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1 Geoffrey Dusheiko, MD London, UK 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 Geoffrey Dusheiko, MD London, UK This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences."— Presentation transcript:

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

2 2 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

3 3 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

4 4 Arms were balanced with respect to demographics and baseline characteristics Afdhal, N. et al. EASL 2014, Abstract #O 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)

5 5 Error bars represent 95% confidence intervals. Afdhal, N. et al. EASL 2014, Abstract #O / Weeks24 Weeks LDV/SOF + RBV 102/ /109 SVR12 (%) 110/111 LDV/SOF + RBV LDV/SOF

6 6 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

7 7 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

8 8 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

9 9 1. Lawitz E, et al. Lancet. 2014;383: Kowdley, K. et al. EASL 2014, Abstract #O56 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 cirrhosis 1 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

10 10 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

11 11 206/216 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.

12 12 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

13 13 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

14 14 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

15 15 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

16 16 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.

17 17 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

18 18 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

19 19 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. Everson 1, T.T. Tran 2, W.J. Towner 3, M.N. Davis 4, D. Wyles 5, R. Nahass 6, J. McNally 7, D.M. Brainard 7, L. Han 7, B. Doehle 7, E. Mogalian 7, W.T. Symonds 7, J.G. McHutchison 7, T. Morgan 8, R.T. Chung 9 1 University of Colorado Denver, Aurora, CO, 2 Cedars-Sinai Medical Center, 3 Kaiser Permanente, Los Angeles, CA, 4 Digestive CARE, South Florida Center of Gastroenterology, LLC, Wellington, FL, 5 University of California, San Diego, CA, 6 ID CARE, Hillsborough, NJ, 7 Gilead Sciences, Inc., Foster City, 8 VA Long Beach, Long Beach, CA, 9 Massachusetts General Hospital, Boston, MA, United States

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

21 21 Everson, G. et al. EASL 2014, Abstract #O111 GT 1GT 2GT 3 26/2728/2810/1110/1025/27

22 22 Everson, G. et al. EASL 2014, Abstract #O111 GT 4GT 5GT 6 7/76/710/104/45/51/1

23 23 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 mg (N=3) compared to GS 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 mg is being evaluated in treatment-experienced patients and patients with cirrhosis Everson, G. et al. EASL 2014, Abstract #O111

24 24 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

25 25 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

26 26 SVR12, % Patients All Patients 96.2% 95.3% 98.0% 455/473307/322148/151 GT1a GT1b Feld, J. et al. EASL 2014, Abstract #O60

27 27 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

28 28 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

29 29 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

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

31 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

32 32 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. Kwo 1, P. Mantry 2, E. Coakley 3, H. Te 4, H. Vargas 5, R. Brown Jr. 6, F. Gordon 7, J. Levitsky 8, N. Terrault 9, J. Burton Jr 10, W. Xie 3, C. Setze 3, P. Badri 3, R.A. Vilchez 3, X. Forns 11 1 Indiana University, Indianapolis, IN, 2 The Liver Institute at Methodist Dallas Medical Center, Dallas, TX, 3 AbbVie Inc., North Chicago, 4 University of Chicago Medicine, Chicago, IL, 5 Mayo Clinic, Phoenix, AZ, 6 Columbia University Medical Center Center for Liver Disease and Transplantation, New York, NY, 7 Lahey Hospital & Medical Center, Burlington, MA, 8 Northwestern University Comprehensive Transplant Center, Chicago, IL, 9 University of California, San Francisco, San Francisco, CA, 10 University of Colorado, Denver, Aurora, CO, United States, 11 Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain

33 33 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 Day 0Week 24 SVR12 To Week 72 3D + RBV (N=34) Kwo, P. et al. EASL 2014, Abstract #O114

34 34 Kwo, P. et al. EASL 2014, Abstract #O114 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

35 35 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 Kwo, P. et al. EASL 2014, Abstract #O114 % Patients 100% 34/ % 34/34 100% 96.2% 32/33 25/26 SVR4 SVR12 RVR (Week 4) EOTR (Week 24)

36 36 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 37 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. Hezode 1, P. Marcellin 2, S. Pol 3, T. Hassanein 4, K. Fleischer-Stepniewska 5, T. Baykal 6, T. Wang 6, S.S. Lovell 6, T. Pilot-Matias 6, R.A. Vilchez 6 1 Assistance Publique Hopitaux de Paris, Paris, 2 Hopital Beaujon Inserm Crb3 - U Service Hepatologie, Clichy, 3 Groupe Hospitalier Cochin-Saint Vincent de Paul, Paris, France, 4 Southern California Liver Centers and Southern California Research Center, Coronado, CA, United States, 5 EMC Instytut Medyczny Spolka Akcyjna, Wroclaw, Poland, 6 AbbVie Inc., North Chicago, IL, United States

38 38 Substudy 1* No Cirrhosis Substudy 2* Compensated Cirrhosis *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 Group 1 (GT4) (n=44) Group 2 (GT1b) (n=42) Group 3 (GT1b) (n=40) Group 4 (GT4) (n=42) Group 5 (GT4) Group 6 (GT4) (n=49) BaselineWeek 12 Week 24 ABT-450/r + Ombitasvir Treatment-Naïve Null Responders ABT-450/r + Ombitasvir + RBV Treatment-Naïve ABT-450/r + Ombitasvir Partial/Null Responders & Relapsers ABT-450/r + Ombitasvir + RBV Partial/Null Responders & Relapsers Group 7 (GT1b) (n=47) Group 8 (GT1b) (n=52) ABT-450/r + Ombitasvir Treatment-Naïve ABT-450/r + Ombitasvir Partial/Null Responders & Relapsers ABT-450/r + Ombitasvir Treatment-Naïve Hezode, C. et al. EASL 2014, Abstract #O58

39 % Patients (%) ABT-450/r + Ombitasvir (N=44) ABT-450/r + Ombitasvir + RBV (N=42) SVR4 SVR12 RVR (Week 4) EOTR (Week 12) 95.5% 93.2% 90.9% 97.6% 100% Hezode, C. et al. EASL 2014, Abstract #O58

40 40 Patients (%) ABT-450/r + Ombitasvir + RBV (N=49) 100% 49/49 37/37 SVR4 RVR (Week 4) EOTR (Week 12) Hezode, C. et al. EASL 2014, Abstract #O58

41 41 All-oral, IFN-free, 12-week regimens of ABT-450/r + ombitasvir resulted 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 42 Safety and Efficacy of the All-oral Regimen of MK- 5172/MK Ribavirin in Treatment-naïve, Non- cirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: The C-WORTHy Study C. Hezode 1, L. Serfaty 2, J.M. Vierling 3, M. Kugelmas 4, B. Pearlman 5, W. Sievert 6, W. Ghesquiere 7, E. Zuckerman 8, F. Sund 9, M. Shaughnessy 10, P. Hwang 10, J. Wahl 10, M.N. Robertson 10, B. Haber 10 1 Department of Hepatology-Gastroenterology, Henri Mondor Hospital, University of Paris-Est, Creteil, 2 Gastroenterology and Hepatology, H_pital Saint Antoine, APHP and INSERM UMR_938, Universit_ Pierre & Marie Curie, Paris, France, 3 Hepatology, Baylor College of Medicine, Houston, TX, 4 South Denver Gastroenterology, PC, Englewood, CO, 5 Center for Hepatitis C, Atlanta Medical Center, Atlanta, GA, United States, 6 Gastrointestinal and Liver Unit, Monash University, Clayton, VIC, Australia, 7 Vancouver Island Health Authority, Victoria, BC, Canada, 8 Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel, 9 Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden, 10 Merck, Whitehouse Station, NJ, United States

43 43 Hezode, C. et al. EASL 2014, Abstract #O10 To assess the efficacy/safety of an 8- to 12-week regimen of MK MK-8742 ± weight-based ribavirin in treatment-naïve, noncirrhotic patients with HCV G1 infection 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 Treatment-naïve, noncirrhotic 12 weeks ± RBV (n=65) Treatment-naïve Noncirrhotic 8-12 weeks ± RBV (n=94) Treatment-naïve Cirrhotic weeks ± RBV (n=123) Null responders Cirrhotic/noncirrhotic weeks ± RBV (n=130) HIV/HCV coinfected Noncirrhotic 12 weeks ± RBV (n=59)

44 44 SVR, sustained virologic response; TW = treatment week. Hezode, C. et al. EASL 2014, Abstract #O110 RBV-Containing RegimenRBV-Free Regimen MK-5172 (100 mg) MK-8742 (20 mg) + RBV MK-5172 (100 mg) MK-8742 (50 mg) + RBV MK-5172 (100 mg) MK-8742 (50 mg) + RBV MK-5172 (100 mg) MK-8742 (50 mg) MK-5172 (100 mg) MK-8742 (50 mg) MK-5172 (100 mg) MK-8742 (50 mg) + RBV PART A SVR24 (AASLD 2013) PART B Follow-up ongoing SVR4/8 at ≥SVR4 (28/30 SVR8) 100% at SVR8 Study Week Part A Part B G1a/b N=25 G1a/b n=27 G1b n=13 G1a n=30 G1a/b n=33 G1a n=31 D1TW4TW8TW12SVR4SVR8SVR12SVR24

45 45 *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 #O /3081/8544/4430/3082/8544/4425/3080/8543/44

46 46 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 RBV for 8 weeks in patients with HCV G1a infection had an SVR4 4/8 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 47 Efficacy and Safety of the All-Oral Regimen, MK-5172/MK /- RBV For 12 Weeks in GT1 HCV/HIV Co-Infected Patients: The C-WORTHY Study Mark Sulkowski 1, Josep Mallolas 2, Marc Bourliere 3, Jan Gerstoft 4, Oren Shibolet 5, Ronald Nahass 6, Edwin DeJesus 7, Melissa Shaughnessy 8, Peggy Hwang 8, Barbara Haber 8 1 Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2 Hospital de Dia. Enfermedades Infecciosas, Barcelona, Spain; 3 Service d'hépato-gastroentérologie, Hôpital Saint-Joseph, Marseille, France; 4 Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark; 5 Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel; 6 ID Care, Hillsborough, NJ, USA; 7 Orlando Immunology Center, Orlando, Florida; 8 Merck & Co., Inc., Whitehouse Station, NJ, USA.

48 48 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) Treatment-naive, non-cirrhotic 12 weeks ± RBV (n = 65) 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) 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 49 MK MK RBV MK MK-8742 (No RBV) N = 29 N = 30 Follow-up D1TW12SVR12TW4TW2TW8SVR24SVR4 Primary endpoint MK-5172 (100 mg QD) + MK-8742 (50 mg QD); 12 weeks Sulkowski, M. et al. EASL 2014, Abstract #O63

50 * 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

51 51 Efficacy Treatment with MK MK-8742 ± RBV for 12 weeks demonstrated high efficacy (90-97% 4 weeks after end-of-treatment; SVR4) Three of 59 patients experienced virologic failure –1 relapse, 2 breakthrough Safety MK MK-8742 ± RBV was generally safe and well tolerated in co- infected patients The most common AEs in co-infected patients were headache and asthenia All co-infected patients had suppressed HIV and stable CD4 counts There were no early discontinuations due to drug-related adverse events Overall Observed efficacy and safety in patients with HIV/HCV coinfection was similar to other patient populations in C-WORTHy Sulkowski, M. et al. EASL 2014, Abstract #O63


Download ppt "1 Geoffrey Dusheiko, MD London, UK This activity is supported by an independent medical education grant from AbbVie, Bristol-Myers Squibb and Gilead Sciences."

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