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Best of HCV From AASLD 2013

Best of HCV From AASLD 2013. Darrell Crawford, MD Brisbane, Australia. This activity has been supported by an independent medical education grant from Bristol Myers Squibb.

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Best of HCV From AASLD 2013

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  1. Best of HCVFrom AASLD 2013 Darrell Crawford, MD Brisbane, Australia 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.

  2. Abstract #LB-1 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. Everson1, Karen D. Sims2, Paul J. Thuluvath3, Eric Lawitz4, Tarek Hassanein5,Maribel Rodriguez-Torres6, Trevor Hawkins7, Howard Schwartz8, Vinod K. Rustgi9, Federico Hinestrosa10, James M. Levin11, Zobair M. Younossi12, Lynn R. Webster13, Timothy Eley2, Shu-Pang Huang14,Fiona McPhee15, Dennis M. Grasela2, David F. Gardiner2 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. Direct-Acting Antiviral Agents • 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 Everson GT, et al. Abstract #LB-1, AASLD 2013

  4. Randomized, Phase 2b Open-Label Study (AI443-014) Primary endpoint: SVR12 DCV 30 mg BID + ASV 200 mg BID + BMS-791325 75 mg BID 12-week follow-up Additional follow-up to SVR48 N = 80 DCV 30 mg BID + ASV 200 mg BID + BMS-791325 150 mgBID N = 86 Week 12 24 0 • 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 (SVR12) • Observed analysis: breakthrough, relapse, addition of pegIFNα/RBV = failure • Modified intent-to-treat analysis: missing, breakthrough, relapse or addition of pegIFNα/RBV = failure Everson GT, et al. Abstract #LB-1, AASLD 2013

  5. Efficacy Through SVR12 (Observed) 97.5 94.2 92.2 91.7 92.4 91.7 DCV + ASV + ‘325 75 mg DCV + ASV + ‘325 150 mg Response, % of patients 78/80 81/86 73/79 77/84 71/77 77/84 End of Treatment SVR4 SVR12 Everson GT, et al. Abstract #LB-1, AASLD 2013

  6. Safety Outcomes Everson GT, et al. Abstract #LB-1, AASLD 2013

  7. Abstract #211 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 Chayama1, Yoshiyuki Suzuki2, Kenji Ikeda2, Joji Toyota3, Yoshiyasu Karino3, Yoshiiku Kawakami1, Akio Ido4, Kazuhide Yamamoto5, Koichi Takaguchi6, Namiki Izumi7, Kazuhiko Koike8, Tetsuo Takehara9, Norifumi Kawada10, Michio Sata11, Hidetaka Miyagoshi12, Timothy Eley13, Fiona McPhee13, Wenhua Hu13, Hiroki Ishikawa12, Eric A. Hughes13, Hiromitsu Kumada2 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. Virologic Response aIneligible naïve: n=100; Intolerant: n=35 bNull responders: n=48; Partial responders: n=36; Undetermined: n=3 Chayama K, et al. Abstract #211, AASLD 2013

  9. Abstract #73 Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin: the ELECTRON trial Edward J. Gane1, Catherine A. Stedman2, Robert H. Hyland3, Xiao Ding3, EvgueniaS. Svarovskaia3, Phil S. Pang3, William T. Symonds3 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. Direct Acting Antiviral Agents Sofosbuvir/LedipasvirFDC • Once daily, oral fixed-dose (400/90 mg) combination tablet • No food effect • >2000 patients treated SOF Nucleotide Polymerase inhibitor LDV NS5A inhibitor 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 Gane EJ, et al. Abstract #73, AASLD 2013

  11. Study Design Wk 0 Wk 6 Wk 12 SOF/LDV FDC (n=10) F4 Randomized SOF/LDV FDC + RBV (n=10) GT 1 Experienced SVR12 SOF/LDV FDC + RBV (n=25) F3/F4 Randomized SOF/LDV FDC + GS-9669 (n=25) GT 1 Naïve SOF/LDV FDC + RBV (n=25) F0/F1/F2 Primary endpoint: SVR12 (HCV RNA <LLOQ) Patients enrolled in ELECTRON or ELECTRON 2 (GT1, F3/F4) All groups were open label Gane EJ, et al. Abstract #73, AASLD 2013

  12. SVR 12 Results: GT 1 Treatment-Experienced Patients with Advanced Fibrosis/Cirrhosis 7/10 9/9 25/25* 26/26* Duration (wk) 12 12 12 12 F4 only F3/F4 *From ELECTRON 2 Gane EJ, et al. Abstract #73, AASLD 2013

  13. SVR12 Results: Treatment DurationGenotype 1, Treatment-naïve, No Cirrhosis 25/25 21/21 17/25 † Duration (wk) 12 8 6 *Gane et al. EASL 2013. †Lawitz et al, Abstract #215, AASLD 2013 (LONESTAR) Gane EJ, et al. Abstract #73, AASLD 2013

  14. Conclusions 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 Gane EJ, et al. Abstract #73, AASLD 2013

  15. Abstract #75 Interferon- and Ribavirin-free Regimen of ABT-450/r + ABT-267 in HCV Genotype 1b-infected Treatment-naïve Patients and Prior Null Responders Eric Lawitz1, Christophe Hezode2, Peter Varunok3, Paul J. Thuluvath4, Tolga Baykal5, Mudra Kapoor5, Sandra S. Lovell5, Tianli Wang5, Tami Pilot-Matias5, Regis A. Vilchez5, Barry Bernstein5 1. The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, United States. 2. Assistance PubliqueHopitaux 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. Background and Aims 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. PEARL-I Study Design PlannedN HCV Genotype/Regimen Treatment Experience Week 12 Week 24 BL Group 1 40 Group 2 40 Group 3 40 Group 4 40 Group 5 40 Group 6 40 Group 7 40 Group 8 40 GT4 ABT-450/r + ABT-267 Treatment-naïve GT1b ABT-450/r + ABT-267 Treatment-naïve Substudy 1: Patients Without Cirrhosis 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 Substudy 2: Patients With Compensated Cirrhosis GT1b ABT-450/r + ABT-267 Treatment-naïve GT1b ABT-450/r + ABT-267 Partial/Null Responders & Relapsers Lawitz E, et al. Abstract #75, AASLD 2013

  18. Efficacy: Treatment-Naïve Patients, ITT 100 97.6 97.6 95.2 100 80 60 Percentage of Patients (%) 40 20 42/42 41/42 41/42 40/42 0 Week 4 Week 12 (EOTR) SVR4 SVR12 Lawitz E, et al. Abstract #75, AASLD 2013

  19. Efficacy: Prior Null Responders, ITT 97.5 97.5 92.5 90.0 100 80 60 Percentage of Patients (%) 40 20 39/40 39/40 37/40 36/40 0 Week 4 SVR4 SVR12 Week 12 (EOTR) Lawitz E, et al. Abstract #75, AASLD 2013

  20. Treatment-Emergent Adverse Events (AEs) Occurring in >10% of Patients in Either Group Lawitz E, et al. Abstract #75, AASLD 2013

  21. Abstract #LB-4 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 Lawitz1, 2, Fred Poordad1, 2, Diana M. Brainard3, Robert H. Hyland3, Di An3, William T. Symonds3, John G. McHutchison3, Fernando E. Membreno1, 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. Study Design Wk 0 Wk 12 Wk24 Wk36 SOF + PEG/RBV GT 2/3(N=47) SVR12 • 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 Lawitz E, et al. Abstract #LB-4, AASLD 2013

  23. Results: SVR12 by HCV Genotype SVR12 (%) 42/47 22/23 20/24 Overall GT 2 GT 3 Lawitz E, et al. Abstract #LB-4, AASLD 2013

  24. Results: SVR12 by Cirrhosis Status SVR12 (%) 9/9 13/14 10/12 10/12 Error bars represent 95% confidence intervals. Lawitz E, et al. Abstract #LB-4, AASLD 2013

  25. Results: Adverse Events Lawitz E, et al. Abstract #LB-4, AASLD 2013

  26. Conclusions Lawitz E, et al. Abstract #LB-4, AASLD 2013 • 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

  27. Abstract #1085 Sofosbuvir + Ribavirin for 12 or 24 Weeks for Patients with HCV Genotype 2 or 3: the VALENCE trial Stefan Zeuzem1, Geoffrey M. Dusheiko2, Riina Salupere3, Alessandra Mangia4, Robert Flisiak5, Robert H. Hyland6, Ari Illeperuma6, Evguenia S. Svarovskaia6, Diana M. Brainard6, William T. Symonds6, John G. McHutchison6, Ola Weiland7, Hendrik W. Reesink8, Peter Ferenci9, Christophe Hezode10, Rafael Esteban11 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 SollievodellaSofferenza" Hospital, San Giovanni Rotondo, Italy. 5. Medical University of Bialystok, Bialystok, Poland. 6. Gilead Sciences, Inc., Foster City, CA, United States. 7. KarolinskaInstitutet, 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. VALENCE: Study Design SVR4, SVR12, SVR24 Wk 0 Wk 12 Wk 24 Placebo*(n = 85) Sofosbuvir + Ribavirin(n = 84)* Sofosbuvir + Ribavirin (n = 250) *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. Zeuzem S, et al. Abstract #1085, AASLD 2013

  29. 212/ 250 68/73 29/30 2/2 30/33 7/8 GT 2 SOF+RBV 12 wk GT 3 SOF+RBV 24 wk Naïve, Noncirrhotic Naïve, Cirrhotic Experienced, Noncirrhotic Experienced, Cirrhotic *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

  30. SVR12 in GT 3 Patients Treated for 24 Weeks 86/92 12/13 87/100 27/45 Naïve, Noncirrhotic Naïve, Cirrhotic Experienced, Noncirrhotic Experienced, Cirrhotic ZeuzemS, et al. Abstract #1085, AASLD 2013

  31. Abstract #212 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. Sulkowski1, Maribel Rodriguez-Torres2, Jacob P. Lalezari3, W. Jeffrey Fessel4, Karam Mounzer5, Margaret C. Shuhart6, Anne Luetkemeyer7, David M. Asmuth8, Anuj Gaggar9, William T. Symonds9, John G. McHutchison9, Susanna Naggie10, Douglas T. Dieterich11 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. Study Design 36 Wk 0 Wk 12 Wk 24 Wk 36 • GT 1 TN SOF + RBV, n=114 • GT 2/3 TN SOF + RBV, n=68 SVR12 SVR12 SVR12 • GT 2/3 TE SOF + RBV, n=41 SulkowskiMS, et al. Abstract #212, AASLD 2013 • 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/mm3 • ART untreated: CD4 T-cell count >500 cells/mm3

  33. Results: Virologic Response Week 4 EOT SVR12 Patients with HCV RNA <LLOQ (%) 110/114 103/103 87/114 25/26 22/23 23/26 41/41 39/40 28/42 SOF + RBV 24 Weeks SOF + RBV 12 Weeks SulkowskiMS, et al. Abstract #212, AASLD 2013

  34. Results: Safety Summary SulkowskiMS, et al. Abstract #212, AASLD 2013

  35. HIV Safety 600 400 Change in HIV-1 RNA from Baseline(%) 200 0 -200 1 2 4 6 8 10 12 16 20 24 4 12 Treatment Period (week) Follow-up SulkowskiMS, et al. Abstract #212, AASLD 2013 • 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 inlymphocyte counts

  36. Abstract #LB-2 Sofosbuvir and Ribavirin for the Treatment of Established Recurrent Hepatitis C Infection After Liver Transplantation:Preliminary Results of a Prospective, Multicenter Study Michael R. Charlton1, Edward J. Gane2, Michael P. Manns3, Robert S. Brown4, Michael P. Curry5,Paul Y. Kwo6, Robert J. Fontana7, Richard Gilroy8, Lewis W. Teperman9, Andrew J. Muir10,John G. McHutchison11, William T. Symonds11, Jill M. Denning11, Lindsay McNair11, Sarah Arterburn11,Norah Terrault12, Didier Samuel13, Xavier Forns14 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.

  37. Background 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 • 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 years1 • Once cirrhosis is established, the probability of liver graft failure is 42% within 12 months2 • Current therapies for HCV treatment used after transplantation have poor tolerance, poor efficacy, severe adverse reactions, and significant interactions with immunosuppression medications

  38. Study Design and Objectives Week 0 12 24 36 SOF 400 mg + RBV 400‒1200 mg (N=40) SVR12 Charlton MR, et al. Abstract #LB-2, AASLD 2013 • 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 virologicresponse 12 weeks post treatment with sofosbuvir+ RBV in liver transplant recipients • Secondary: safety, tolerability and viral kinetics

  39. Key Inclusion/Exclusion Criteria Charlton MR, et al. Abstract #LB-2, AASLD 2013 • 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

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

  41. Concomitant Immunosuppression Patients (%) Tacrolimus Mycophenolate mofetil Prednisone Cyclosporin Azathioprine • No interactions reported between SOF and any immunosuppressive agents during study • 4 patients increased tacrolimus dosing during SOF therapy Charlton MR, et al. Abstract #LB-2, AASLD 2013

  42. Results: Grade 3 and 4 Laboratory Abnormalities Charlton MR, et al. Abstract #LB-2, AASLD 2013

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