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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 IC-HEP Educational supporters include Bristol Myers Squibb and Janssen Therapeutics EMEA. Supporters do not influence IC-HEP faculty selection or educational content. Paul Kwo, MD Indianapolis, Indiana, USA

2 2 Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS 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 –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 mg BID DCV 30 mg BID + ASV 200 mg BID + BMS mg BID 12-week follow-up Additional follow-up to SVR N = 80 N = 86 Week Primary endpoint: SVR 12

5 5 End of TreatmentSVR 4 SVR 12 Response, % of patients DCV + ASV + ‘ mg DCV + ASV + ‘ mg /8081/8673/7977/8471/7777/84

6 6 Event, n (%) DCV + ASV + ‘ mg N = 80 DCV + ASV + ‘ 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 (92.6)77 (88.5)202 (91.0) SVR (93.3)71 (81.6)197 (88.7) SVR (88.9)70 (80.5)190 (85.6) SVR (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 SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: The COSMOS study Ira M. Jacobson 1, Reem H. Ghalib 2, Maribel Rodriguez-Torres 3, Zobair M. Younossi 4, Ana Corregidor 5, Mark S. Sulkowski 6, Edwin DeJesus 7, Brian Pearlman 8, Mordechai Rabinovitz 9, Norman Gitlin 10, Joseph K. Lim 11, Paul J. Pockros 12, Bart Fevery 13, Tom Lambrecht 14, Sivi Ouwerkerk-Mahadevan 13, Katleen Callewaert 13, William T. Symonds 15, Gaston Picchio 16, Karen Lindsay 16, Maria Beumont-Mauviel 13, Eric Lawitz Weill Cornell Medical College, New York, NY, United States. 2. Medicine and Gastroenterology and Hepatology, The Liver Institute, Dallas, TX, United States. 3. Fundación de Investigación, San Juan, Puerto Rico, United States. 4. Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States. 5. Borland-Groover Clinic, 4800 Belfort Rd, Jacksonville, FL, United States. 6. Johns Hopkins University School of Medicine, Baltimore, MD, United States. 7. Orlando Immunology Center, Orlando, FL, United States. 8. Atlanta Medical Center, Atlanta, GA, United States. 9. University of Pittsburgh Medical Center, Pittsburgh, PA, United States. 10. Atlanta Gastroenterology Association, Atlanta, GA, United States. 11. Yale School of Medicine, New Haven, CT, United States. 12. Scripps Clinic, La Jolla, CA, United States. 13. Janssen Research & Development, Beerse, Belgium. 14. Novellas Healthcare, Zellik, Belgium. 15. Gilead Sciences Inc, Foster City, CA, United States. 16. Janssen Research & Development LLC, Titusville, NJ, United States. 17. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States.

10 10 Simeprevir (TMC435) is an investigational, one pill, once- daily, potent oral HCV NS3/4A protease inhibitor recently approved in Japan and currently under regulatory review in North America and Europe Sofosbuvir (GS-7977) is an HCV nucleotide NS5B polymerase inhibitor also currently under regulatory review COSMOS is a Phase IIa, randomized, open-label study investigating simeprevir + sofosbuvir +/- ribavirin Interim analysis

11 11 Cohort 1: Prior null responders (METAVIR F0-F2) –Final SVR12 for all arms Cohort 2: Treatment-naïve and prior null responders (METAVIR F3-F4) –Interim SVR4 for Arms 3 and 4 SMV + SOF + RBVPost-treatment follow-up Arm 1 Week SMV + SOF SMV + SOF + RBV SMV + SOF Post-treatment follow-up Arm 2 Arm 3 Arm 4 Enrollment ratio 2:1:2:1 N=14 N=24 N=14 N=27

12 12 24 week treatment 13/14 26/27 SMV/SOF 12 wks SMV/SOF/RBV 12 wks SVR12 (SMV/SOF) SVR12 (SMV/SOF/RBV) 1/27 1/14 14/15 19/24 SMV/SOF 24 wks SMV/SOF/RBV 24 wks Patients (%) 1/24 4/24 1/15 Non-virologic failure Relapse 12 week treatment 6.7

13 13 Patients (%) 1/27 SVR4 (SMV/SOF) SVR4 (SMV/SOF/RBV) 12 week treatment 7/712/127/714/15 1/15 Relapse 26/27 14/14

14 14 24 weeks12 weeks Patients, n (%) SMV + SOF + RBV (n=54) SMV + SOF (n=31) SMV + SOF + RBV (n=54) SMV + SOF (n=28) Fatigue20 (37.0)10 (32.3)13 (24.1)7 (25.0) Headache11 (20.4)7 (22.6)9 (16.7)6 (21.4) Nausea6 (11.1)4 (12.9)8 (14.8)6 (21.4) Insomnia9 (16.7)2 (6.5)5 (9.3)4 (14.3) Rash7 (13.0)3 (9.7)8 (14.8)1 (3.6) Pruritus9 (16.7)1 (3.2)5 (9.3)3 (10.7) Photosensitivity/sunburn a 2 (3.7)1 (3.2)3 (5.6)2 (7.1) Anemia11 (20.4)1 (3.2)6 (11.1)0 a No sun-protective measures were in place for this trial RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir

15 15 Treatment with SMV + SOF ± RBV results in: –High SVR12 rates in HCV GT 1 null responder patients –High SVR4 rates in naïve and null-responder patients with METAVIR F3-F4 Addition of RBV to SMV + SOF may not be needed to achieve high rates of SVR in this patient population 12 weeks of treatment may confer similar SVR rates compared with 24 weeks of treatment SMV + SOF ± RBV was generally well tolerated

16 16 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.

17 17 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

18 18 Primary endpoint: SVR12 (HCV RNA

19 19 Duration (wk) 12 F4 onlyF3/F4 12 7/109/925/25*26/26*

20 20 *Gane et al. EASL † Lawitz et al, Abstract #215, AASLD 2013 (LONESTAR) Gane EJ, et al. Abstract #73, AASLD 2013 Duration (wk) /2521/2117/25 †

21 21 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

22 22 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.

23 23 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

24 24 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 rbv Treatment-naïve GT4 ABT-450/r + ABT-267 Partial/Null Responders & Relapsers GT4 ABT-450/r + ABT 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

25 25 Week 4Week 12 (EOTR) SVR 4 SVR Percentage of Patients (%) /4241/42 40/ Lawitz E, et al. Abstract #75, AASLD 2013

26 26 39/40 37/ /40 Week 4 Week 12 (EOTR) SVR 4 SVR Percentage of Patients (%) Lawitz E, et al. Abstract #75, AASLD 2013

27 27 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

28 28 Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin Resulted in ≥95% Sustained Virologic Response In Patients with HCV Genotype 1, Including Patients with Cirrhosis: the LONESTAR trial Eric Lawitz 1, Fred Poordad 1, Robert H. Hyland 2, Xiao Ding 2, Christy Hebner 2, Phil S. Pang 2, William T. Symonds 2, John G. McHutchison 2, Fernando E. Membreno 1 1. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States. 2. Gilead Science, Inc, Foster City, CA, United States.

29 29 Single center study of GT 1 patients Broad inclusion criteria –No upper limit to age or BMI –Platelets ≥50,000/mm 3 Randomized 1:1 SOF/LDV SOF/LDV + RBV SOF/LDV Treatment Naïve (No cirrhosis) PI Failures (50% cirrhosis) SOF/LDV + RBV COHORT 1 (n=60) COHORT 2 (n=40) Wk 0 Wk 8Wk 12 Randomized 1:1:1 Wk 24Wk 20 SVR12 Lawitz E, et al. Abstract #215, AASLD 2013

30 30 All patients were required to have experienced virologic failure –Patients who stopped prior therapy due to an AE were excluded PI Failures n=40 Prior treatment with boceprevir22/40 (55) Prior treatment with telaprevir18/40 (45) Cirrhosis, n (%)22/40 (55) Mean platelet count, x 10 3 /µL107 Mean albumin, g/dL3.8 Lawitz E, et al. Abstract #215, AASLD 2013

31 31 Treatment Naïve (No Cirrhosis) PI Failures (50% Cirrhosis) ─── Patients (%) 19/2021/2118/19 21/21 RBV Duration (week) Lawitz E, et al. Abstract #215, AASLD 2013

32 32 No CirrhosisCirrhosis ─ + RBV 12Duration (week) Patients (%) 18/1921/21 Overall 10/1011/118/810/11 12 ─ + ─ + Lawitz E, et al. Abstract #215, AASLD 2013

33 33 *Peptic ulcer, spinal compression fracture; † Delirium, suicidal ideation. Lawitz E, et al. Abstract #215, AASLD 2013

34 34 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.

35 35 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

36 36 OverallGT 2GT 3 42/4722/2320/24 SVR12 (%) Lawitz E, et al. Abstract #LB-4, AASLD 2013

37 37 SVR12 (%) 9/913/1410/12 Error bars represent 95% confidence intervals. Lawitz E, et al. Abstract #LB-4, AASLD 2013

38 38 Patients, n (%) SOF + PEG/RBV 12 weeks (N=47) Overall safety AEs45 (96) Grade 3-4 AEs15 (32) Serious AEs4 (9) Treatment discontinuation due to AEs2 (4) Hematologic abnormalities Grade 3-4 laboratory abnormality28 (60) Hemoglobin <10 g/dL13 (28) Hemoglobin <8.5 g/dL4 (9) Absolute neutrophil count <750/mm 3 13 (28) Platelets <50,000/mm 3 7 (15) Lawitz E, et al. Abstract #LB-4, AASLD 2013

39 39 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 39 Lawitz E, et al. Abstract #LB-4, AASLD 2013

40 40 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 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.

41 41 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

42 42 *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/ /302/ 2 30/337/ 8

43 43 Naïve, Noncirrhotic Naïve, Cirrhotic Experienced, Noncirrhotic Experienced, Cirrhotic 86/9212/1327/4587/100 Zeuzem S, et al. Abstract #1085, AASLD 2013

44 44 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

45 45 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: Charlton MR, et al. Abstract #LB-2, AASLD 2013

46 46 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 Charlton MR, et al. Abstract #LB-2, AASLD 2013

47 47 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

48 48 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

49 49 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

50 50 Charlton MR, et al. Abstract #LB-2, AASLD 2013

51 51 Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation Michael P. Curry 1, Xavier Forns 2, Raymond T. Chung 3, Norah Terrault 4, Robert S. Brown 5, Jonathan M. Fenkel 6, Fredric D. Gordon 7, Jacqueline G. O'Leary 8, Alexander Kuo 9, Thomas D. Schiano 10, Gregory T. Everson 11, Eugene R. Schiff 12, Alex Befeler 13, John G. McHutchison 14, William T. Symonds 14, Jill M. Denning 14, Lindsay McNair 14, Sarah Arterburn 14, Dilip Moonka 15, Edward J. Gane 16, Nezam H. Afdhal 1 1. Beth Israel Deaconess Medical Center, Boston, MA, United States. 2. The Liver Unit, Barcelona, Spain. 3. Massachusetts General Hospital, Boston, MA, United States. 4. University of California San Francisco, San Francisco, CA, United States. 5. Columbia University, New York, NY, United States. 6. Thomas Jefferson University Hospital, Philadelphia, PA, United States. 7. Lahey Clinic, Burlington, MA, United States. 8. Baylor University Medical Center, Dallas, TX, United States. 9. University of California San Diego, La Jolla, CA, United States. 10. Mount Sinai School of Medicine, New York, NY, United States. 11. University of Colorado, Denver, CO, United States. 12. University of Miami, Miami, FL, United States. 13. St. Louis University, St. Louis, MO, United States. 14. Gilead Sciences, Foster City, CA, United States. 15. Henry Ford Health System, Detroit, MI, United States. 16. Auckland City Hospital, Auckland, New Zealand.

52 52 Recurrent HCV infection of the allograft is universal in patients with detectable HCV RNA at the time of liver transplantation (LT) and may result in accelerated progression to cirrhosis and graft loss. Interferon-based antiviral treatment before LT can prevent HCV recurrence, but this treatment is poorly tolerated and effective in only a minority of patients. Curry MP, et al. Abstract #213, AASLD 2013

53 53 In this phase 2 open-label study, patients with chronic HCV infection of any genotype (GT) listed for LT for hepatocellular carcinoma (HCC) received up to 48 weeks of SOF 400 mg/day and RBV mg/day before LT. All patients had HCC within Milan criteria and well compensated cirrhosis (Child-Pugh-Turcotte score of ≤7). The primary endpoint was virologic response (HCV RNA <25 IU/mL) 12 weeks after LT in patients who had HCV RNA <25 IU/mL at their last measurement prior to LT (SVR12). Post-LT immunosuppressive regimen was tacrolimus plus prednisone with or without mycophenolate mofetil. Curry MP, et al. Abstract #213, AASLD 2013

54 54 36 patients included in efficacy analysis Received a mean of 17.1 (range 3.3 to 33.7) weeks of treatment prior to LT At the time of writing, 26 patients have reached at least 12 weeks post- transplant, of whom 18 (69%, 90% CI 51% to 84%) achieved SVR12. The most frequently reported adverse events were fatigue, anemia, and rash. Two patients discontinued treatment due to AEs of acute renal failure and pneumonitis, neither was attributed to study drug. One SAE, anemia, was considered related to study drug. Curry MP, et al. Abstract #213, AASLD 2013


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