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Best of HCV from EASL 2014

Best of HCV from EASL 2014. Geoffrey Dusheiko , MD London, UK. This activity is supported by an independent medical education grant from AbbVie , Bristol-Myers Squibb and Gilead Sciences. Abstract #O109.

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Best of HCV from EASL 2014

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  1. Best of HCV from EASL 2014 Geoffrey Dusheiko, MD London, UK This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences

  2. Abstract #O109 All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With or Without Ribavirin for 12 or 24 Weeks in Treatment-Experienced Genotype 1 HCV-Infected Patients: The Phase 3 ION-2 Study Nezam Afdhal1, Rajender K. Reddy2, Paul Pockros3, Adrian M. Di Bisceglie4, Sanjeev Arora5,Jenny C. Yang6, Hadas Dvory-Sobol6, Yanni Zhu6, Phil S. Pang6, William T. Symonds6,John G. McHutchison6, Mark Sukowski7, Paul Kwo8 1Beth Israel Deaconess Medical Center, Boston, MA, USA; 2University of Pennsylvania, Philadelphia, PA, USA; 3Scripps Clinic, La Jolla, CA; 4St Louis University, Saint Louis, MO, USA; 5University of New Mexico, Albuquerque, NM; 6Gilead Sciences, Inc., Foster City, CA; 7Johns Hopkins Medical Center, Baltimore, MD, USA; 8Indiana University School of Medicine, Indianapolis, IN, USA

  3. Study DesignGT 1 Treatment-Experienced (ION-2) • GT 1 HCV patients who had failed prior IFN-based therapy, including regimens containing a NS3/4A protease inhibitor • Broad inclusion criteria • Targeted 20% enrollment of patients with cirrhosis • No upper age or BMI limit • Platelet count ≥50,000/mm3, no neutrophil minimum • 440 patients randomized 1:1:1:1 across four arms • Stratified by HCV subtype (1a or 1b), cirrhosis, prior treatment response Wk12 Wk24 Wk36 Wk 0 LDV/SOF SVR12 LDV/SOF + RBV SVR12 LDV/SOF SVR12 LDV/SOF + RBV SVR12 Afdhal, N. et al. EASL 2014, Abstract #O109

  4. Results: DemographicsGT 1 Treatment-Experienced (ION-2) • Arms were balanced with respect to demographics and baseline characteristics Afdhal, N. et al. EASL 2014, Abstract #O109

  5. Results: SVR12GT 1 Treatment-Experienced (ION-2) Error bars represent 95% confidence intervals. SVR12 (%) 102/109 107/111 110/111 108/109 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Afdhal, N. et al. EASL 2014, Abstract #O109

  6. SVR12: PEG/RBV vs PI + PEG/RBV Failures GT 1 Treatment-Experienced (ION-2) Failed PEG/RBV Failed Protease Inhibitor SVR12 (%) 58/58 58/59 49/50 62/66 45/47 62/64 40/43 51/51 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Error bars represent 95% confidence intervals. Afdhal, N. et al. EASL 2014, Abstract #O109

  7. SVR12: Absence of Cirrhosis vs CirrhosisGT 1 Treatment-Experienced (ION-2) Absence of Cirrhosis Cirrhosis SVR12 (%) 83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22 LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Weeks 24 Weeks Error bars represent 95% confidence intervals. Afdhal, N. et al. EASL 2014, Abstract #O109

  8. Abstract #O56 Ledipasvir/Sofosbuvir With and Without Ribavirin for 8 Weeks Compared to Ledipasvir/Sofosbuvir for 12 Weeks in Treatment-Naïve Noncirrhotic Genotype-1 HCV-Infected Patients: The Phase 3 ION-3 Study Kris V. Kowdley1, Stuart C. Gordon 2, K. Rajender Reddy3, Lorenzo Rossaro4, David E. Bernstein5,Di An6, Evguenia S. Svarovskaia6, Robert H. Hyland6, Phillip S. Pang6, William T. Symonds6, John G. McHutchison6, Andrew J. Muir7, Paul J. Pockros8, David C. Pound9, Michael W. Fried10 1Virginia Mason Medical Center, Seattle, WA, USA; 2Henry Ford Health System, Detroit, MI, USA; 3Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA; 4University of California Davis Medical Center, Sacramento, CA, USA; 5North Shore University Hospital, Manhasset, NY, USA; 6Gilead Sciences, Inc., Foster City, CA; 7Division of Gastroenterology and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; 8Scripps Clinic, La Jolla, CA; 9Indianapolis Gastroenterology Research Foundation, Indianapolis, IN, USA; 10University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

  9. Background and AimsGT 1 Treatment-Naïve (ION-3) • Short, safe, and effective interferon- and ribavirin-free treatment options for patients with chronic HCV GT 1 infection are currently lacking • LDV/SOF ± RBV for 8 weeks and LDV/SOF for 12 weeks demonstrated high SVR rates in the Phase 2 LONESTAR study in treatment-naïve HCV patients without cirrhosis1 • To evaluate whether LDV/SOF for 8 weeks is effective for HCV treatment-naïve, non-cirrhotic, GT 1 patients or if RBV or a longer treatment duration of 12 weeks is required to achieve high SVR rate 1. Lawitz E, et al. Lancet. 2014;383:515-23. Kowdley, K. et al. EASL 2014, Abstract #O56

  10. Study DesignGT 1 Treatment-Naïve (ION-3) • GT 1 treatment-naïve patients without cirrhosis • Broad inclusion criteria • No upper age or BMI limit • Opiate substitution therapy allowed • 647 patients randomized 1:1:1 across three arms • Stratified by HCV subtype (1a or 1b) Wk 8 Wk 12 Wk20 Wk24 Wk 0 LDV/SOF SVR12 LDV/SOF + RBV SVR12 LDV/SOF SVR12 Kowdley, K. et al. EASL 2014, Abstract #O56

  11. Results: Non-Inferiority ComparisonGT 1 Treatment-Naïve (ION-3) p=0.52 Error bars represent 95% confidence intervals. SVR12 (%) 206/216 202/215 201/216 206/216 LDV/SOF LDV/SOF + RBV LDV/SOF 8 Weeks 12 Weeks Kowdley, K. et al. EASL 2014, Abstract #O56

  12. ConclusionsGT 1 Treatment-Naïve (ION-3) • LDV/SOF ± RBV for 8 or 12 weeks results in highSVR12 rates • No difference in efficacy among the groups was observed • Host and viral factors traditionally associated with lower SVR rates did not affect SVR12 rates • LDV/SOF ± RBV was safe and well tolerated • RBV contributed to a higher incidence of AEs and laboratory abnormalities • An 8 week LDV/SOF treatment regimen is a safe and effective treatment for treatment-naïve non-cirrhotic patients with HCV GT 1 infection Kowdley K, et al. NEJM In Press Kowdley, K. et al. EASL 2014, Abstract #O56

  13. Abstract #O6 Sofosbuvir/Ledipasvir Fixed Dose Combination is Safe and Effective in Difficult-to-treat Populations Including Genotype-3 Patients, Decompensated Genotype-1 Patients, and Genotype-1 Patients With Prior Sofosbuvir Treatment Experience E.J. Gane1, R.H. Hyland2, D. An2, P.S. Pang2, W.T. Symonds2, J.G. McHutchison2, C.A. Stedman3 1Auckland Clinical Studies, Auckland, New Zealand; 2Gilead Sciences, Inc., Foster City, CA, United States; 3Christchurch Clinical Studies Trust, Christchurch, New Zealand

  14. ELECTRON-2: Study Design • HCV GT 1, relapsed after previous treatment with SOF-containing regimens in ELECTRON-1 • HCV GT 1 decompensated cirrhosis (Child Pugh Turcotte B) • HCV GT 3, treatment naïve Wk 12 Wk 24 Wk 0 SVR12 GT 1Prior SOF exposure LDV/SOF+ RBV, n=19 GT 1CPT class B LDV/SOF, n=20 GT 3Treatment naïve LDV/SOF, n=25 Randomized LDV/SOF + RBV, n=26 Gane, E. et al. EASL 2014, Abstract #O6

  15. ELECTRON-2 Results:(1) Prior Sofosbuvir-Treated GT 1 Patients • All 19 previous SOF-regimen failures had relapsed Re-treatment SOF+RBV 12 wk Prior Null Responders SOF+RBV 12 wk Treatment Naïve n=4 SVR12 (%) n=6 n=1 GS-9669 + SOF +RBV 12 wk Treatment Naïve LDV/SOF+RBV 6 wk Treatment Naïve n=8 19/19 19/19 Gane, E. et al. EASL 2014, Abstract #O6

  16. ELECTRON-2 Results:(2) Patients With CPT B Cirrhosis 7 relapsers SVR12 (%) 13/20 Error bar represents the 95% confidence interval. Gane, E. et al. EASL 2014, Abstract #O6

  17. ELECTRON-2 Results:(3) Patients With HCV GT 3, Treatment Naïve 100 100 64* 80 60 SVR12 (%) 40 20 16/25 26/26 16/25 26/26 0 LDV/SOF 12 Weeks LDV/SOF + RBV 12 Weeks *Failure due to relapse (n=8) or discontinuation due to AE (n=1) Gane, E. et al. EASL 2014, Abstract #O6

  18. ELECTRON-2 Conclusions LDV/SOF regimens for 12 weeks are safe and effective IFN-free treatments for many diverse and difficult-to-treat patient populations including: • Patients infected with HCV GT 1 who have failed previous SOF-containing regimens • Patients infected with HCV GT 1 with decompensated cirrhosis • Patients infected with HCV GT 3 Gane, E. et al. EASL 2014, Abstract #O6

  19. Abstract #O111 Safety and Efficacy of Treatment With the Interferon-free, Ribavirin-free Combination of Sofosbuvir+GS-5816 For 12 Weeks in Treatment Naïve Patients With Genotype 1-6 HCV Infection G.T. Everson1, T.T. Tran2, W.J. Towner3, M.N. Davis4, D. Wyles5, R. Nahass6, J. McNally7,D.M. Brainard7, L. Han7, B. Doehle7, E. Mogalian7, W.T. Symonds7, J.G. McHutchison7, T. Morgan8,R.T. Chung9 1University of Colorado Denver, Aurora, CO, 2Cedars-Sinai Medical Center, 3Kaiser Permanente, Los Angeles, CA, 4Digestive CARE, South Florida Center of Gastroenterology, LLC, Wellington, FL, 5University of California, San Diego, CA, 6ID CARE, Hillsborough, NJ, 7Gilead Sciences, Inc., Foster City, 8VA Long Beach, Long Beach, CA, 9Massachusetts General Hospital, Boston, MA, United States

  20. Study Design • Open label • SOF 400 mg + GS-5816 25 mg for 12 weeks or • SOF 400 mg + GS-5816 100 mg for 12 weeks • Treatment-naïve patients with HCV GT 1-6 without cirrhosis • No ribavirin administered Wk 0 Wk 12 Wk 24 GT 1 (N=55) SOF + GS-5816 25 mg SOF + GS-5816 100 mg SVR12 GT 3 (N=54) SOF + GS-5816 25 mg SOF + GS-5816 100 mg GT 2-6 (N=45) SOF + GS-5816 25 mg SOF + GS-5816 100 mg Everson, G. et al. EASL 2014, Abstract #O111

  21. Results: SVR12 GT 1 GT 2 GT 3 26/27 28/28 10/11 10/10 25/27 25/27 Everson, G. et al. EASL 2014, Abstract #O111

  22. Results: SVR12 GT 4 GT 5 GT 6 7/7 6/7 1/1 10/10 4/4 5/5 Everson, G. et al. EASL 2014, Abstract #O111

  23. Conclusions • SOF + GS-5816 for 12 weeks resulted in SVR12 rates >90% in all HCV genotypes (1-6) • Relapse was observed more often in patients treated with GS-5816 25 mg (N=3) compared to GS-5816 100 mg (N=1) • The presence of pre-treatment NS5A variants was not predictive of failure to achieve SVR 12 • SOF + GS-5816 was well tolerated with no discontinuations due to AEs • The combination of SOF 400 mg and GS-5816 100 mg is being evaluated in treatment-experienced patients and patients with cirrhosis Everson, G. et al. EASL 2014, Abstract #O111

  24. Abstract #O60 SAPPHIRE-I: Phase 3 Placebo-Controlled Study of Interferon-Free, 12-Week Regimen of ABT-450/r/ABT-267, ABT-333, and Ribavirin in 631 Treatment-Naïve Adults With Hepatitis C Virus Genotype 1 J.J. Feld1, K.V. Kowdley2, E. Coakley3, S. Sigal4, D. Nelson5, D. Crawford6,7, O. Weiland8, H. Aguilar9,J. Xiong3, B. DaSilva-Tillmann3, L. Larsen3, T. Podsadecki3 1Toronto Western Hospital Liver Centre, Toronto, ON, Canada, 2Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, 3AbbVie Inc., North Chicago, IL, 4NYU Langone Medical Center, New York, NY, 5University of Florida College of Medicine, Gainesville, FL, United States, 6Gallipoli Medical Research Foundation, 7The University of Queensland, Brisbane, QLD, Australia, 8Karolinska University Hospital Huddinge, KarolinskaInstitutet, Stockholm, Sweden, 9Louisiana Research Center, LLC, Shreveport, LA, United States

  25. SAPPHIRE-I: Placebo-Controlled Design (N=631) • 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID • RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg, respectively) Open-Label Treatment Period Double-Blind Treatment Period 3D + RBV (n=473) 48-Week Follow-Up Placebo (n=158) 48-Week Follow-Up 3D + RBV Week 0 Week 12 Week 24 Week 60 Week 72 Primary Analysis: SVR12 Feld, J. et al. EASL 2014, Abstract #O60

  26. SAPPHIRE-I Results: ITT SVR12 Rates (Superiority to Calculated Placebo Rate) 98.0% 96.2% 95.3% SVR12, % Patients 455/473 307/322 148/151 GT1a GT1b All Patients Feld, J. et al. EASL 2014, Abstract #O60

  27. SAPPHIRE-I: Reasons for Non-SVR12 Breakthrough and relapse rates of 0.2% and 1.5%, respectively *Patients (n=7) who prematurely discontinued without breakthrough; 2 due to adverse events, 5 withdrew consent/ lost to follow-up. Feld, J. et al. EASL 2014, Abstract #O60

  28. Abstract #O163 TURQUOISE-II: SVR12 Rates of 92%-96% in 380 Hepatitis C Virus Genotype 1-Infected Adults With Compensated Cirrhosis Treated With ABT-450/r/ABT-267 and ABT-333 Plus Ribavirin (3D+RBV) F. Poordad1, C. Hezode2, R. Trinh3, K.V. Kowdley4, S. Zeuzem5, K. Agarwal6, M.L. Shiffman7,H. Wedemeyer8, T. Berg9, E.M. Yoshida10, X. Forns11, S.S. Lovell3, B. Da Silva-Tillmann3,A.L. Campbell3, T. Podsadecki3 1The Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, United States, 2Henri Mondor Hospital, APHP, University Paris-Est, Inserm U955, Creteil, France, 3AbbVie Inc., North Chicago, IL, 4Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States, 5J.W. Goethe University, Frankfurt, Germany, 6Institute of Liver Studies, Kings College Hospital, London, United Kingdom, 7Liver Institute of Virginia, Newport News, VA, United States, 8Medizinische Hochschule Hannover, Hannover, 9Universit_tsklinikum Leipzig, Leipzig, Germany, 10University of British Columbia, Vancouver, BC, Canada, 11Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain

  29. TURQUOISE-II Study Design: Phase 3 Trial Conducted Exclusively in GT1-Infected Cirrhotic Patients (N=380) • 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID • RBV: 1000-1200 mg daily according to body weight (<75 kg and >75kg, respectively) SVR12 3D + RBV (N=208) SVR12 3D + RBV (N=172) All patients to be followed through 48 weeks post-treatment Day 0 Week 12 Week 24 Poordad, F. et al. EASL 2014, Abstract #O163

  30. TURQUOISE-II Results: ITT SVR12 Rates of 92% to 96% 95.9 91.8 P=0.089 SVR12, % Patients 191/208 165/172 12 Weeks 3D + RBV 24 Weeks 3D + RBV Poordad, F. et al. EASL 2014, Abstract #O163

  31. TURQUOISE-II Results: ITT SVR12 Rates by Prior Treatment Response in HCV Subtype 1a 92.2 92.9 93.3 100 100 100 80.0 92.9 3D + RBV 12-week arm 24-week arm SVR12, % Patients 10/10 52/56 11/11 39/42 59/64 13/13 40/50 14/15 Prior Partial Response Prior Null Response Naïve Prior Relapse Response HCV Subtype 1a Poordad, F. et al. EASL 2014, Abstract #O163

  32. Abstract #O114 Results Of The Phase 2 Study M12-999:Interferon-Free Regimen Of ABT-450/r/ABT-267+ABT-333+Ribavirin In Liver Transplant Recipients With Recurrent HCV Genotype 1 Infection P. Kwo1, P. Mantry2, E. Coakley3, H. Te4, H. Vargas5, R. Brown Jr.6, F. Gordon7, J. Levitsky8, N. Terrault9, J. Burton Jr10, W. Xie3, C. Setze3, P. Badri3, R.A. Vilchez3, X. Forns11 1Indiana University, Indianapolis, IN, 2The Liver Institute at Methodist Dallas Medical Center, Dallas, TX, 3AbbVie Inc., North Chicago, 4University of Chicago Medicine, Chicago, IL, 5Mayo Clinic, Phoenix, AZ, 6Columbia University Medical Center Center for Liver Disease and Transplantation, New York, NY, 7Lahey Hospital & Medical Center, Burlington, MA, 8Northwestern University Comprehensive Transplant Center, Chicago, IL, 9University of California, San Francisco, San Francisco, CA, 10University of Colorado, Denver, Aurora, CO, United States, 11Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain

  33. Study M12-999: Design • 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID • RBV: dosing was managed at the discretion of the investigator and closely monitored per protocol SVR12 3D + RBV (N=34) Day 0 Week 24 To Week 72 Kwo, P. et al. EASL 2014, Abstract #O114

  34. Calcineurin Inhibitor (CNI) Dosing With 3D Regimen • Based on previous drug-drug interaction findings, recommended dosing during 3D treatment was: • TAC • 0.5 mg once weekly or • 0.2 mg every 3 days • CYA • 1/5 of the daily pre-3D treatment dose given once daily Kwo, P. et al. EASL 2014, Abstract #O114

  35. Study M12-999: Preliminary Efficacy Results 100% 100% 97.0% 96.2% • No patient had breakthrough • One patient had a relapse (post-treatment day 3) • At the time of relapse, this patient had R155K in NS3 protease, M28T+Q30R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline % Patients 32/33 34/34 25/26 34/34 SVR12 RVR (Week 4) EOTR(Week 24) SVR4 Kwo, P. et al. EASL 2014, Abstract #O114

  36. Study M12-999: Conclusions • An IFN-free, 24-week regimen of ABT-450/r/ombitasvir + dasabuvir + RBV achieved high response rates in immunosuppressed liver transplant recipients with recurrent HCV GT1 infection • In this on-going study: • 100% achieved RVR (34/34) and EOTR (34/34) • 97.0% (32/33) achieved SVR4 and 96.2% (25/26) achieved SVR12 • The regimen was generally well tolerated with 1 patient discontinuing study drug due to AEs • No deaths, graft losses, or episodes of rejection • CNI dosing was manageable over the period of the study Kwo, P. et al. EASL 2014, Abstract #O114

  37. Abstract #O58 Results From the Phase 2 PEARL-I Study: Interferon-Free Regimens of ABT-450/R + ABT-267 With or Without Ribavirin in Patients With HCV Genotype 4 Infection C. Hezode1, P. Marcellin2, S. Pol3, T. Hassanein4, K. Fleischer-Stepniewska5, T. Baykal6, T. Wang6,S.S. Lovell6, T. Pilot-Matias6, R.A. Vilchez6 1Assistance PubliqueHopitaux de Paris, Paris, 2Hopital BeaujonInserm Crb3 - U 773 - Service Hepatologie, Clichy, 3Groupe Hospitalier Cochin-Saint Vincent de Paul, Paris, France, 4Southern California Liver Centers and Southern California Research Center, Coronado, CA, United States, 5EMC InstytutMedycznySpolkaAkcyjna, Wroclaw, Poland, 6AbbVie Inc., North Chicago, IL, United States

  38. PEARL-I: Study Design Substudy 1* No Cirrhosis Group 1 (GT4) (n=44) ABT-450/r + Ombitasvir Treatment-Naïve Group 2 (GT1b) (n=42) ABT-450/r + Ombitasvir Treatment-Naïve Group 3 (GT1b) (n=40) ABT-450/r + Ombitasvir Null Responders Group 4 (GT4) (n=42) ABT-450/r + Ombitasvir + RBV Treatment-Naïve Group 5 (GT4) ABT-450/r + Ombitasvir Partial/Null Responders & Relapsers Group 6 (GT4) (n=49) ABT-450/r + Ombitasvir + RBV Partial/Null Responders & Relapsers Substudy 2* Compensated Cirrhosis Group 7 (GT1b) (n=47) ABT-450/r + Ombitasvir Treatment-Naïve Group 8 (GT1b) (n=52) ABT-450/r + Ombitasvir Partial/Null Responders & Relapsers Week 24 Baseline Week 12 *Planned number of patients: 40 per treatment arm ABT-450/r (150/100 mg qd); ombitasvir(25 mg QD); RBV (weight-based 1000 or 1200 mg/day divided BID) All patients followed through 48 weeks post-treatment Hezode, C. et al. EASL 2014, Abstract #O58

  39. PEARL-I GT4-Infected Treatment-Naïve Patients: ITT Efficacy Analysis 100% 100% 100% 97.6% 97.7% 95.5% 93.2% RVR (Week 4) 90.9% EOTR (Week 12) SVR4 SVR12 Patients (%) 43 44 42 44 41 44 40 44 41 42 42 42 42 42 42 42 ABT-450/r + Ombitasvir + RBV (N=42) ABT-450/r + Ombitasvir (N=44) Hezode, C. et al. EASL 2014, Abstract #O58

  40. PEARL-I GT4-Infected Treatment-Experienced Patients: ITT Efficacy Analysis 100% 100% 100% RVR (Week 4) EOTR (Week 12) SVR4 Patients (%) 49/49 49/49 37/37 ABT-450/r + Ombitasvir + RBV (N=49) Hezode, C. et al. EASL 2014, Abstract #O58

  41. PEARL-I GT4-Infected Patients:Conclusions • All-oral, IFN-free, 12-week regimens of ABT-450/r + ombitasvirresulted in: • High SVR12 rates in treatment-naïve HCV GT4-infected patients • 90.9% with ABT-450/r + ombitasvir • 100% with ABT-450/r + ombitasvir + RBV • An SVR4 rate of 100% in treatment-experienced patients receiving ABT-450/r + ombitasvir + RBV • 12-week regimens of ABT-450/r + ombitasvir +/- RBV were generally well-tolerated, with no study drug discontinuations or interruptions due to AEs, and few decreases in hemoglobin <10 g/dL Hezode, C. et al. EASL 2014, Abstract #O58

  42. Abstract #O10 Safety and Efficacy of the All-oral Regimen of MK-5172/MK-8742 + Ribavirin in Treatment-naïve, Non-cirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: The C-WORTHyStudy C. Hezode1, L. Serfaty2, J.M. Vierling3, M. Kugelmas4, B. Pearlman5, W. Sievert6, W. Ghesquiere7,E. Zuckerman8, F. Sund9, M. Shaughnessy10, P. Hwang10, J. Wahl10, M.N. Robertson10, B. Haber10 1Department of Hepatology-Gastroenterology, Henri Mondor Hospital, University of Paris-Est, Creteil, 2Gastroenterology and Hepatology, H_pital Saint Antoine, APHP and INSERM UMR_938, Universit_ Pierre & Marie Curie, Paris, France, 3Hepatology, Baylor College of Medicine, Houston, TX, 4South Denver Gastroenterology, PC, Englewood, CO, 5Center for Hepatitis C, Atlanta Medical Center, Atlanta, GA, United States, 6Gastrointestinal and Liver Unit, Monash University, Clayton, VIC, Australia, 7Vancouver Island Health Authority, Victoria, BC, Canada, 8Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel, 9Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden, 10Merck, Whitehouse Station, NJ, United States

  43. Aim: C-WORTHy TN • To assess the efficacy/safety of an 8- to 12-week regimen of MK-5172 + MK-8742 ± weight-based ribavirin in treatment-naïve, noncirrhotic patients with HCV G1 infection Treatment-naïve, noncirrhotic 12 weeks ± RBV (n=65) Treatment-naïve Noncirrhotic8-12 weeks ± RBV (n=94) Treatment-naïve Cirrhotic12-18 weeks ± RBV (n=123) Null responders Cirrhotic/noncirrhotic12-18 weeks ± RBV (n=130) HIV/HCV coinfectedNoncirrhotic12 weeks ± RBV (n=59) • Key inclusion/exclusion criteria: • Treatment-naïve patients ≥ 18 years old with chronic HCV G1a or G1b infection • Liver biopsy or noninvasive test (METAVIR F0-F3) • Minimum baseline hemoglobin: 12 g/dL (females) or 13 g/dL (males) • HIV and hepatitis B virus negative • Alanine aminotransferase (ALT) as aspartate aminotransferase (AST) <350 IU/L Hezode, C. et al. EASL 2014, Abstract #O10

  44. Study Design RBV-Containing Regimen RBV-Free Regimen MK-5172 (100 mg) MK-8742 (20 mg) + RBV G1a/b N=25 PART A SVR24 (AASLD 2013) MK-5172 (100 mg) MK-8742 (50 mg) + RBV G1a/b n=27 Part A MK-5172 (100 mg) MK-8742 (50 mg) G1b n=13 at ≥SVR4 (28/30 SVR8) MK-5172 (100 mg) MK-8742 (50 mg) + RBV G1a n=30 PART B Follow-up ongoing SVR4/8 MK-5172 (100 mg) MK-8742 (50 mg) + RBV G1a/b n=33 Part B 100% at SVR8 MK-5172 (100 mg) MK-8742 (50 mg) G1a n=31 D1 TW4 TW8 TW12 SVR4 SVR8 SVR12 SVR24 Study Week SVR, sustained virologic response; TW = treatment week. Hezode, C. et al. EASL 2014, Abstract #O110

  45. C-WORTHy (A+B) – Overall Efficacy (SVR4-24)*Intention-to-Treat (Nonvirologic Discontinuation = Failure) 30/30 81/85 44/44 30/30 82/85 44/44 25/30 80/85 43/44 4-24 *Part A: 100% of patients have completed SVR24; Part B: 8-week arm, 93% of patients have completed SVR8; 12-week arms, 100% of patients have completed SVR8; 2 patients (Part A), 2 patients (Part B) discontinued early (and are counted as failures). Hezode, C. et al. EASL 2014, Abstract #O110

  46. Summary • Efficacy • MK-5172/MK8742 once daily with or without RBV for 12 weeks is highly efficacious with a SVR of 94%-98% • MK-5172/MK-8742 + RBV for 8 weeks in patients with HCV G1a infection had an SVR44/8 of 83% • Most common type of virologic failure was relapse after a treatment duration of 8 weeks • Safety • All treatment regimens were generally safe and well-tolerated • There were no early discontinuations due to drug-related Aes • No grade 3 or 4 laboratory abnormalities Hezode, C. et al. EASL 2014, Abstract #O110

  47. Abstract #O63 Efficacy and Safety of the All-Oral Regimen, MK-5172/MK-8742 +/- RBV For 12 Weeks in GT1 HCV/HIV Co-Infected Patients: The C-WORTHY Study Mark Sulkowski1, Josep Mallolas2, Marc Bourliere3, Jan Gerstoft4, Oren Shibolet5, Ronald Nahass6, Edwin DeJesus7, Melissa Shaughnessy8, Peggy Hwang8, Barbara Haber8 1Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Hospital de Dia. EnfermedadesInfecciosas, Barcelona, Spain; 3Service d'hépato-gastroentérologie, Hôpital Saint-Joseph, Marseille, France; 4Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark; 5Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel; 6ID Care, Hillsborough, NJ, USA; 7Orlando Immunology Center, Orlando, Florida; 8Merck & Co., Inc., Whitehouse Station, NJ, USA.

  48. Background • Globally, ~7 million patients are co-infected with HIV and HCV(1) • HIV/HCV co-infected patients have a higher rate of progression to cirrhosis and hepatic decompensation than HCV mono-infected patients(1-4) • MK-5172 and MK-8742 can be dosed with raltegravir + dual NRTI (tenofovir or abacavir + emtricitabine or lamivudine) without dosage adjustments • MK-5172/MK-8742 has the potential to provide an all-oral, highly efficacious, simple, and well-tolerated regimen C-WORTHy: MK-5172/MK-8742 ± RBV in 471 HCV G1-infected patients Treatment-naive, non-cirrhotic 12 weeks ± RBV (n = 65) Null responders Cirrhotic / Non-cirrhotic 12-18 weeks ± RBV (n = 130) Treatment-naive Non-cirrhotic 8-12 weeks ± RBV (n = 94) Treatment-naive Cirrhotic 12-18 weeks ± RBV (n = 123) HIV/HCV co-infected Non-cirrhotic 12 weeks ± RBV (n = 59) 1. Sulkowski, et al., Clin Infect Dis. 30 (Suppl 1):S77, 2000; 2. Rockstroh JK, et al., Am J Gastroenterol. 91:2563, 1996; 3. DHHS Antiretroviral Guidelines; for Adults and Adolescents. February, 2013; 4. Naggie S, et al. Gastroenterology. 142:1324, 2012 Sulkowski, M. et al. EASL 2014, Abstract #O63

  49. Study DesignHIV/HCV Co-infected Non-cirrhotic Patients MK-5172 + MK-8742 + RBV Follow-up N = 29 Follow-up MK-5172 + MK-8742 (No RBV) N = 30 Primary endpoint D1 TW2 TW4 TW8 TW12 SVR4 SVR12 SVR24 MK-5172 (100 mg QD) + MK-8742 (50 mg QD); 12 weeks Sulkowski, M. et al. EASL 2014, Abstract #O63

  50. Virologic Responses ITT Population 29 29 30 30 29 29 27 30 29 29 27 30 28 29 26 29* Virologic Failures: 1 relapse in +RBV arm; 2 breakthrough and 1 lost to follow up in No RBV arm * One patient has not yet reached FU4 Sulkowski, M. et al. EASL 2014, Abstract #O63

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