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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. Kimberly A. Brown, MD Detroit, Michigan, USA

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 The all oral, interferon and ribavirin-free combination of DCV, ASV and BMS-791325 in treatment naïve Genotype 1 resulted in overall SVR12 rates of 91.7- 92.2% The combination was well tolerated with 1.1% of patients discontinuing treatment due to AE Excellent safety was observed with 1.6% of patients experiencing a serious AE with only 1 patient experiencing a Grade 3/4 AE during the study

8 8 High Efficacy and Safety of the All-Oral Combination Regimen, MK-5172/MK-8742 +/- RBV for 12 Weeks in HCV Genotype 1 Infected Patients: The C-WORTHY Study Eric Lawitz 1, John M. Vierling 2, Abel Murillo 3, Marcelo Kugelmas 4, Jan Gerstoft 5, Peter Winkle 6, Luis A. Balart 7, Peer B. Christensen 8, Reem H. Ghalib 9, Ronald Nahass 10, Melissa Shaughnessy 11, Xiao Sun 11, Peggy Hwang 11, Janice Wahl 11, Michael Robertson 11, Barbara Haber 11 1. University of Texas Health Science Center, Texas Liver Institute, San Antonio, TX, United States. 2. Baylor College of Medicine, Houston, TX, United States. 3. Advanced Intervention & Pain Management Research Clinic, Miami, FL, United States. 4. South Denver Gastroenterology, PC, Englewood, CO, United States. 5. Epidemiklinikken, Rigshospitalet, Copenhagen, Denmark. 6. Anaheim Clinical Trials, Anaheim, CA, United States. 7. Tulane University Medical Center, New Orleans, LA, United States. 8. Infektionsmed. Afd Q 2 sal, Odense Universitets Hospital, Odense, Denmark.

9 9 MK-5172 is a selective inhibitor of hepatitis C virus NS3/4a protease which is effective across genotypes and resistant variants MK-8742 is an investigational HCV NS5A replication complex inhibitor Lawitz E, et al. Abstract #76, AASLD 2013

10 10 D1 TW12SVR24 SVR4SVR8 TW4 SVR12 n=25 n=13 n=27 Follow-up MK-5172 (100 mg) + MK-8742 (20 mg) + RBV; G1a & G1b MK-5172 (100 mg) + MK-8742 (50 mg); G1b MK-5172 (100 mg) + MK-8742 (50 mg) + RBV; G1a & G1b Lawitz E, et al. Abstract #76, AASLD 2013 Genotype 1a and 1b treatment naïve, non-cirrhotic

11 11 25 27 13 24 25 27 13 24 25 24 27 13 24 25 24 27 13 Treatment Follow-up Lawitz E, et al. Abstract #76, AASLD 2013

12 12 Common Adverse Event Number of patients (%) MK-5172 100 mg + MK-8742 20 mg + RBV n=25 MK-5172 100 mg + MK-8742 50 mg + RBV n=28 MK-5172 100 mg + MK-8742 50 mg n=12 All arms N=65 Fatigue8 (32) 5 (18)4 (33)17 (26) Headache4 (16) 5 (18)5 (42)14 (22) Nausea3 (12) 7 (25)2 (17)12 (18) Diarrhea3 (12) 4 (14)1 (8)8 (12) Dizziness4 (16) 2 (7)1 (8)7 (11) Rash1 (4) 5 (18)1 (8)7 (11) * Incidence ≥10% in all arms Lawitz E, et al. Abstract #76, AASLD 2013

13 13 12 week treatment with a combination of MK-5172 and MK-8742 plus RBV resulted in high SVR 12 rates in GT 1a and 1b non-cirrhotic patients of 89-96% 12 week treatment with MK-5172 and MK-8742 without RBV resulted in a 100% SVR 12 in GT 1b non-cirrhotic patients Treatment overall was well tolerated with good safety Lawitz E, et al. Abstract #76, AASLD 2013

14 14 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.

15 15 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

16 16 Primary endpoint: SVR12 (HCV RNA { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/8/2363631/slides/slide_16.jpg", "name": "16 Primary endpoint: SVR12 (HCV RNA

17 17 Duration (wk) 12 F4 onlyF3/F4 12 7/109/925/25*26/26*

18 18 *Gane et al. EASL 2013. † Lawitz et al, Abstract #215, AASLD 2013 (LONESTAR) Duration (wk) 1286 25/2521/2117/25 †

19 19 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

20 20 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.

21 21 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

22 22 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

23 23 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

24 24 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

25 25 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

26 26 Treatment of both naïve and cirrhotic GT 1b patients with a combination of ABT 450/r and ABT 267 resulted in high SVR12 rates (95.2% and 90%) The combination was well tolerated with good safety Lawitz E, et al. Abstract #75, AASLD 2013

27 27 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.

28 28 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

29 29 OverallGT 2GT 3 42/4722/2320/24 SVR12 (%) Lawitz E, et al. Abstract #LB-4, AASLD 2013

30 30 SVR12 (%) 9/913/1410/12 Error bars represent 95% confidence intervals. Lawitz E, et al. Abstract #LB-4, AASLD 2013

31 31 Lawitz E, et al. Abstract #LB-4, AASLD 2013

32 32 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

33 33 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.

34 34 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

35 35 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

36 36 Treatment Naïve (No Cirrhosis) PI Failures (50% Cirrhosis) ─── ++ 812 8 Patients (%) 19/2021/2118/19 21/21 RBV Duration (week) Lawitz E, et al. Abstract #215, AASLD 2013

37 37 No CirrhosisCirrhosis ─ + RBV 12Duration (week) Patients (%) 18/1921/21 Overall 10/1011/118/810/11 12 ─ + ─ + Lawitz E, et al. Abstract #215, AASLD 2013

38 38 *Peptic ulcer, spinal compression fracture; † Delirium, suicidal ideation. Lawitz E, et al. Abstract #215, AASLD 2013

39 39 Once daily SOF/LDV Fixed Dose Combination with or without RBV resulted in ≥95% SVR12 in patients with HCV GT 1, including patients with cirrhosis Patients with cirrhosis previously failing PI therapy had 100% SVR12 with the combination of SOF/LDV fixed dose combination with RBV for 12 weeks Similarly to prior reports, the combination was well tolerated with an excellent safety profile Lawitz E, et al. Abstract #215, AASLD 2013

40 40 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 17 1. 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.

41 41 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

42 42 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 0412243648 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

43 43 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

44 44 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

45 45 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

46 46 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

47 47 Twice-Daily Telaprevir in Combination with Peginterferon Alfa-2a/Ribavirin in Genotype 1 HCV Liver Transplant Recipients: Interim Week 16 Safety and Efficacy Results of the Prospective, Multicenter REFRESH Study Kimberly Ann Brown 1, Robert J. Fontana 2, Mark W. Russo 3, Josh Levitsky 4, Eric M. Yoshida 5, Hugo E. Vargas 6, Mohammad Bsharat 7, Raymond A. Rubin 7, Robert S. Brown 8 1. Henry Ford Hospital, Detroit, MI, United States. 2. University of Michigan, Ann Arbor, MI, United States. 3. Carolinas Medical Center, Charlotte, NC, United States. 4. Northwestern University, Chicago, IL, United States. 5. University of British Columbia, Chicago, IL, United States. 6. Mayo Clinic, Scottsdale, AZ, United States. 7. Vertex Pharmaceuticals Incorporated, Cambridge, MA, United States. 8. Columbia University, New York, NY, United States.

48 48 No PR lead-in used Patients received T/PR (TVR, 1125 mg twice daily; Peg-IFN 180 µg/week; RBV 600 mg/day [initial dosage]) for 12 weeks, plus 36 weeks of PR –Since treatment with T/PR has not been previously studied in liver transplant recipients with HCV infection, this study was designed in two parts. After all patients in Part A reached week 4, a safety review of available safety, PK, and HCV RNA data was conducted before initiating enrollment in Part B –Dose adjustments in Peg-IFN and/or RBV permitted All study drugs were discontinued if HCV RNA was >1000 IU/mL at weeks 4, 8, or 12, or if it was <25 IU/mL, target detected at weeks 24 or 36 *The design was the same for both Parts A and B. SVR12, sustained viral virologic response at 12 weeks. Brown KA, et al. Abstract #3, AASLD 2013 T/PRPR SVR 12 Follow-up Week041224364860 Week 4 safety review before enrolling patients in Part B

49 49 n=23n=18 n=3 n=6 Week 4 (n=43)* Patients (%) n=11 n=3 n=0 Week 12 (n=30)* *As the study is ongoing, data are reported for patients with HCV RNA assessments available at the time of interim analysis. LLOQ = 25 IU/mL. Brown KA, et al. Abstract #3, AASLD 2013

50 50 Five (13%) patients in the TAC group experienced serious AEs* Two (29%) patients in the CsA group experienced serious AEs* No rejections, autoimmune hepatitis, or deaths have been reported to date Event, n (%) TAC (n=39) CsA (n=7) Total (N=46) Any AE36 (92)6 (86)42 (91) AEs occurring in ≥20% of patients overall Fatigue23 (59)4 (57)27 (59) Anemia † 17 (44)5 (71)22 (48) Headache17 (44)4 (57)21 (46) Nausea16 (41)3 (43)19 (41) Anorectal † 14 (36)5 (71)19 (41) Diarrhea16 (41)1 (14)17 (37) Rash † 12 (31)4 (57)16 (35) Pruritus † 10 (26)010 (22) *Patients may have reported ≥1 serious AE. †Grouped adverse event terms. Brown KA, et al. Abstract #3, AASLD 2013

51 51 Results of this interim analysis of the REFRESH study found that, despite prior antiviral therapy in 70% of patients and potent immunosuppression after transplantation, 53% (23/43) and 60% (18/30) of patients had HCV RNA not detected at weeks 4 and 12, respectively AEs are manageable when T/PR is used with TAC or CsA –Anemia was more common than in non–liver transplant patients, despite reduced doses of RBV –No moderate, severe, or serious rash reported –No rejections, autoimmune hepatitis, or deaths have been reported to date –Grade 2 or 3 creatinine toxicity was observed in 12/46 patients Brown KA, et al. Abstract #3, AASLD 2013

52 52 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

53 53 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

54 54 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

55 55 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

56 56 Charlton MR, et al. Abstract #LB-2, AASLD 2013

57 57 24 weeks of SOF and RBV following liver transplantation resulted in a 77% SVR rate in this difficult to treat patient population Safety profile and tolerability was excellent Consideration of longer therapy may be made given the 100% EOT response on therapy Charlton MR, et al. Abstract #LB-2, AASLD 2013

58 58 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.

59 59 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 1000-1200 mg/day before LT. All patients had HCC within Milan criteria and well compensated cirrhosis (Child-Pugh-Turcotte score of ≤7). Post-LT immunosuppressive regimen was tacrolimus plus prednisone with or without mycophenolate mofetil. Induction was excluded Curry MP, et al. Abstract #213, AASLD 2013

60 60 37 patients included in efficacy analysis Received a mean of 17.1 (range 3.3 to 33.7) weeks of treatment prior to LT 23 out of 37 patients had no recurrence following transplantation The most frequently reported adverse events were fatigue, anemia, and rash The most significant predictor of recurrence was duration of undetectable HCV RNA <30 days while on treatment Curry MP, et al. Abstract #213, AASLD 2013

61 61 These data suggest that this regimen is safe and well tolerated in a select group of patients moving to transplant Time undetectable appears to be related to relapse Curry MP, et al. Abstract #213, AASLD 2013


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