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1 Savino Bruno, MD Milano, Italy This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences.

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Presentation on theme: "1 Savino Bruno, MD Milano, Italy This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences."— Presentation transcript:

1 1 Savino Bruno, MD Milano, Italy This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences

2 2 Once-Daily Simeprevir (TMC435) Plus Sofosbuvir (GS-7977) With or Without Ribavirin in HCV Genotype 1 Prior Null Responders With Metavir F0-2: Cosmos Study Subgroup Analysis M. Sulkowski 1, I.M. Jacobson 2, R. Ghalib 3, M. Rodriguez-Torres 4, Z. Younossi 5, A. Corregidor 6, B. Fevery 7, K. Callewaert 8, W. Symonds 9, G. De La Rosa 10, G. Picchio 11, S. Ouwerkerk-Mahadevan 8, T. Lambrecht 12, E. Lawitz 13 1 Johns Hopkins University School of Medicine, Baltimore, MD, 2 Weill Cornell Medical College, New York, NY, 3 Texas Clinical Research Institute, Arlington, TX, 4 Fundaci_n de Investigaci_n, San Juan, PR, 5 Department of Internal Medicine, Inova Fairfax Hospital, Falls Church, VA, Belfort Rd, Jacksonville, FL, United States, 7 Janssen Research & Development, Janssen Infectious Diseases BVBA, Beerse, Belgium, 8 Janssen Research & Development, Beerse, Belgium, 9 Gilead Sciences, Inc., Foster City, CA, 10 Janssen Global Services, Raritan, NJ, United States, 11 Novellas Healthcare, Zellick, Belgium, 12 Janssen Research & Development, Titusville, NJ, 13 The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States

3 3 Cohort 1: METAVIR F0-F2, prior null responders to PR therapy –Stratified by IL28B, HCV GT 1 subtype Primary endpoint: SVR12 Secondary endpoints included RVR and relapse rate 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 Sulkowski, M. 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 24 weeks SMV/SOF + RBVSMV/SOF 100 SVR12 Proportion of patients (%) 1/24 4/24 12 weeks Non-VFRelapse 1/ /1519/2413/1426/27 SMV/SOF + RBVSMV/SOF 100 1/14 1/ ITT, intent-to-treat; Non-VF, Non-virologic failure, patients who did not achieve SVR12 for reasons other than virologic failure Sulkowski, M. et al. EASL 2014, Abstract #O7

5 5 *Excluding patients who discontinued for non-virologic reasons Sulkowski, M. et al. EASL 2014, Abstract #O7 SMV/SOF±RBV SVR12 (%) SMV/SOF + RBV SMV/SOF 24 weeks 12 weeks Overall 4/47/78/93/37/73/36/612/128/94/4 5/617/1730/3024/27

6 6 SMV/SOF QD led to high SVR12 rates in HCV GT1- infected patients regardless of treatment duration or the addition of RBV SVR12 rates were high, regardless of baseline characteristics: –HCV GT1 subtype, Q80K polymorphism, IL28B genotype On-treatment virologic response, including RVR, was not predictive of SVR Two Phase 3 trials investigating SMV/SOF without ribavirin 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 Sulkowski, M. et al. EASL 2014, Abstract #O7

7 7 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

8 8 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%

9 9 *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

10 10 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) Lawitz, E. et al. EASL 2014, Abstract #O165

11 11 Sofosbuvir and Ribavirin for the Treatment of Chronic HCV With Cirrhosis and Portal Hypertension With and Without Decompensation: Early Virologic Response and Safety Nezam Afdhal, 1 Gregory Everson, 2 Jose Luis Calleja, 3 Geoffrey McCaughan, 4 William T. Symonds, 5 Diana Brainard, 5 Jill Denning, 5 Theo Brandt-Sarif, 5 Lindsay McNair, 5 John G. McHutchison, 5 Sarah Arterburn, 5 Jaime Bosch, 10 Michael Charlton, 6 Rajender Reddy, 7 Tarik Asselah, 8 Edward Gane, 9 Xavier Forns 10 1 Beth Israel Deaconess Medical Center, Boston, MA, USA; 2 University of Colorado Denver, Aurora, CO, USA; 3 Hospital Puerta de Hierro, Madrid, Spain; 4 Royal Prince Alfred Hospital, University of Sydney, New South Wales, Australia; 5 Gilead Sciences, Inc., Foster City, CA, USA; 6 Mayo Clinic, Rochester, MN, USA; 7 University of Pennsylvania, Philadelphia, PA, USA; 8 Hopital Beaujon, INSERM U 773 and University Paris-Diderot, Clichy, France; 9 Auckland City Hospital, Grafton, Auckland, New Zealand; 10 Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain

12 12 Aim: To explore the safety and efficacy of SOF+RBV in HCV-infected patients with portal hypertension ± decompensated liver disease Primary objective: SVR12 Secondary objectives –Effects of 48 weeks of treatment on hepatic portal pressure and function –Safety and clinical improvement as measured by clinical outcomes, CPT, MELD, and biochemical test results Study results through the first 24 weeks are presented Afdhal, N. et al. EASL 2014, Abstract #O68 SOF 400 mg + RBV mg SVR 12 SOF 400 mg + RBV mg Wk 0 Wk 24Wk 48Wk 96Wk 72 HVPG at Day 0 and Week 48 HVPG at Day 0, and Weeks 24 and 72 Arm 1 N=25 Arm 2 N=25 SVR 12 Observation

13 13 *1 patient was a non-responder at Week 8. Afdhal, N. et al. EASL 2014, Abstract #O68 5/97/169/912/168/815/168/815/167/714/15

14 14 In HCV-infected patients with portal hypertension with and without hepatic decompensation, treatment with SOF+RBV for up to 24 weeks resulted in: –High rates of virologic suppression irrespective of severity of liver disease –Decreased necroinflammation with ALT normalization –Improvements in platelet count and albumin –Improvement in ascites and hepatic encephalopathy SOF+RBV for up to 24 weeks was generally safe and well tolerated with low rates of treatment discontinuation due to AEs –No patients developed worsening or new onset hepatic decompensation Afdhal, N. et al. EASL 2014, Abstract #O68

15 15 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

16 16 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

17 17 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

18 18 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.

19 19 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

20 20 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

21 21 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

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=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

23 23 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

24 24 Zeuzem, S. et al. EASL 2014, Abstract #O1 SVR12, % Patients All Patients 96.3% 96.0% 96.7% 286/297166/173119/123 GT1a GT1b

25 25 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

26 26 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

27 27 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

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) 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

29 29 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

30 30 SVR12, % Patients 12 Weeks 3D + RBV / / Weeks 3D + RBV P=0.089 Poordad, F. et al. EASL 2014, Abstract #O163

31 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

32 32 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 Poordad, F. et al. EASL 2014, Abstract #O163

33 33 PEARL-III: 12 Weeks of ABT-450/R/267 + Abt-333 Achieved SVR in >99% of 419 Treatment-Naïve HCV Genotype 1b- Infected Adults With or Without Ribavirin P. Ferenci 1, A. Nyberg 2, P. Enayati 3, D. Bernstein 4, Y. Baruch 5, F.A. Caruntu 6, V. Chulanov 7, E. Janczewska 8, Z. Younes 9, R.T. Marinho 10, G.Rizzardini 11, J. Gervain 12, R. Planas 13, C. Moreno 14, W. Xie 15, D.Cohen 15, M. King 15, T. Podsadecki 15, K.R. Reddy 16 1 Universitaetsklinik fuer Innere Medizin III, Vienna, Austria, 2 KaiserPermanente, San Diego, 3 California Liver Institute, Los Angeles, 4 North Shore University Hospital, Manhasset, CA, United States, 5 Rambam Health Care Campus, Haifa, Israel, 6 Institutul National de Boli Infectioase 'Prof. Dr. Matei Bals', Bucharest, Romania, 7 Federal Budget Institute of Science Central Research Institute of Epidemiology, Moscow, Russian Federation, 8 ID Clinic, Mysłowice, Poland, 9 GastroOne, Germantown, TN, United States, 10 Centro Hospitalar Lisboa Norte, Lisboa, Portugal, 11 Ospedale Luigi Sacco, Milano, Italy, 12 Szent György Hospital, Székesfehérvár, Hungary, 13 Hospital Germans Trías i Pujol, CIBERehd, Badalona, Spain, 14 CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium, 15 AbbVie Inc., North Chicago, IL, 16 University of Pennsylvania, Philadelphia, PA, United States

34 34 All patients received the 3D regimen –ABT-450/r/ombitasvir: 150 mg/100 mg/25 mg QD –Dasabuvir: 250 mg BID –RBV 1000 mg if body weight was <75 kg, 1200 mg if body weight ≥75 kg (divided BID), or matching placebo ABT-450/r/Ombitasvir + Dasabuvir + RBV ABT-450/r/Ombitasvir + Dasabuvir + Placebo for RBV 3D + RBV N = 210 3D N = 209 Study drug dosing Assess for SVR wk Follow-up Day 0Week 12Week 24Week 60 Ferenci, P. et al. EASL 2014, Abstract #P1299

35 35 Ferenci, P. et al. EASL 2014, Abstract #P1299 SVR 12, % Patients Superiority 84% Noninferiority 73% 3D + RBV3D / /209

36 36 SVR 12 rates of 99.5% and 99% were achieved in treatment- naïve non-cirrhotic patients with GT1b infection following 12-week treatment with ABT-450/r/ombitasvir and dasabuvir with and without RBV, respectively 1 of 419 patients experienced virologic failure No patient discontinued prematurely due to adverse events in either treatment group Hematologic abnormalities and some adverse events were less frequent in the absence of RBV The addition of RBV in this population did not provide additional clinical benefit

37 37 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 Hopital 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 Hopital 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

38 38 Primary endpoint: proportion of DCV + ASV-treated patients with SVR 12 Patients infected with HCV genotype 1b –Treatment-naïve –Nonresponders: prior null or partial response to pegIFN/RBV –Interferon-ineligible/intolerant (treatment-naïve 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-naïve 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

39 39 Treatment- naïve NonrespondersIneligible/ intolerant SVR 12 (% of patients) a,b SVR 12 rates documented on or after posttreatment Week 12 –Treatment-naïve: 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

40 40 182/ / /235 29/32 55/63 88/ / /142104/124 SVR12 (%) Manns, M. et al. EASL 2014, Abstract #O166

41 41 All-oral DCV + ASV therapy achieved SVR 12 rates up to 91% in treatment-naïve, 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

42 42 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

43 43 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 Treatment-naïve Non-cirrhotic 8-12 weeks ± RBV (n = 94) Treatment-naïve Non-cirrhotic 8-12 weeks ± RBV (n = 94) Treatment-naïve Cirrhotic weeks ± RBV (n = 123) Treatment-naïve 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) 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 Lawitz, E. et al. EASL 2014, Abstract #O61

44 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

45 * 32 32* TW4TW12FU4/8 *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 Breakthrough Relapse Discontinuation

46 46 Efficacy MK MK-8742 ± RBV demonstrated high efficacy: –90-97% of cirrhotic patients achieved SVR4/8 –91-100% of prior null responders achieved SVR4/8 In treatment-naïve patients with cirrhosis, high efficacy was achieved regardless of use of RBV or extended treatment duration In prior null-responder patients, a 12-week RBV-free regimen resulted in >90% SVR4/8 Safety All treatment regimens were generally safe and well- tolerated These results support the ongoing Phase 3 development of MK MK-8742 ± RBV in various patient populations Lawitz, E. et al. EASL 2014, Abstract #O61


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