vs. non-cirrhotic patients but the difference was less apparent in the BID treatment arm • The safety and tolerability profile appeared to be good in the BID 28 week treatment arm and was similar in cirrhotics and non-cirrhotics • Phase III will evaluate 24 weeks’ faldaprevir + BI 207127 (BID) + RBV in patients with compensated cirrhosis

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