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1 Stefan Zeuzem, MD Frankfurt, Germany This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead.

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Presentation on theme: "1 Stefan Zeuzem, MD Frankfurt, Germany This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead."— Presentation transcript:

1 1 Stefan Zeuzem, MD Frankfurt, Germany This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences

2 2 Simeprevir Plus Sofosbuvir With/Without Ribavirin in HCV Genotype-1 Prior Null-responder / Treatment-naïve Patients (COSMOS Study): Primary Endpoint (SVR12) Results in Patients With METAVIR F3-4 (Cohort 2) Eric Lawitz, 1 Reem Ghalib, 2 Maribel Rodriguez-Torres, 3 Zobair M Younossi, 4 Ana Corregidor, 5 Mark S Sulkowski, 6 Edwin DeJesus, 7 Brian Pearlman, 8 Mordechai Rabinovitz, 9 Norman Gitlin, 10 Joseph K Lim, 11 Paul J Pockros, 12 Bart Fevery, 13 Tom Lambrecht, 14 Sivi Ouwerkerk-Mahadevan, 13 Katleen Callewaert, 13 William T Symonds, 15 Gaston Picchio, 16 Karen Lindsay, 17 Maria Beumont-Mauviel, 13 Ira M Jacobson 18 1 The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA; 2 Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX, USA; 3 Fundación de Investigación, San Juan, Puerto Rico, USA; 4 Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA; 5 Borland-Groover Clinic, Jacksonville, FL, USA; 6 Johns Hopkins University School of Medicine, Baltimore, MD, USA; 7 Orlando Immunology Center, Orlando, FL, USA; 8 Atlanta Medical Center, Atlanta, GA, USA; 9 University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 10 Atlanta Gastroenterology Association, Atlanta, GA, USA; 11 Yale School of Medicine, New Haven, CT, USA; 12 Scripps Clinic, La Jolla, CA, USA; 13 Janssen Research & Development, Beerse, Belgium; 14 Novellas Healthcare, Zellik, Belgium; 15 Gilead Sciences Inc, Foster City, CA, USA; 16 Janssen Research & Development LLC, Titusville, NJ, USA; 17 Formerly of Janssen Research & Development LLC, Titusville, NJ, USA; 18 Weill Cornell Medical College, New York, NY, USA

3 3 Cohort 1: METAVIR F0-F2, prior null responders Cohort 2: METAVIR F3-F4, prior null responders or treatment-naïve –Stratified by treatment history, HCV GT 1a/1b Primary endpoint: SVR12 Secondary endpoints: RVR, on-treatment failure, relapse rate, safety and tolerability BID, twice daily; GT, genotype; QD, once daily; RBV, ribavirin; RVR, rapid virologic response; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatment Lawitz, E. et al. EASL 2014, Abstract #O Week SMV + SOF + RBVPost-treatment follow-up SMV + SOFPost-treatment follow-up SMV + SOF Arm 1 Arm 2 Randomised 2:1:2:1 Arm 3 Arm 4 SMV + SOF + RBV SMV 150 mg QD + SOF 400 mg QD±RBV 1000/1200 mg/day (BID)

4 4 ITT, intent-to-treat; Non-VF, Non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment end Non-VF, patients who did not achieve SVR12 for reasons other than virologic failure Lawitz, E. et al. EASL 2014, Abstract #O165 SMV/SOF±RBV Proportion of patients (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall SVR12Non-VFRelapse 93%100%93% 94% 2/301/142/27 3/87 2/87 28/3016/1613/1425/2782/87 3% 2%

5 5 GT 1b *Excluding patients who discontinued for non-virologic reasons GT, genotype; non-VF, non-virologic failure; RBV, ribavirin SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment end Lawitz, E. et al. EASL 2014, Abstract #O165 SMV/SOF±RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall 6/611/11 4/47/74/45/513/147/83/37/83/318/1838/4025/

6 6 GT 1b *Excluding patients who discontinued for non-virologic reasons GT, genotype; non-VF, non-virologic failure; RBV, ribavirin SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment end Lawitz, E. et al. EASL 2014, Abstract #O165 GT 1a without Q80K SMV/SOF±RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall 6/611/11 4/47/74/45/513/147/83/37/83/318/1838/4025/

7 7 GT 1b *Excluding patients who discontinued for non-virologic reasons GT, genotype; non-VF, non-virologic failure; RBV, ribavirin SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment end Lawitz, E. et al. EASL 2014, Abstract #O165 GT 1a without Q80K GT 1a with Q80K SMV/SOF±RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall 6/611/11 4/47/74/45/513/147/83/37/83/318/1838/4025/

8 8 *Excluding patients who discontinued for non-virologic reasons Non-VF, non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment end Lawitz, E. et al. EASL 2014, Abstract #O165 SMV/SOF±RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall 16/1612/126/69/915/1610/117/76/744/4537/39 F3F4

9 9 *Excluding patients who discontinued for non-virologic reasons Non-VF, non-virologic failure; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after planned treatment end Lawitz, E. et al. EASL 2014, Abstract #O165 SMV/SOF±RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall 9/93/34/45/54/56/64/42/321/2216/17 Null respondersTreatment naïves

10 10 All Oral Fixed-Dose Combination Ledipasvir/Sofosbuvir With Or Without Ribavirin for 12 or 24 Weeks in Treatment-Naive Genotype 1 HCV-Infected Patients: the Phase 3 ION-1 Study Alessandra Mangia, 1 Patrick Marcellin, 2 Paul Kwo, 3 Graham R. Foster, 4 Maria Buti, 5 Norbert Bräu, 6 Andrew Muir, 7 Jenny C. Yang, 8 Hongmei Mo, 8 Xiao Ding, 8 Phil S. Pang, 8 William T. Symonds, 8 John G. McHutchison, 8 Stefan Zeuzem, 9 Nezam Afdhal 10 1 Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy; 2 Centre Hospitalier Universitaire Beaujon, Clichy-sous-Bois, France; 3 Indiana University School of Medicine, Indianapolis, IN, USA; 4 Queen Mary’s University of London, Barts Health, UK; 5 Hospital Universitario Valle de Hebrón, Barcelona, Cataluña, Spain; 6 Mount Sinai School of Medicine, New York, NY, USA; 7 Duke University Medical Center, Durham, NC, USA; 6 Gilead Sciences, Inc., Foster City, CA; 9 Johann Wolfgang Goethe University, Frankfurt, Germany; 10 Beth Israel Deaconess Medical Center, Boston, MA, USA

11 11 GT 1 HCV treatment-naïve patients in Europe and USA Broad inclusion criteria –Targeted 20% enrollment of patients with cirrhosis –No upper age or BMI limit –Platelet count ≥50,000/mm 3, no neutrophil minimum 865 patients randomized 1:1:1:1 across four arms Stratified by HCV subtype (1a or 1b) and cirrhosis Wk 0 Wk 12Wk 36Wk 24 LDV/SOF SVR12 LDV/SOF + RBV LDV/SOF LDV/SOF + RBV SVR12 Mangia, A. et al. EASL 2014, Abstract #O164

12 12 Arms were balanced with respect to demographics and baseline characteristics 12 Weeks24 Weeks LDV/SOF n=214 LDV/SOF+RBV n=217 LDV/SOF n=217 LDV/SOF+RBV n=217 Mean age, y (range)52 (18–75)52 (18–78)53 (22–80)53 (24–77) Male, n (%)127 (59)128 (59)139 (64)119 (55) Black, n (%)24 (11)26 (12)32 (15)26 (12) Hispanic, n (%)26 (12)20 (9)29 (13)26 (12) Region Europe89 (42)99 (46)85 (39)80 (37) Mean BMI, kg/m 2 (range)27 (18–41)27 (18–42)27 (18–48)26 (18–48) Cirrhosis34 (16)33 (15) 36 (17) IL28B CC, n (%)55 (26)76 (35)52 (24)73 (34) Interferon ineligible14 (7)20 (9)19 (9)14 (7) GT 1a, n (%)144 (67)148 (68)146 (67)143 (66) Mean HCV RNA, log 10 IU/mL (range) 6.4 (1.6–7.5)6.4 (4.4–7.6)6.3 (3.7–7.4)6.3 (3.2–7.5) HCV RNA ≥800,000 IU/mL169 (79)173 (80)168 (77)173 (80) Mangia, A. et al. EASL 2014, Abstract #O164

13 13 USA N=512 Europe N=353 Mean age, y (range)54 (19–77)51 (18–80) Male, n (%)328 (64)185 (52) Black, n (%)100 (20)8 (2) Hispanic, n (%)45 (9)56 (16) Mean BMI, kg/m 2 (range)28 (18–48)25 (18–37) Cirrhosis81 (16)55 (16) IL28B CC, n (%)158 (31)98 (28) Interferon ineligible43 (8)24 (7) GT 1a, n (%)372 (73)209 (59) Mean baseline HCV RNA, log 10 IU/mL (range) 6.3 (1.6–7.5)6.4 (3.2–7.6) Baseline HCV RNA ≥800,000 IU/mL 399 (78)284 (80) Mangia, A. et al. EASL 2014, Abstract #O164

14 14 Error bars represent 95% confidence intervals. Mangia, A. et al. EASL 2014, Abstract #O / Weeks24 Weeks LDV/SOF + RBV 211/ /217 SVR12 (%) 215/217 LDV/SOF + RBV LDV/SOF

15 15 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 Afdhal 1, Rajender K. Reddy 2, Paul Pockros 3, Adrian M. Di Bisceglie 4, Sanjeev Arora 5, Jenny C. Yang 6, Hadas Dvory-Sobol 6, Yanni Zhu 6, Phil S. Pang 6, William T. Symonds 6, John G. McHutchison 6, Mark Sukowski 7, Paul Kwo 8 1 Beth Israel Deaconess Medical Center, Boston, MA, USA; 2 University of Pennsylvania, Philadelphia, PA, USA; 3 Scripps Clinic, La Jolla, CA; 4 St Louis University, Saint Louis, MO, USA; 5 University of New Mexico, Albuquerque, NM; 6 Gilead Sciences, Inc., Foster City, CA; 7 Johns Hopkins Medical Center, Baltimore, MD, USA; 8 Indiana University School of Medicine, Indianapolis, IN, USA

16 16 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/mm 3, no neutrophil minimum 440 patients randomized 1:1:1:1 across four arms Stratified by HCV subtype (1a or 1b), cirrhosis, prior treatment response Wk 0 Wk 12Wk 36Wk 24 LDV/SOF SVR12 LDV/SOF + RBV LDV/SOF LDV/SOF + RBV SVR12 Afdhal, N. et al. EASL 2014, Abstract #O109

17 17 Arms were balanced with respect to demographics and baseline characteristics 12 Weeks24 Weeks LDV/SOF n=109 LDV/SOF+RBV n=111 LDV/SOF n=109 LDV/SOF+RBV n=111 Mean age, y (range)56 (24–67)57 (27–75)56 (25–68)55 (28–70) Male, n (%)74 (68)71 (64)74 (68)68 (61) Black, n (%)24 (22)16 (14)17 (16)20 (18) Hispanic, n (%)7 (6)12 (11)11 (10) Mean BMI, kg/m 2 (range)29 (19–47)28 (19–45)28 (19–41)28 (19–50) IL28B CC, n (%)10 (9)11 (10)16 (15)18 (16) GT 1a, n (%)86 (79)88 (79)85 (78)88 (79) Mean HCV RNA, log 10 IU/mL (range) 6.5 (5.0–7.5)6.4 (4.6–7.3)6.4 (4.7–7.4)6.5 (3.1–7.4) HCV RNA ≥800,000 IU/mL103 (95)98 (88)93 (85)96 (87) Prior non-responders, n (%)49 (45)46 (41)49 (45)51 (46) Prior protease inhibitor failures, n (%) 66 (61)64 (58)50 (46)51 (46) Cirrhosis, n (%)22 (20) Afdhal, N. et al. EASL 2014, Abstract #O109

18 18 107/ Weeks24 Weeks LDV/SOF + RBV 102/ /109 SVR12 (%) 110/111 LDV/SOF + RBV LDV/SOF Error bars represent 95% confidence intervals. Afdhal, N. et al. EASL 2014, Abstract #O109

19 19 Error bars represent 95% confidence intervals. Afdhal, N. et al. EASL 2014, Abstract #O109 Failed PEG/RBVFailed Protease Inhibitor SVR12 (%) 40/43 62/6645/4762/64 58/58 49/50 58/59 51/51 12 Weeks24 Weeks LDV/SOF + RBV LDV/SOF

20 20 Absence of CirrhosisCirrhosis SVR12 (%) 83/8719/2289/8918/2286/8722/2288/8922/22 12 Weeks24 Weeks LDV/SOF + RBV LDV/SOF Error bars represent 95% confidence intervals. Afdhal, N. et al. EASL 2014, Abstract #O109

21 21 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. Feld 1, K.V. Kowdley 2, E. Coakley 3, S. Sigal 4, D. Nelson 5, D. Crawford 6,7, O. Weiland 8, H. Aguilar 9, J. Xiong 3, B. DaSilva-Tillmann 3, L. Larsen 3, T. Podsadecki 3 1 Toronto Western Hospital Liver Centre, Toronto, ON, Canada, 2 Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, 3 AbbVie Inc., North Chicago, IL, 4 NYU Langone Medical Center, New York, NY, 5 University of Florida College of Medicine, Gainesville, FL, United States, 6 Gallipoli Medical Research Foundation, 7 The University of Queensland, Brisbane, QLD, Australia, 8 Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden, 9 Louisiana Research Center, LLC, Shreveport, LA, United States

22 22 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID RBV: mg daily according to body weight ( 75kg, respectively) Week 0Week 12Week 24Week 60Week 72 3D + RBV (n=473) Placebo (n=158) 3D + RBV Double-Blind Treatment Period Open-Label Treatment Period Primary Analysis: SVR12 48-Week Follow-Up 48-Week Follow-Up Feld, J. et al. EASL 2014, Abstract #O60

23 23 SVR12, % Patients All Patients 96.2% 95.3% 98.0% 455/473307/322148/151 GT1a GT1b Feld, J. et al. EASL 2014, Abstract #O60

24 24 Event, n/N (%) 3D + RBV (N=473) SVR12455/473 (96.2) Non-SVR1218/473 (3.8) Virologic failure Breakthrough 1/473 (0.2) Relapse 7/463 (1.5) Prematurely discontinued study drug* 7/473 (1.5) Lost to follow-up after completion of treatment 3/473 (0.6) 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

25 25 SVR12, % Patients Male FemaleBlackNon- Black <30>30F0- F1 F2F3<800K >800K Yes No Gender RaceRBV Modification BMI (kg/m 2 ) Fibrosis Stage Baseline HCV RNA (IU/mL) Feld, J. et al. EASL 2014, Abstract #O60

26 26 Event, n (%) 3D + RBV (N=473) Placebo (N=158)P Value Any AE414 (87.5)116 (73.4)<0.05 Fatigue164 (34.7)45 (28.5)NS Headache156 (33.0)42 (26.6)NS Nausea112 (23.7)21 (13.3)<0.05 Pruritus80 (16.9)6 (3.8)<0.05 Insomnia66 (14.0)12 (7.6)<0.05 Diarrhea65 (13.7)11 (7.0)<0.05 Asthenia57 (12.1)6 (3.8)<0.05 Rash51 (10.8)9 (5.7)NS AEs were generally mild. Feld, J. et al. EASL 2014, Abstract #O60

27 27 SAPPHIRE II: Phase 3 Placebo-Controlled Study of Interferon-Free, 12-Week Regimen of ABT-450/r/ABT-267, ABT-333, and Ribavirin in Treatment-Experienced Adults With Hepatitis C Virus Genotype 1 S. Zeuzem 1, I. Jacobson 2, T. Baykal 3, R.T. Marinho 4, F. Poordad 5, M. Bourliere 6, M. Sulkowski 7, H. Wedemeyer 8, E. Tam 9, P. Desmond 10, D. Jensen 11, A.M. Di Bisceglie 12, P. Varunok 13, T. Hassanein 14, J. Xiong 3, B. DaSilva-Tillmann 3, L. Larsen 3, T. Podsadecki 3 1 J.W. Goethe University, Frankfurt, Germany, 2 Weill Cornell Medical College, New York, NY, 3 AbbVie Inc., North Chicago, IL, United States, 4 Centro Hospitalar de Lisboa Norte, Lisbon, Portugal, 5 The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States, 6 H_pital Saint Joseph, Marseille, France, 7 Johns Hopkins University, Baltimore, MD, United States, 8 Medizinische Hochschule Hannover, Hannover, Germany, 9 LAIR Centre, Vancouver, BC, Canada, 10 St Vincent's Hospital (Melbourne), Fitzroy, VIC, Australia, 11 Center for Liver Diseases, University of Chicago Medical Center Chicago, Chicago, IL, 12 Saint Louis University, St. Louis, MO, 13 Premier Medical Group of the Hudson Valley, PC, Poughkeepsie, NY, 14 Southern California Liver Centers and Southern California Research Center, Coronado, CA, United States

28 28 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID RBV: mg daily according to body weight ( 75kg, respectively) Zeuzem, S. et al. EASL 2014, Abstract #O1 Week 0Week 12Week 24Week 60Week 72 3D + RBV (n=297) Placebo (n=97) 3D + RBV Double-Blind Treatment Period Open-Label Treatment Period 48-Week Follow-Up 48-Week Follow-Up Primary Analysis: SVR12

29 29 3D + RBV (N=297) Placebo (N=97) Male / female, n (%)167 (56.2) / 130 (43.8)60 (61.9) / 37 (38.1) White, n (%)269 (90.6)86 (88.7) Median age, years (range)54.0 ( )56.0 ( ) Median BMI, kg/m 2 (range)26.0 ( )26.1 ( ) Fibrosis stage, n (%) F0-F1202 (68.0)65 (67.0) F253 (17.8)17 (17.5) F342 (14.1)15 (15.5) IL28B non-CC genotype, n (%)263 (88.6)90 (92.8) HCV subtype, n (%) 1a173 (58.2)57 (58.8) 1b123 (41.4)40 (41.2) Median HCV RNA, log 10 IU/mL (range)6.66 ( )6.55 ( ) Prior pegIFN/RBV response, n (%) Relapse86 (29.0)29 (29.9) Partial response65 (21.9)21 (21.6) Null response146 (49.2)47 (48.5) Zeuzem, S. et al. EASL 2014, Abstract #O1

30 30 SVR12, % Patients All Patients 96.3% 96.0% 96.7% 286/297166/173119/123 GT1a GT1b Zeuzem, S. et al. EASL 2014, Abstract #O1

31 31 SVR12, % Patients Prior Relapse 95.3% 100% 95.2% 82/8665/65139/146 Prior Partial Response Prior Null Response Zeuzem, S. et al. EASL 2014, Abstract #O1

32 32 No patient had breakthrough and 2.4% of patients had a relapse All Patients (N=297) Prior Relapsers (N=86) Prior Partial Responders (N=65) Prior Null Responders (N=146) SVR12, n/N (%) 286/297 (96.3) 82/86 (95.3) 65/65 (100) 139/146 (95.2) Virologic failure, n Breakthrough0000 Relapse7106 Prematurely discontinued study drug,* n 4301 *Patients (n=4) who prematurely discontinued without breakthrough; 3 due to adverse events, 1 withdrew consent during week 11. Zeuzem, S. et al. EASL 2014, Abstract #O1

33 33 Event, n (%) 3D + RBV (N=297) Placebo (N=97)P Value Any AE271 (91.2)80 (82.5)<0.05 Headache108 (36.4)34 (35.1)NS Fatigue99 (33.3)22 (22.7)NS Nausea60 (20.2)17 (17.5)NS Asthenia47 (15.8)11 (11.3)NS Insomnia42 (14.1)7 (7.2)NS Pruritus41 (13.8)5 (5.2)<0.05 Diarrhea39 (13.1)12 (12.4)NS Dyspnea37 (12.5)10 (10.3)NS Cough32 (10.8)5 (5.2)NS Myalgia23 (7.7)10 (10.3)NS AEs were generally mild. Zeuzem, S. et al. EASL 2014, Abstract #O1

34 34 Event, n/N (%) 3D + RBV (N=297) Placebo (N=97) ALT >5X ULN 5/296 (1.7)3/96 (3.1) AST >5X ULN 3/296 (1.0)1/96 (1.0) Alkaline phosphatase >5X ULN 00 Total bilirubin >3X ULN 7/296 (2.4)0 Zeuzem, S. et al. EASL 2014, Abstract #O1 No patient met Hy’s Law criteria Elevations in total bilirubin were mainly transient and predominantly indirect bilirubin Bilirubin elevations were not concomitant with ALT or AST elevations Total bilirubin increases normalized by post-treatment week 4

35 35 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. Poordad 1, C. Hezode 2, R. Trinh 3, K.V. Kowdley 4, S. Zeuzem 5, K. Agarwal 6, M.L. Shiffman 7, H. Wedemeyer 8, T. Berg 9, E.M. Yoshida 10, X. Forns 11, S.S. Lovell 3, B. Da Silva-Tillmann 3, A.L. Campbell 3, T. Podsadecki 3 1 The Texas Liver Institute/University of Texas Health Science Center, San Antonio, TX, United States, 2 Henri Mondor Hospital, APHP, University Paris-Est, Inserm U955, Creteil, France, 3 AbbVie Inc., North Chicago, IL, 4 Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, United States, 5 J.W. Goethe University, Frankfurt, Germany, 6 Institute of Liver Studies, Kings College Hospital, London, United Kingdom, 7 Liver Institute of Virginia, Newport News, VA, United States, 8 Medizinische Hochschule Hannover, Hannover, 9 Universit_tsklinikum Leipzig, Leipzig, Germany, 10 University of British Columbia, Vancouver, BC, Canada, 11 Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain

36 36 3D: co-formulated ABT-450/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID RBV: mg daily according to body weight ( 75kg, respectively) Day 0Week 24Week 12 SVR12 3D + RBV N=208 (N=208) 3D + RBV (N=172) All patients to be followed through 48 weeks post-treatment Poordad, F. et al. EASL 2014, Abstract #O163

37 37 Poordad, F. et al. EASL 2014, Abstract #O163 Treatment-naïve and pegIFN/RBV-experienced genotype 1 HCV infected patients, with no prior therapy with direct acting antiviral agents Compensated (Child-Pugh A) cirrhosis at screening Cirrhosis documented using liver biopsy, or FibroScan (≥14.6 kPa) within 6 months of or during screening Platelet count ≥60,000 cells/mL Serum albumin ≥2.8 g/dL Total bilirubin <3 mg/dL INR ≤2.3 AFP ≤100 ng/mL Patients with radiographic ascites and patients with varices were allowed

38 38 12-Week Arm (N=208) 24-Week Arm (N=172) Male (%) White race (%) Hispanic or Latino ethnicity (%) Mean age (years) Mean BMI (kg/m 2 ) 27.9 IL28B non-CC (%) HCV genotype 1a (%) Treatment-naïve (%) Treatment-experienced (%) Relapse Partial responder Null responder Platelet count <100 x 10 9 /L (%) Serum albumin <3.5 g/dL (%) Child-Pugh score >5 (%) D + RBV Poordad, F. et al. EASL 2014, Abstract #O163

39 39 Poordad, F. et al. EASL 2014, Abstract #O163 SVR12, % Patients 12 Weeks 3D + RBV / / Weeks 3D + RBV P=0.089

40 week arm 24-week arm 92.9 NaïvePrior Relapse Response 3D + RBV SVR12, % Patients 59/64 14/15 52/56 13/ /11 40/50 10/10 39/42 Prior Partial Response Prior Null Response HCV Subtype 1a Poordad, F. et al. EASL 2014, Abstract #O163

41 41 All-Oral Dual Therapy With Daclatasvir and Asunaprevir in Patients With HCV Genotype 1b Infection: Phase 3 HALLMARK-DUAL Study Results M. Manns 1, S. Pol 2, I. Jacobson 3, P. Marcellin 4, S. Gordon 5, C.-Y. Peng 6, T.-T. Chang 7, G. Everson 8, J. Heo 9, G. Gerken 10, B. Yoffe 11, W.J. Towner 12, M. Bourliere 13, S. Metivier 14, C.-J. Chu 15, W. Sievert 16, J.-P. Bronowicki 17, D. Thabut 18, Y.-J. Lee 19, J.-H. Kao 20, F. McPhee 21, J. Kopit 21, P. Mendez 22, M. Linaberry 22, E. Hughes 22, S. Noviello 22, HALLMARK DUAL Study Team 1 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany, 2 H_pital Cochin, Paris, France, 3 Weill Cornell Medical College, New York, NY, United States, 4 Hopital Beaujon, Clichy, France, 5 Henry Ford Health Systems, Detroit, MI, United States, 6 School of Medicine, China Medical University, Taichung, 7 National Chen Kung University Hospital, Tainan, Taiwan, 8 University Of Colorado Denver, Aurora, CO, United States, 9 Pusan National University Hospital, Busan, Korea, Republic of, 10 University of Duisburg-Essen, Essen, Germany, 11 VAMC, Baylor College of Medicine, Houston, TX, 12 Kaiser Permanente, Los Angeles, CA, United States, 13 H_pital Saint Joseph, Marseille, 14 CHU Purpan, Toulouse, France, 15 Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, 16 Monash Health and Monash University, Melbourne, VIC, Australia, 17 INSERM Unit_ 954, Centre Hospitalier Universitaire de Nancy and Universit_ de Lorraine, Vandoeuvre-l_s-Nancy, 18 H_pital Piti_- Salp_tri_re, Paris, France, 19 Inje University Busan Paik Hospital, Busan, Korea, Republic of, 20 National Taiwan University Hospital, Taipei, Taiwan, 21 Bristol-Myers Squibb Research and Development, Wallingford, CT, 22 Bristol-Myers Squibb Research and Development, Princeton, NJ, United States

42 42 Primary endpoint: proportion of DCV + ASV-treated patients with SVR 12 Patients infected with HCV genotype 1b –Treatment-naive –Nonresponders: prior null or partial response to pegIFN/RBV –Interferon-ineligible/intolerant (treatment-naive or -experienced) due to Depression Anemia/neutropenia Compensated advanced fibrosis/cirrhosis (F3/F4) with thrombocytopenia 42 Manns, M. et al. EASL 2014, Abstract #O166 Randomization 2:1 STOP DCV + ASV 24 weeks (N = 205) DCV + ASV 24 weeks (N = 235) Week 24Week 48Day 1 Week 12 Nonresponder Ineligible/intolerant Treatment-naive DCV 60 mg QD + ASV 100 mg BID 24 weeks (N = 203) a DCV-PBO + ASV-PBO 12 weeks (N = 102) Enter another study: DCV + ASV 24 weeks Follow up 24 weeks SVR 12 a Excludes 2 patients inadvertently assigned, instead of randomized, to DCV + ASV; patients were excluded from efficacy analyses but both achieved SVR 12

43 43 Manns, M. et al. EASL 2014, Abstract #O166 Parameter Treatment-naive DCV + ASV (N = 205) Treatment-naive Placebo (N = 102) Nonresponder a (N = 205) Ineligible/ intolerant b (N = 235) Age, median years Male, n (%)101 (49)54 (53)111 (54)98 (42) Race, n (%) White135 (66)59 (58)148 (72)169 (72) Black14 (7)8 (8)10 (5)10 (4) Asian52 (25)33 (32)45 (22)56 (24) HCV RNA, n (%) < 800,000 log 10 IU/mL53 (26)26 (25)27 (13)48 (20) ≥ 800,000 log 10 IU/mL152 (74)76 (75)178 (87)187 (80) Cirrhosis, n (%)33 (16)16 (16)63 (31)111 (47) IL28B genotype, n (%) CC76 (37)N/A29 (14)82 (35) Non-CC129 (63)N/A173 (84)143 (61) a Includes 119 (58%) null responders, 84 (41%) partial responders, and 2 (1%) relapsers. b Includes 71 (30%) patients with depression, 87 (37%) with anemia/neutropenia, and 77 (33%) with compensated advanced fibrosis/cirrhosis with thrombocytopenia (6 with advanced fibrosis [F3], 70 with cirrhosis [F4], and 1 not reported).

44 44 Treatment- naive NonrespondersIneligible/ intolerant SVR 12 (% of patients) a,b a HCV RNA < lower limit of assay quantitation (25 IU/mL) b Patients with missing SVR12 data counted as treatment failures Manns, M. et al. EASL 2014, Abstract #O166 SVR 12 rates documented on or after posttreatment Week 12 –Treatment-naive: 91% –Nonresponders: 82% –Ineligible/intolerant: 83% 182/ / /235

45 45 SVR 12 (% of patients) NonresponderIneligible/intolerantTreatment-naive NullPartialDepressionAnemia/ neutropenia a Advanced fibrosis/cirrhosis w/ thrombocytopenia b a Anemia: screening hemoglobin 8.5 to < 12 (female) or < 13 (male) g/dL and/or history of anemia on pegIFN/RBV; neutropenia: screening absolute neutrophils 0.5 to < 1.5 x 10 9 cells/L and/or history of neutropenia on pegIFN/RBV b Screening platelets 50 to < 90 x 10 9 cells/L and/or history of thrombocytopenia on pegIFN/RBV Manns, M. et al. EASL 2014, Abstract #O /20398/11968/84 57/71 79/87 56/77

46 46 Manns, M. et al. EASL 2014, Abstract #O166 Patients, n (%) Treatment- naive (N = 203) Nonresponder (N = 205) Ineligible/intole rant (N = 235) All21 (10)37 (18)43 (18) On-treatment failures Virologic breakthrough9 (4)26 (13)20 (9) Futility001 (0.4) Detectable or missing RNA at end of treatment 4 (2)3 (1)8 (3) Posttreatment failures Relapse a 5 (3)7 (4)12 (6) Missing RNA at posttreatment Week 12 a 3 (2)1 (1)2 (1) a Percentages based on number of patients with undetectable HCV RNA at end of treatment (treatment-naive, n = 189; nonresponder, n = 174; ineligible/intolerant, n = 204).

47 47 Efficacy and Safety of MK-5172 And MK-8742 ± Ribavirin in Hepatitis C Genotype 1 Infected Patients With Cirrhosis or Previous Null Response: The C-WORTHy Study E. Lawitz 1, C. Hezode 2, E. Gane 3, E. Tam 4, M. Lagging 5, L. Balart 6, L. Rossaro 7, R. Ghalib 8, M. Shaughnessy 9, P. Hwang 9, J. Wahl 9, M.N. Robertson 9, B. Haber 9 1 The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States, 2 Department of Hepatology-Gastroenterology, Henri Mondor Hospital, University of Paris-Est, Creteil, France, 3 Auckland Clinical Studies, Grafton, Auckland, New Zealand, 4 LAIR Centre, Vancouver, BC, Canada, 5 Department of Infectious Disease, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden, 6 Gastroenterology & Hepatology, Tulane University Medical Center, New Orleans, LA, 7 Gastroenterology and Hepatology, University of California, Davis Medical Center, Sacramento, CA, 8 Texas Clinical Research Institute, Arlington, TX, 9 Merck, Whitehouse Station, NJ, United States

48 48 Lawitz, E. et al. EASL 2014, Abstract #O61 Aim: To assess the efficacy, safety and optimal treatment duration of MK MK-8742 ± ribavirin in patients with HCV genotype 1 infection who are: –Treatment naïve with cirrhosis; or –Null responders to prior peginterferon/ribavirin (PR) ± cirrhosis Key eligibility criteria: Treatment-naïve patients ≥18 years old with chronic HCV GT1a or GT1b infection Null response = <2 log 10 decline from baseline in HCV RNA after 12 weeks of prior PR Liver biopsy or noninvasive test Minimum baseline hemoglobin: 12 g/dL (females) or 13 g/dL (males) HIV and HBV negative ALT and AST <350 IU/L Albumin ≥3.0 g/dL; platelets ≥70,000/mm 3 Treatment-naive Non-cirrhotic 8-12 weeks ± RBV (n = 94) Treatment-naive Non-cirrhotic 8-12 weeks ± RBV (n = 94) Treatment-naive Cirrhotic weeks ± RBV (n = 123) Treatment-naive Cirrhotic weeks ± RBV (n = 123) HIV/HCV co-infected Non-cirrhotic 12 weeks ± RBV (n = 59) HIV/HCV co-infected Non-cirrhotic 12 weeks ± RBV (n = 59) Null responders Cirrhotic / Non-cirrhotic weeks ± RBV (n = 130) Null responders Cirrhotic / Non-cirrhotic weeks ± RBV (n = 130)

49 Breakthrough * 30 31* TW4TW12FU4/8 Relapse Discontinuation *Excludes patients who have not yet reached the FU4 time point 12 week arms include 97% of FU8 results Lawitz, E. et al. EASL 2014, Abstract #O61

50 * 32 32* TW4TW12FU4/8 *Excludes patients who have not yet reached the FU4 time point 12 week arms include 97% of FU8 results Breakthrough Relapse Discontinuation Lawitz, E. et al. EASL 2014, Abstract #O61


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