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1 Catherine Stedman, MD Christchurch, New Zealand This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb.

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Presentation on theme: "1 Catherine Stedman, MD Christchurch, New Zealand This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb."— Presentation transcript:

1 1 Catherine Stedman, MD Christchurch, New Zealand This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences

2 2 Successful Retreatment of HCV Genotype-1 Infected Patients Who Failed Prior Therapy with Peg-interferon + Ribavirin Plus 1 or 2 Other Direct-Acting Antiviral Agents with Sofosbuvir Stanislas Pol 1, Mark Sulkowski 2, Tarek Hassanein 3, Ed Gane 4, Liyun Ni 5, Hongmei Mo 5, Bittoo Kanwar 5, Diana Brainard 5, GM Subramanian 5, William T. Symonds 5, John G. McHutchison 5, Michael Bennett 6, Ira M. Jacobson 7 1 Universite Paris Decartes, Hopital Cochin, Paris, France; 2 John Hopkins University, Baltimore, MD, USA; 3 Southern California Liver Center, Coronado, CA, USA; 4 Aukland City Hospital, Auckland, NZ; 5 Gilead Sciences, Inc., Foster City, CA, USA; 6 Medical Associates Research Group, San Diego, CA, USA; 7 Weill Cornell Medical College, New York, NY, USA

3 3 All patients were previously treated with PEG+RBV and an investigational protease inhibitor (GS-9451 or GS-9256) +/- one or two additional DAA –Tegobuvir (NS5b non-nucleoside polymerase inhibitor) –Ledipasvir (NS5a inhibitor) No patients had documented cirrhosis as per the prior protocols SVR 12 SOF + PEG/RBV Wk 0 Wk 12Wk 24 Pol, S. et al. EASL 2014, Abstract #O55

4 4

5 5 66/67 67/67 37/50 Pol, S. et al. EASL 2014, Abstract #O55

6 6 Three quarters (74%) of DAAs-experienced patients achieved an SVR with 12 weeks of SOF + PEG/RBV therapy despite multiple resistance variants and prior courses of therapy The presence of baseline RAVs against any or all 3 non structural proteins (NS3, NS5a, NS5b) did not impact overall SVR The 12-week SOF + PEG/RBV regimen was safe and well tolerated Sofosbuvir-containing regimens are effective in these patients with no other currently approved alternatives Pol, S. et al. EASL 2014, Abstract #O55

7 7 Successful Retreatment With Sofosbuvir-containing Regimens for HCV Genotype 2 or 3 Infected Patients who Failed Prior Sofosbuvir Plus Ribavirin Therapy Rafael Esteban 1, Lisa Nyberg 2, Jay Lalezari 3, Liyun Ni 4, Brian Doehle 4, Bittoo Kanwar 4, Diana Brainard 4, GM Subramanian 4, William T. Symonds 4, John G. McHutchison 4, Maribel Rodriquez-Torres 5, Stefan Zeuzem 6 1 Vall d’Hebron Hospital, Barcelona, Spain; 2 Kaiser Permanente, San Diego, CA, USA; 3 Quest Clinical Research, San Francisco, CA, USA; 4 Gilead Sciences, Inc., Foster City, CA, USA; 5 Fundacion de Investigacion, San Juan, Puerto Rico; 6 JW Goethe University Hospital, Frankfurt, Germany

8 8 Open-label study offered to all GT 2 or 3 treatment failures from FISSION, POSITRON and FUSION Patients offered 2 possible treatment options –Choice based on patient’s eligibility for IFN and patient/investigator recommendation Included patients with compensated cirrhosis SVR 12 SOF + PEG/RBV SVR 12 SOF + RBV Wk 0 Wk 12Wk 24Wk 36 Esteban, R. et al. EASL 2014, Abstract #O8

9 9 *Cirrhosis status determined in parent protocol. Esteban, R. et al. EASL 2014, Abstract #O8

10 10 28/2850/5024/2625/40 28/2850/50 Relapse accounted for all virologic failures Error bars represent 95% confidence intervals. Esteban, R. et al. EASL 2014, Abstract #O8

11 11 13/14 7/8 17/237/15 Esteban, R. et al. EASL 2014, Abstract #O8

12 12 Retreatment with an extended duration of SOF + RBV to 24 weeks or the addition of IFN to a 12 week regimen resulted in high SVR rates in GT 2 and GT 3 patients who previously failed SOF+RBV-containing regimens The 12-week regimen containing IFN had higher overall rates of SVR and was more effective in patients with cirrhosis The 24-week IFN-free regimen was safe and well tolerated and offers a retreatment option for those ineligible to receive IFN Esteban, R. et al. EASL 2014, Abstract #O8

13 13 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) E. Lawitz 1, R. Ghalib 2, M. Rodriguez-Torres 3, Z.M. Younossi 4, A. Corregidor 5, M.S. Sulkowski 6, E. DeJesus 7, B. Pearlman 8, M. Rabinovitz 9, N. Gitlin 10, J.K. Lim 11, P.J. Pockros 12, B. Fevery 13, T. Lambrecht 14, S. Ouwerkerk-Mahadevan 13, K. Callewaert 13, W.T. Symonds 15, G. Picchio 16, K. Lindsay 16, M. Beumont-Mauviel 13, I.M. Jacobson 17 1 Texas Liver Institute, San Antonio, 2 Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX, 3 Fundacion de Investigacion, San Juan, PR, 4 Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, 5 Borland-Groover Clinic, 4800 Belfort Rd, Jacksonville, FL, 6 Johns Hopkins University School of Medicine, Baltimore, MD, 7 Orlando Immunology Center, Orlando, FL, 8 Atlanta Medical Center, Atlanta, GA, 9 University of Pittsburgh Medical Center, Pittsburgh, PA, 10 Atlanta Gastroenterology Association, Atlanta, GA, 11 Yale School of Medicine, New Haven, CT, 12 Scripps Clinic, La Jolla, CA, United States, 13 Janssen Research & Development, Beerse, 14 Novellas Healthcare, Zellik, Belgium, 15 Gilead Sciences Inc, Foster City, CA, 16 Janssen Research & Development LLC, Titusville, NJ, 17 Weill Cornell Medical College, New York, NY, United States

14 14 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)

15 15 Non-VF, patients who did not achieve SVR12 for reasons other than virologic failure 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 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 #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%

16 16 *Excluding patients who discontinued for non-virologic reasons SMV/SOF±RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall GT 1b 6/611/11 4/47/74/45/513/147/83/37/83/318/1838/4025/ 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

17 17 *Excluding patients who discontinued for non-virologic reasons GT 1a without Q80K SMV/SOF±RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall GT 1b 6/611/11 4/47/74/45/513/147/83/37/83/318/1838/4025/ 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

18 18 *Excluding patients who discontinued for non-virologic reasons GT 1a without Q80K GT 1a with Q80K SMV/SOF±RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall GT 1b 6/611/11 4/47/74/45/513/147/83/37/83/318/1838/4025/ 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

19 19 *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 9/93/34/45/54/56/64/42/321/2216/17 Null respondersTreatment naïves

20 20 SMV/SOF QD led to SVR12 rates of % (ITT) in HCV GT 1 infected treatment-naïve and prior null-responder patients with METAVIR F3-4 SVR12 rates were high, regardless of baseline characteristics: –HCV GT 1 subtype, Q80K polymorphism, METAVIR score, IL28B GT, prior treatment history SMV/SOF QD +/- RBV was safe and well tolerated Two Phase 3 trials investigating SMV/SOF without RBV are ongoing (OPTIMIST-1 and -2) GT, genotype; ITT, Intent-to-treat; QD, once daily; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12, sustained virologic response 12 weeks after end of treatment Lawitz, E. et al. EASL 2014, Abstract #O165

21 21 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

22 22 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 Lawitz, E. et al. EASL 2014, Abstract #O109

23 23 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 #O109

24 24 211/ Weeks24 Weeks LDV/SOF + RBV 211/ /217 SVR12 (%) 215/217 LDV/SOF + RBV LDV/SOF Mangia, A. et al. EASL 2014, Abstract #O109 Error bars represent 95% confidence intervals.

25 25 LDV/SOF for 12 weeks achieved SVR12 rate of 99% in treatment-naive GT 1 patients –Adding RBV and/or extending LDV/SOF treatment duration to 24 weeks did not increase SVR12 rates –Cirrhotic patients achieved SVR12 rates of % with weeks of treatment with LDV/SOF with or without RBV LDV/SOF with or without RBV was safe and well tolerated –Addition of RBV contributed to higher incidence of AEs and laboratory abnormalities A single tablet regimen with the fixed-dose combination LDV/SOF for 12 weeks achieved SVR in most GT 1 previously un-treated patients Mangia, A. et al. EASL 2014, Abstract #O109

26 26 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

27 27 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 #O164

28 28 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 #O164

29 29 107/ Weeks24 Weeks LDV/SOF + RBV 102/ /109 SVR12 (%) 110/111 LDV/SOF + RBV LDV/SOF Afdhal, N. et al. EASL 2014, Abstract #O164 Error bars represent 95% confidence intervals.

30 30 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 Afdhal, N. et al. EASL 2014, Abstract #O164 Error bars represent 95% confidence intervals.

31 31 Absence of CirrhosisCirrhosis SVR12 (%) 83/8719/2289/8918/2286/8722/2288/8922/22 12 Weeks24 Weeks LDV/SOF + RBV LDV/SOF Afdhal, N. et al. EASL 2014, Abstract #O164 Error bars represent 95% confidence intervals.

32 32 Single tablet fixed dose combination of LDV/SOF with or without RBV in treatment-experienced GT 1 patients resulted in an SVR of % Baseline NS5a or NS3/4 mutations had no effect on SVR RBV did not enhance SVR rates, alter viral kinetics or prevent relapse The majority of subjects who relapsed had cirrhosis LDV/SOF ± RBV was safe and well tolerated –Addition of RBV contributed to higher incidence of AEs and laboratory abnormalities Afdhal N, et al. NEJM In Press Afdhal, N. et al. EASL 2014, Abstract #O164

33 33 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. Kowdley 1, Stuart C. Gordon 2, K. Rajender Reddy 3, Lorenzo Rossaro 4, David E. Bernstein 5, Di An 6, Evguenia S. Svarovskaia 6, Robert H. Hyland 6, Phillip S. Pang 6, William T. Symonds 6, John G. McHutchison 6, Andrew J. Muir 7, Paul J. Pockros 8, David C. Pound 9, Michael W. Fried 10 1 Virginia Mason Medical Center, Seattle, WA, USA; 2 Henry Ford Health System, Detroit, MI, USA; 3 Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA, USA; 4 University of California Davis Medical Center, Sacramento, CA, USA; 5 North Shore University Hospital, Manhasset, NY, USA; 6 Gilead Sciences, Inc., Foster City, CA; 7 Division of Gastroenterology and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; 8 Scripps Clinic, La Jolla, CA; 9 Indianapolis Gastroenterology Research Foundation, Indianapolis, IN, USA; 10 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

34 34 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) LDV/SOF LDV/SOF + RBV Wk 0 Wk 8Wk 12Wk 24Wk 20 SVR12 Kowdley, K. et al. EASL 2014, Abstract #O56

35 35 206/216 8 Weeks12 Weeks LDV/SOF LDV/SOF + RBV 201/216202/215206/216 SVR12 (%) p=0.52 Kowdley, K. et al. EASL 2014, Abstract #O56 Error bars represent 95% confidence intervals.

36 36 Kowdley K, et al. NEJM In Press Kowdley, K. et al. EASL 2014, Abstract #O56 LDV/SOF ± RBV for 8 or 12 weeks results in high SVR12 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

37 37 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. Gane 1, R.H. Hyland 2, D. An 2, P.S. Pang 2, W.T. Symonds 2, J.G. McHutchison 2, C.A. Stedman 3 1 Auckland Clinical Studies, Auckland, New Zealand; 2 Gilead Sciences, Inc., Foster City, CA, United States; 3 Christchurch Clinical Studies Trust, Christchurch, New Zealand

38 38 Wk 0 Wk 12Wk 24 SVR12 LDV/SOF + RBV, n=26 LDV/SOF, n=25 GT 3 Treatment naïve Randomized 1. HCV GT 1, relapsed after previous treatment with SOF-containing regimens in ELECTRON-1 2. HCV GT 1 decompensated cirrhosis (Child Pugh Turcotte B) 3. HCV GT 3, treatment naïve LDV/SOF + RBV, n=19 GT 1 Prior SOF exposure GT 1 CPT class B LDV/SOF, n=20 Gane, E. et al. EASL 2014, Abstract #O6

39 39 19/19 SVR12 (%) Re-treatment GS SOF +RBV 12 wk Treatment Naïve SOF+RBV 12 wk Prior Null Responders n=6 n=4 n=8 n=1 LDV/SOF +RBV 6 wk Treatment Naïve SOF+RBV 12 wk Treatment Naïve 19/19 All 19 previous SOF-regimen failures had relapsed Gane, E. et al. EASL 2014, Abstract #O6

40 40 SVR12 (%) 13/20 GT 1 CPT Class B Median total bilirubin, mg/dL (range) 1.5 ( ) Median serum albumin, g/dL (range) 3.1 ( ) Median INR (range) 1.2 ( ) Ascites, n (%)4 (20) Hepatic encephalopathy, n (%) 6 (30) Median platelet count, 10 3 /µL (range) 84 (44-162) 7 relapsers Gane, E. et al. EASL 2014, Abstract #O6 Error bar represents the 95% confidence interval.

41 41 SVR12 (%) 16/2526/ * LDV/SOF + RBV 12 Weeks 26/2616/25 LDV/SOF 12 Weeks *Failure due to relapse (n=8) or discontinuation due to AE (n=1) Gane, E. et al. EASL 2014, Abstract #O6

42 42 Gane, E. et al. EASL 2014, Abstract #O6 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

43 43 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

44 44 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

45 45 HCV genotype and subtype were assessed using the Versant HCV Genotype Inno-LiPA Assay, v2.0. 3D + RBV (N=473) Placebo (N=158) Male, n (%) 271 (57.3)73 (46.2) Race, n (%) White 428 (90.5)144 (91.1) Black 26 (5.5)8 (5.1) Hispanic/Latino ethnicity, n (%) 27 (5.7)5 (3.2) Median age, years (range) 52.0 ( )52.0 ( ) Median BMI, kg/m 2 (range) 25.2 ( )25.5 ( ) Fibrosis stage, n (%) F0-F1 363 (76.7)116 (73.4) F2 70 (14.8)27 (17.1) F3 40 (8.5)15 (9.5) IL28B non-CC genotype, n (%) 329 (69.6)108 (68.4) HCV subtype, n (%) 1a 322 (68.1)105 (66.5) 1b 151 (31.9)53 (33.5) Median HCV RNA, log 10 IU/mL (range) 6.51 ( )6.64 ( ) Feld, J. et al. EASL 2014, Abstract #O60

46 46 SVR12, % Patients All Patients 96.2% 95.3% 98.0% 455/ /322148/151 GT1a GT1b Feld, J. et al. EASL 2014, Abstract #O60

47 47 Feld, J. et al. EASL 2014, Abstract #O60 The ITT SVR12 rate was 96.2% (455/473) for treatment- naïve GT1-infected patients receiving 12 weeks of co- formulated ABT-450/r/ombitasvir + dasabuvir + RBV SVR12 rates (ITT) were high regardless of HCV subtype The rate of virologic failure was low: –0.2% breakthrough rate –1.5% relapse rate The regimen was generally well-tolerated, with a low rate of study drug discontinuation due to AE(s) (0.6%)

48 48 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 Hopital 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

49 49 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=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 Zeuzem, S. et al. EASL 2014, Abstract #O1

50 50 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-F1 202 (68.0)65 (67.0) F2 53 (17.8)17 (17.5) F3 42 (14.1)15 (15.5) IL28B* non-CC genotype, n (%) 263 (88.6)90 (92.8) HCV subtype, n (%) 1a 173 (58.2)57 (58.8) 1b 123 (41.4)40 (41.2) Median HCV RNA, log 10 IU/mL (range) 6.66 ( )6.55 ( ) Prior pegIFN/RBV response, n (%) Relapse 86 (29.0)29 (29.9) Partial response 65 (21.9)21 (21.6) Null response 146 (49.2)47 (48.5) *IL28B rs HCV genotype and subtype assessed using the Versant HCV Genotype Inno-LiPA Assay, v2.0. HCV RNA level measured by COBAS TaqMan real-time reverse-transcriptase–polymerase-chain-reaction assay, v2.0 (Roche). Zeuzem, S. et al. EASL 2014, Abstract #O1

51 51 Zeuzem, S. et al. EASL 2014, Abstract #O1 SVR12, % Patients All Patients 96.3% 96.0% 96.7% 286/297166/173119/123 GT1a GT1b

52 52 Zeuzem, S. et al. EASL 2014, Abstract #O1 SVR12, % Patients Prior Relapse 95.3% 100% 95.2% 82/8665/65139/146 Prior Partial Response Prior Null Response

53 53 The ITT SVR12 rate was 96.3% (286/297) for treatment-experienced GT1-infected patients receiving 12 weeks of ABT-450/r/ombitasvir + dasabuvir + RBV High SVR12 rates regardless of HCV subtype and across all prior pegIFN/RBV response groups The regimen was generally well-tolerated, with a low rate of study drug discontinuation due to AE(s) (1.0%) Zeuzem, S. et al. EASL 2014, Abstract #O1

54 54 TURQUOISE-II: SVR12 Rate 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 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

55 55 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=208 (N=208) 3D + RBV (N=172) 3D + RBV (N=172) Poordad, F. et al. EASL 2014, Abstract #O163 All patients to be followed through 48 weeks post-treatment

56 56 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

57 57 SVR12, % Patients 12 Weeks 3D + RBV / / Weeks 3D + RBV P=0.089 Poordad, F. et al. EASL 2014, Abstract #O163

58 NaïvePrior Relapse Response 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 12-week arm 24-week arm 3D + RBV Poordad, F. et al. EASL 2014, Abstract #O163

59 59 First dedicated trial of IFN-free regimen in cirrhotic patients, including patients often ineligible for clinical trials (low platelets, low albumin, radiographic ascites) SVR rates of 92% to 96% with 12 and 24 weeks of treatment, with high SVR rates in all subgroups analyzed 12 or 24 weeks of treatment were similarly well tolerated, with low rates of treatment discontinuation Efficacy and safety in this large cirrhotic population is similar to non-cirrhotics treated with the same regimen

60 60 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

61 61 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 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 Manns, M. et al. EASL 2014, Abstract #O166

62 62 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). Manns, M. et al. EASL 2014, Abstract #O166

63 63 Treatment- naive NonrespondersIneligible/ intolerant SVR 12 (% of patients) a,b SVR 12 rates documented on or after posttreatment Week 12 –Treatment-naive: 91% –Nonresponders: 82% –Ineligible/intolerant: 83% a HCV RNA < lower limit of assay quantitation (25 IU/mL) b Patients with missing SVR 12 data counted as treatment failures Manns, M. et al. EASL 2014, Abstract #O / / /235

64 64 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

65 65 Patients, n (%) Treatment- naive (N = 203) Nonresponder (N = 205) Ineligible/intoler ant (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). Manns, M. et al. EASL 2014, Abstract #O166

66 66 All-oral DCV + ASV therapy achieved SVR 12 rates up to 91% in treatment-naive, 82% in nonresponder, and 83% in ineligible/intolerant patients with genotype 1b –SVR 12 rates were similar in non-cirrhotic (85%) and cirrhotic (84%) patients –No differences by age, gender, race, IL28B genotype, or prior IFN/RBV treatment experience DCV + ASV was generally safe and well tolerated –Only 2% of patients discontinued treatment due to adverse events DCV is being further evaluated in all-oral combinations in multiple patient populations of high unmet need Manns, M. et al. EASL 2014, Abstract #O166


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