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1 This activity has been supported by an independent medical education grant from Bristol Myers Squibb. 2013 IC-HEP Educational supporters include Bristol.

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Presentation on theme: "1 This activity has been supported by an independent medical education grant from Bristol Myers Squibb. 2013 IC-HEP Educational supporters include Bristol."— Presentation transcript:

1 1 This activity has been supported by an independent medical education grant from Bristol Myers Squibb. 2013 IC-HEP Educational supporters include Bristol Myers Squibb and Janssen Therapeutics EMEA. Supporters do not influence IC-HEP faculty selection or educational content. Darrell Crawford, MD Brisbane, Australia

2 2 Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks in treatment-naïve patients with chronic HCV genotype 1 infection Gregory T. Everson 1, Karen D. Sims 2, Paul J. Thuluvath 3, Eric Lawitz 4, Tarek Hassanein 5, Maribel Rodriguez-Torres 6, Trevor Hawkins 7, Howard Schwartz 8, Vinod K. Rustgi 9, Federico Hinestrosa 10, James M. Levin 11, Zobair M. Younossi 12, Lynn R. Webster 13, Timothy Eley 2, Shu-Pang Huang 14, Fiona McPhee 15, Dennis M. Grasela 2, David F. Gardiner 2 1. University of Colorado Denver, Aurora, CO, United States. 2. Bristol-Myers Squibb, Hopewell, NJ, United States. 3. Mercy Medical Center, Baltimore, MD, United States. 4. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States. 5. Southern California Liver Centers, Coronado, CA, United States. 6. Fundación de Investigación, San Juan, Puerto Rico, United States. 7. Southwest CARE Center, Santa Fe, NM, United States. 8. Miami Research Associates, South Miami, FL, United States. 9. Metropolitan Research, Arlington, VA, United States. 10. Orlando Immunology Center, Orlando, FL, United States. 11. Dean Foundation for Health, Research and Education, Inc, Madison, WI, United States. 12. Inova Fairfax Hospital, Center for Liver Diseases, Falls Church, VA, United States. 13. CRI Lifetree, Salt Lake City, UT, United States. 14. Bristol-Myers Squibb, Princeton, NJ, United States. 15. Bristol-Myers Squibb, Wallingford, CT, United States.

3 3 Daclatasvir (DCV) –NS5A replication complex inhibitor with potent, pan-genotypic activity in vitro –Studied in over 5500 patients Asunaprevir (ASV) –NS3 protease inhibitor active against genotypes (GT) 1, 4, 5, and 6 in vitro –Studied in over 2000 patients BMS-791325 –Non-nucleoside, NS5B polymerase inhibitor active against GT 1, 3, 4, 5, and 6 in vitro –Studied in over 500 patients

4 4 Patients: treatment-naive, stratified by GT 1a/1b and presence of biopsy-confirmed cirrhosis (82% GT1a and 9% cirrhotics). Primary end point: HCV RNA < LLOQ 12 weeks post-treatment (SVR 12 ) –Observed analysis: breakthrough, relapse, addition of pegIFNα/RBV = failure –Modified intent-to-treat analysis: missing, breakthrough, relapse or addition of pegIFNα/RBV = failure DCV 30 mg BID + ASV 200 mg BID + BMS-791325 75 mg BID DCV 30 mg BID + ASV 200 mg BID + BMS-791325 150 mg BID 12-week follow-up Additional follow-up to SVR 48 0 1224 N = 80 N = 86 Week Primary endpoint: SVR 12

5 5 End of TreatmentSVR 4 SVR 12 Response, % of patients DCV + ASV + ‘325 75 mg DCV + ASV + ‘325 150 mg 97.594.2 92.491.7 92.291.7 78/8081/8673/7977/8471/7777/84

6 6 Event, n (%) DCV + ASV + ‘325 75 mg N = 80 DCV + ASV + ‘325 150 mg N = 86 Total N = 166 Serious AEs1 (1.3)2 (2.3)3 (1.6) AEs leading to discontinuation1 (1.3)1 (1.2)2 (1.1) Grade 3/4 AEs 01 (1.2)1 (0.5) Most frequent on-treatment AEs (≥ 10%) Headache17 (21.3)24 (27.9)41 (24.7) Diarrhea12 (15.0)13 (15.1)25 (15.1) Fatigue12 (15.0)7 (8.1)19 (11.4) Nausea10 (12.5)7 (8.1)17 (10.2) Grade 3/4 lab abnormalities Aspartate aminotransferase (AST)1 (1.3)01 (0.5) Glucose, fasting serum (high)1 (1.3)1 (1.2)2 (1.2) Phosphorus, inorganic01 (1.2)1 (0.5) Bilirubin, total01 (1.2)1 (0.5)

7 7 All-oral Combination of Daclatasvir Plus Asunaprevir in Interferon Ineligible Naive/Intolerant and Nonresponder Japanese Patients Chronically Infected with HCV Genotype 1b: Results from a Phase 3 Trial Kazuaki Chayama 1, Yoshiyuki Suzuki 2, Kenji Ikeda 2, Joji Toyota 3, Yoshiyasu Karino 3, Yoshiiku Kawakami 1, Akio Ido 4, Kazuhide Yamamoto 5, Koichi Takaguchi 6, Namiki Izumi 7, Kazuhiko Koike 8, Tetsuo Takehara 9, Norifumi Kawada 10, Michio Sata 11, Hidetaka Miyagoshi 12, Timothy Eley 13, Fiona McPhee 13, Wenhua Hu 13, Hiroki Ishikawa 12, Eric A. Hughes 13, Hiromitsu Kumada 2 1. Hiroshima University, Hiroshima, Japan. 2. Toranomon Hospital, Tokyo, Japan. 3. Sapporo-Kousei General Hospital, Sapporo, Japan. 4. Kagoshima University, Kagoshima, Japan. 5. Okayama University, Okayama, Japan. 6. Kagawa Prefectural Hospital, Kagawa, Japan. 7. Musashino Red Cross Hospital, Tokyo, Japan. 8. University of Tokyo, Tokyo, Japan. 9. Osaka University, Osaka, Japan. 10. Osaka City University, Osaka, Japan. 11. Kurume University, Fukuoka, Japan. 12. Bristol-Myers KK, Tokyo, Japan. 13. Bristol-Myers Squibb, Princeton, NJ, United States.

8 8 HCV RNA < LLOQ, n (%) Ineligible naïve/Intolerant (IN/I) Patients n = 135 a Nonresponder (NR) Patients n = 87 b Total N = 222 RVR, Week 4114 (84.4)53 (60.9)167 (75.2) cEVR, Week 12125 (92.6)77 (88.5)202 (91.0) SVR 4 126 (93.3)71 (81.6)197 (88.7) SVR 12 120 (88.9)70 (80.5)190 (85.6) SVR 24 118 (87.4)70 (80.5)188 (84.7) a Ineligible naïve: n=100; Intolerant: n=35 b Null responders: n=48; Partial responders: n=36; Undetermined: n=3

9 9 Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the ELECTRON trial Edward J. Gane 1, Catherine A. Stedman 2, Robert H. Hyland 3, Xiao Ding 3, Evguenia S. Svarovskaia 3, Phil S. Pang 3, William T. Symonds 3 1. Auckland Clinical Studies, Auckland, New Zealand. 2. Christchurch Clinical Studies Trust, Christchurch, New Zealand. 3. Gilead Science, Inc, Foster City, CA, United States.

10 10 GS-9669 HCV NS5B non-nucleoside inhibitor, binding at thumb site II of the polymerase Potent antiviral activity with QD dosing Nanomolar potency against GT 1a and 1b Sofosbuvir/Ledipasvir FDC Once daily, oral fixed-dose (400/90 mg) combination tablet No food effect >2000 patients treated SOF Nucleotide Polymerase inhibitor LDV NS5A inhibitor

11 11 Primary endpoint: SVR12 (HCV RNA { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/2692760/10/slides/slide_10.jpg", "name": "11 Primary endpoint: SVR12 (HCV RNA

12 12 Duration (wk) 12 F4 onlyF3/F4 12 7/109/925/25*26/26*

13 13 Duration (wk) 1286 25/2521/2117/25 † *Gane et al. EASL 2013. † Lawitz et al, Abstract #215, AASLD 2013 (LONESTAR) Gane EJ, et al. Abstract #73, AASLD 2013

14 14 In treatment-experienced patients with advanced fibrosis/cirrhosis, either RBV or GS-9669 may enhance the efficacy of SOF/LDV given for 12 weeks The optimal duration of SOF/LDV in treatment-naïve GT 1 patients, even with the addition of RBV, is more than 6 weeks Regimens of SOF/LDV alone, or with RBV or GS- 9669, were safe and well tolerated

15 15 Interferon- and Ribavirin-free Regimen of ABT-450/r + ABT-267 in HCV Genotype 1b-infected Treatment-naïve Patients and Prior Null Responders Eric Lawitz 1, Christophe Hezode 2, Peter Varunok 3, Paul J. Thuluvath 4, Tolga Baykal 5, Mudra Kapoor 5, Sandra S. Lovell 5, Tianli Wang 5, Tami Pilot-Matias 5, Regis A. Vilchez 5, Barry Bernstein 5 1. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States. 2. Assistance Publique Hopitaux de Paris, Paris, France. 3. Premier Medical Group of the Hudson Valley, PC, Poughkeepsie, NY, United States. 4. The Institute for Digestive Health and Liver Disease at Mercy, Baltimore, MD, United States. 5. AbbVie Inc., North Chicago, IL, United States.

16 16 ABT-450 is an HCV protease inhibitor (dosed with ritonavir 100 mg, ABT-450/r) ABT-267 is an NS5A inhibitor Both compounds have shown potent antiviral activity in vitro against HCV genotypes (GT) 1-4 and 6. Lawitz E, et al. Abstract #75, AASLD 2013

17 17 Substudy 1: Patients Without Cirrhosis Substudy 2: Patients With Compensated Cirrhosis Group 1 40 Group 2 40 Group 3 40 Group 4 40 Group 5 40 Group 6 40 Group 7 40 Group 8 40 Planned N HCV Genotype/Regimen Treatment Experience Week 12Week 24 GT4 ABT-450/r + ABT-267 Treatment-naïve GT1b ABT-450/r + ABT-267 Treatment-naïve GT1b ABT-450/r + ABT-267 Null Responders GT4 ABT-450/r + ABT-267 + rbv Treatment-naïve GT4 ABT-450/r + ABT-267 Partial/Null Responders & Relapsers GT4 ABT-450/r + ABT-267 + rbv Partial/Null Responders & Relapsers GT1b ABT-450/r + ABT-267 Treatment-naïve GT1b ABT-450/r + ABT-267 Partial/Null Responders & Relapsers BL Lawitz E, et al. Abstract #75, AASLD 2013

18 18 Week 4Week 12 (EOTR) SVR 4 SVR 12 0 20 40 60 80 100 Percentage of Patients (%) 100 97.6 42/4241/42 40/42 97.6 95.2 Lawitz E, et al. Abstract #75, AASLD 2013

19 19 39/40 37/40 97.5 92.5 90.0 36/40 Week 4 Week 12 (EOTR) SVR 4 SVR 12 0 20 40 60 80 100 Percentage of Patients (%) Lawitz E, et al. Abstract #75, AASLD 2013

20 20 Event, n (%) GT1b-infected Treatment-naïve Patients (N=42) GT1b-infected Prior Null Responders (N=40) Headache14 (33.3)10 (25.0) Nausea8 (19.0)0 Dry Skin7 (16.7)0 Fatigue6 (14.3)0 Pruritus6 (14.3)0 Diarrhea6 (14.3)0 Lawitz E, et al. Abstract #75, AASLD 2013

21 21 Sofosbuvir in Combination With PegIFN and Ribavirin for 12 Weeks Provides High SVR Rates in HCV-Infected Genotype 2 or 3 Treatment Experienced Patients with and without Compensated Cirrhosis: Results from the LONESTAR-2 Study Eric Lawitz 1, 2, Fred Poordad 1, 2, Diana M. Brainard 3, Robert H. Hyland 3, Di An 3, William T. Symonds 3, John G. McHutchison 3, Fernando E. Membreno 1, 2 1. Texas Liver Institute, San Antonio, TX, United States. 2. University of Texas Health Science Center, San Antonio, TX, United States. 3. Gilead Science, Inc, Foster City, CA, United States.

22 22 SOF + PEG/RBV SVR12 GT 2/3 (N=47) Study population –HCV GT 2 or 3 –Failed treatment with pegylated interferon and ribavirin –Approximately 50% with compensated cirrhosis –HIV and HBV coinfected patients excluded Wk 0Wk 12 Wk 24 Wk 36 Lawitz E, et al. Abstract #LB-4, AASLD 2013

23 23 OverallGT 2GT 3 42/4722/2320/24 SVR12 (%) Lawitz E, et al. Abstract #LB-4, AASLD 2013

24 24 SVR12 (%) 9/913/1410/12 Error bars represent 95% confidence intervals. Lawitz E, et al. Abstract #LB-4, AASLD 2013

25 25 Lawitz E, et al. Abstract #LB-4, AASLD 2013

26 26 SOF + PEG/RBV for 12 weeks demonstrated high efficacy in treatment-experienced GT 2/3 patients who have historically low response rates and limited treatment options –SVR rates were similar in patients with and without cirrhosis SOF + PEG/RBV was generally safe and well tolerated –Safety profile consistent with PEG/RBV treatment –Low discontinuation rates Lawitz E, et al. Abstract #LB-4, AASLD 2013

27 27 Sofosbuvir + Ribavirin for 12 or 24 Weeks for Patients with HCV Genotype 2 or 3: the VALENCE trial Stefan Zeuzem 1, Geoffrey M. Dusheiko 2, Riina Salupere 3, Alessandra Mangia 4, Robert Flisiak 5, Robert H. Hyland 6, Ari Illeperuma 6, Evguenia S. Svarovskaia 6, Diana M. Brainard 6, William T. Symonds 6, John G. McHutchison 6, Ola Weiland 7, Hendrik W. Reesink 8, Peter Ferenci 9, Christophe Hezode 10, Rafael Esteban 11 1. Johann Wolfgang Goethe University, Frankfurt, Germany. 2. Royal Free and University College School of Medicine, Royal Free Hospital, London, United Kingdom. 3. Tartu University Hospital, Tartu, Estonia. 4. "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy. 5. Medical University of Bialystok, Bialystok, Poland. 6. Gilead Sciences, Inc., Foster City, CA, United States. 7. Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. 8. Academic Medical Center, Amsterdam, Netherlands. 9. Medical University of Vienna, Vienna, Austria. 10. Hôpital Henri Mondor, Créteil, France. 11. Hospital Universitario Val d’Hebron, Barcelona, Spain.

28 28 Wk 0Wk 24 SVR4, SVR12, SVR24 Placebo* (n = 85) Sofosbuvir + Ribavirin (n = 250) Sofosbuvir + Ribavirin (n = 84)* *Protocol amended to eliminate placebo arm and to extend treatment duration to 24 weeks for patients with genotype 3 HCV irrespective of prior treatment history. Wk 12 Zeuzem S, et al. Abstract #1085, AASLD 2013

29 29 *3 of 11 patients (27%) with HCV GT 3 who received 12 weeks of SOF+RBV achieved SVR 12. Zeuzem S, et al. Abstract #1085, AASLD 2013 GT 2 SOF+RBV 12 wk GT 3 SOF+RBV 24 wk Naïve, Noncirrhotic Naïve, Cirrhotic Experienced, Noncirrhotic Experienced, Cirrhotic 68/73 212/ 250 29/302/ 2 30/337/ 8

30 30 Naïve, Noncirrhotic Naïve, Cirrhotic Experienced, Noncirrhotic Experienced, Cirrhotic 86/9212/1327/4587/100 Zeuzem S, et al. Abstract #1085, AASLD 2013

31 31 All-Oral Therapy With Sofosbuvir Plus Ribavirin For the Treatment of HCV Genotype 1, 2, and 3 Infection in Patients Co-infected With HIV (PHOTON-1) Mark S. Sulkowski 1, Maribel Rodriguez-Torres 2, Jacob P. Lalezari 3, W. Jeffrey Fessel 4, Karam Mounzer 5, Margaret C. Shuhart 6, Anne Luetkemeyer 7, David M. Asmuth 8, Anuj Gaggar 9, William T. Symonds 9, John G. McHutchison 9, Susanna Naggie 10, Douglas T. Dieterich 11 1. Johns Hopkins Medical Center, Baltimore, MD, United States. 2. Fundacion De Investigacion, San Juan, Puerto Rico, United States. 3. Quest Clinical Research, San Francisco, CA, United States. 4. Kaiser Permanente, San Francisco, CA, United States. 5. Philadelphia FIGHT, Philadelphia, PA, United States. 6. Harborview Medical Center, Seattle, WA, United States. 7. San Francisco General Hospital, San Francisco, CA, United States. 8. University of California Davis Medical Center, Sacramento, CA, United States. 9. Gilead Sciences, Inc., Foster City, CA, United States. 10. Duke Clinical Research Institute, Durham, NC, United States. 11. Mount Sinai School of Medicine, New York, NY, United States.

32 32 36 Wk 0Wk 12Wk 24Wk 36 SOF + RBV, n=114 GT 1 TN SVR12 SOF + RBV, n=41 GT 2/3 TE SVR12 SOF + RBV, n=68 GT 2/3 TN SVR12 Broad inclusion criteria –Cirrhosis permitted with no platelet cutoff –Hemoglobin: ≥12 mg/dL (males); ≥11 mg/dL (females) Wide range of ART regimens allowed –Undetectable HIV RNA for >8 weeks on stable ART regimen Baseline CD4 count –ART treated: CD4 T-cell count >200 cells/mm 3 –ART untreated: CD4 T-cell count >500 cells/mm 3 Sulkowski MS, et al. Abstract #212, AASLD 2013

33 33 Patients with HCV RNA { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/2692760/10/slides/slide_32.jpg", "name": "33 Patients with HCV RNA

34 34 Patients, % SOF + RBV 24 Weeks (n=114)12 Weeks (n=68) AEs 9384 AEs in ≥10% of patients Fatigue 3635 Insomnia 1321 Headache 1413 Nausea 1618 Diarrhea 119 Irritability 1210 URI 1112 Grade 3-4 AEs 1310 Serious AEs 77 Treatment D/C due to AEs 34 Death 01 Sulkowski MS, et al. Abstract #212, AASLD 2013

35 35 -200 0 200 400 600 Change in HIV-1 RNA from Baseline(%) 124681012162024412 Treatment Period (week)Follow-up Two patients with transient HIV viral breakthrough –Both with documented nonadherance to ART No decrease in CD4 T-cell % with SOF treatment –Decrease in absolute CD4 T-cell number consistent with ribavirin-mediated decrease in lymphocyte counts Sulkowski MS, et al. Abstract #212, AASLD 2013

36 36 Sofosbuvir and Ribavirin for the Treatment of Established Recurrent Hepatitis C Infection After Liver Transplantation: Preliminary Results of a Prospective, Multicenter Study 1. Mayo Clinic, Rochester, MN, United States. 2. Auckland City Hospital, Auckland, New Zealand. 3. Hannover Medical School, Hannover, Germany. 4. Columbia University, New York, NY, United States. 5. Beth Israel Deaconess Medical Center, Boston, MA, United States. 6. Indiana School of Medicine, Indianapolis, IN, United States. 7. University of Michigan, Ann Arbor, MI, United States. 8. Kansas University Medical Center, Lawrence, KS, United States. 9. NYU Medical Center, New York, NY, United States. 10. Duke University Medical Center, Durham, NC, United States. 11. Gilead Sciences, Foster City, CA, United States. 12. University of California, San Francisco, CA, United States. 13. Université Paris-Sud, Villejuif, France. 14. The Liver Unit, Barcelona, Spain. Michael R. Charlton 1, Edward J. Gane 2, Michael P. Manns 3, Robert S. Brown 4, Michael P. Curry 5, Paul Y. Kwo 6, Robert J. Fontana 7, Richard Gilroy 8, Lewis W. Teperman 9, Andrew J. Muir 10, John G. McHutchison 11, William T. Symonds 11, Jill M. Denning 11, Lindsay McNair 11, Sarah Arterburn 11, Norah Terrault 12, Didier Samuel 13, Xavier Forns 14

37 37 Reinfection of the transplanted liver is universal in patients who are serum HCV RNA-positive at the time of transplantation Recurrence of HCV is the most common cause of mortality and graft loss following transplantation –10–50% of patients with recurrent infection progress to cirrhosis within 5 years 1 Once cirrhosis is established, the probability of liver graft failure is 42% within 12 months 2 Current therapies for HCV treatment used after transplantation have poor tolerance, poor efficacy, severe adverse reactions, and significant interactions with immunosuppression medications 1. Berenguer M, et al. Clin Liver Dis 2007;11:355–76; 2. Berenguer M, et al. Hepatology 2002;36:202-10. Charlton MR, et al. Abstract #LB-2, AASLD 2013

38 38 Patients with recurrent HCV post-liver transplant, all genotypes Low, ascending-dose RBV regimen starting at 400 mg/day, escalated based on hemoglobin levels Study objectives –Primary: sustained virologic response 12 weeks post treatment with sofosbuvir + RBV in liver transplant recipients –Secondary: safety, tolerability and viral kinetics SOF 400 mg + RBV 400 ‒ 1200 mg (N=40) SVR12 Week 012 24 36 Charlton MR, et al. Abstract #LB-2, AASLD 2013

39 39 Inclusion criteria –Liver transplant ≥6 and ≤150 months prior to enrollment –Treatment-naïve or experienced –CPT ≤7 and MELD ≤17 –Primary or secondary, liver alone or liver-kidney transplant –Absence of organ rejection Exclusion criteria –Current signs of decompensation –Use of corticosteriods at any dose >5 mg of prednisone/day Charlton MR, et al. Abstract #LB-2, AASLD 2013

40 40 40/40 27/35 † Virologic Response Rate (%) *1 patient still on treatment; † 4 patients have not reached SVR4 visit. Charlton MR, et al. Abstract #LB-2, AASLD 2013

41 41 No interactions reported between SOF and any immunosuppressive agents during study 4 patients increased tacrolimus dosing during SOF therapy TacrolimusMycophenolate mofetil PrednisoneCyclosporinAzathioprine Patients (%) Charlton MR, et al. Abstract #LB-2, AASLD 2013

42 42 Charlton MR, et al. Abstract #LB-2, AASLD 2013


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