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October 29 - November 2, 2010 Boston, Massachusetts

Highlights From AASLD 2010 CCO Official Conference Coverage of the 61st Annual Meeting of the American Association for the Study of Liver Diseases. October 29 - November 2, 2010 Boston, Massachusetts. This program is supported by educational grants from.

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October 29 - November 2, 2010 Boston, Massachusetts

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  1. Highlights From AASLD 2010CCO Official Conference Coverage of the 61st Annual Meeting of the American Association for the Study of Liver Diseases October 29 - November 2, 2010 Boston, Massachusetts This program is supported by educational grants from This program is supported by an educational grant from

  2. About These Slides • Our thanks to the presenters who gave permission to include their original data • Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. Faculty and Disclosures Robert G. Gish, MD Chief of HepatologyProfessor of Clinical MedicineMedical DirectorCenter for Hepatobiliary Disease and Abdominal TransplantationUniversity of California, San DiegoSan Diego, California Stephen A. Harrison, MD, FACPClinical Associate Professor of Medicine University of Texas Health Science CenterSan Antonio, Texas Robert G. Gish, MD, has disclosed that he has received grant or research support from Bayer-Onyx, Bristol-Myers Squibb, Genentech, Gilead Sciences, Hoffmann-La Roche, Pharmasset, and Zymogenetics; has served as a consultant to Abbott, Anadys, Bayer AG, Bristol-Myers Squibb, Durect, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Hepahope, Hoffmann-La Roche, Human Genome Sciences, Merck, Metabasis Therapeutics, OSI/Astellas, Pharmasset, Schering-Plough, Three Rivers Pharmaceuticals, Vital Therapies, and Zymogenetics; has served on speaker bureaus for Bayer, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, Merck, Onyx, Roche, Salix, Schering-Plough, SciClone Pharmaceuticals, and Three Rivers Pharmaceuticals; and holds stock in Hepahope. Stephen A. Harrison, MD, FACP, has disclosed that he has served as a consultant for and has received fees for non-CME services from Bristol-Myers Squibb and Onyx.

  4. Outline • Investigational Agents for the Treatment of HCV • Advances in HBV Therapy

  5. Investigational Agents for the Treatment of HCV

  6. Boceprevir and Telaprevir • Boceprevir, a potent inhibitor of HCV NS3 protease • Telaprevir, a potent inhibitor of HCV NS3/4A protease • Both being tested in combination with standard-of-care peginterferon alfa-2/ ribavirin in phase III studies in chronic HCV infection Trials reported at AASLD 2010 • Boceprevir • SPRINT-III: naive GT1 patients • RESPOND-2: nonresponder GT1 patients • Telaprevir • ADVANCE: naive GT1 patients • ILLUMINATE: response-guided therapy in naive GT1 patients

  7. Phase III SPRINT-2: Boceprevir + PegIFN/RBV in GT1 Tx-Naive Patients • Randomized, placebo-controlled trial Wk 28 Wk 72 Wk 48 Wk 4 RVR† PR*(n = 316, 52) BOC + PR*(n = 316 nonblack, 52 black) Follow-up PR* Follow-up No RVR Treatment-naive patients withgenotype 1 HCV (2 cohorts: N = 938 nonblack and 159 black) PR*(n = 311,55) BOC + PR*(n = 311 nonblack, 55 black) Follow-up PR*(n = 311 nonblack, 52 black) Follow-up *BOC 800 mg q8h; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. †Undetectable HCV RNA at Wk 4 of BOC treatment (ie, at Wk 8) and at all subsequent assays. Poordad F, et al. AASLD 2010. Abstract LB-4.

  8. SPRINT-2: Response Rates According to Race 4-wk PR + response-guided BOC + PR 4-wk PR + 44 weeks BOC + PR 48-wk PR Nonblack Patients Black Patients 100 100 P < .0001 P = .044 80 80 68 67 P = .004 60 60 53 Patients (%) Patients (%) 42 40 40 40 23 23 20 20 17 14 9 12 8 213 125 18 37 22 3 6 2 n = 211 21 29 12 0 0 Relapse SVR Relapse SVR Poordad F, et al. AASLD 2010. Abstract LB-4.

  9. Phase III ADVANCE: Telaprevir + PegIFN/RBV in GT1 Tx-Naive Patients • Randomized, placebo-controlled trial Wk 24 Wk 72 Wk 48 Wk 12 Wk 8 TVR + PR*(n = 364) eRVR†: PR* Follow-up PR* Follow-up Treatment-naive patients with genotype1 HCV (N = 1088) TVR + PR*(n = 363) eRVR†: PR* Follow-up PR* Follow-up PR*(n = 361) Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12. Jacobson IM, et al. AASLD 2010. Abstract 211.

  10. ADVANCE: Overall SVR and Relapse Rates 8-wk TVR + PR + 16/40-wk PR (n = 364) P < .0001 for both treatment arms vs control 12-wk TVR + PR + 12/36-wk PR (n = 363) 100 48-wk PR (n = 361) 80 75 69 60 Patients (%) 44 40 28 20 9 9 n = 271 n = 28 64 250 158 27 0 SVR Relapse Jacobson IM, et al. AASLD 2010. Abstract 211.

  11. Phase III ILLUMINATE: Response-Guided Telaprevir + PegIFN/RBV in GT1 Naive Pts • Open-label, randomized trial Wk 12 Wk 20 Wk 24 Wk 48 Wk 72 TVR + PR* PR* PR*(n = 162) Follow-up eRVR† Treatment-naive patients with GT1 HCV (N = 540) PR*(n = 160) Follow-up No eRVR† PR*(n = 218) Follow-up *TVR 750 mg q8h; pegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12. Sherman KE, et al. AASLD 2010. Abstract LB-2.

  12. ILLUMINATE: Overall SVR Rates 100 92 88 80 72 60 SVR (%) 40 20 140/160 n/N = 388/540 149/162 0 Overall 24-wk therapy 48-wk therapy Patients With eRVR Sherman KE, et al. AASLD 2010. Abstract LB-2.

  13. Similarities and Differences in Phase III Studies of TVR and BOC in GT1 Naive Pts 1. Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. AASLD 2010. Abstract LB-4.

  14. Phase III RESPOND-2: Boceprevir in GT1 Prior Nonresponders to PegIFN/RBV Wk 36 Wk 48 Wk 8 If detectable at Wk 8 BOC+ PR* PR* Follow-up† BOC + PR* PR*(n = 162) Follow-up† Treatment-experienced patients with GT1 HCV (N = 403) PR*(n = 161) BOC + PR* Follow-up† PR*(n = 80) Follow-up† *BOC 800 mg TID; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day. †Follow-up for 24 wks after completion of therapy. Bacon BR, et al. AASLD 2010. Abstract 216.

  15. RESPOND-2: SVR Rates According to Treatment Arm and Prior Response 4-wk PR + response-guided BOC + PR (n = 162) P < .0001 vs control (both arms) 100 4-wk PR + 44-wk BOC + PR (n = 161) 80 48-wk PR (n = 80) 75 69 66 59* 60 52 SVR (%) 40 40 29 21 20 95/ 162 7 107/161 17/80 23/57 30/58 72/105 77/103 15/51 2/29 0 Overall PreviousNonresponders PreviousRelapsers Bacon BR, et al. AASLD 2010. Abstract 216.

  16. GS-9256 + Tegobuvir Alone, With RBV, or With PegIFN/RBV in GT1 Tx-Naive Patients • Phase II study of tegobuvir (GS-9190), an NS5B nonnucleoside polymerase inhibitor, and GS-9256, an NS3 protease inhibitor as part of HCV therapy Wk 48 Wk 4 PR*(n = 16) GS-9256 75 mg BID +Tegobuvir 40 mg BID(n = 16)† Treatment-naive patients with GT1 HCV Part A GS-9256 75 mg BID +Tegobuvir 40 mg BID + RBV*† (n = 15) PR*(n = 15) Part B(nonrandomized) GS-9256 75 mg BID +Tegobuvir 40 mg BID + PR* (n = 15) PR*(n = 15) *PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †PegIFN/RBV started early if virologic breakthrough. Zeuzem S, et al. AASLD 2010. Abstract LB-1.

  17. GS-9256 + Tegobuvir Alone, With RBV, or With PegIFN/RBV: Virologic Response Zeuzem S, et al. AASLD 2010. Abstract LB-1.

  18. BMS-790052 + BMS-650032 Alone or With PegIFN/RBV in GT1 Null Responders • Open-label, randomized, placebo-controlled phase IIa trial • BMS-790052: NS5A polymerase inhibitor • BMS-650032: NS3 protease inhibitor Wk 72 Wk 24 BMS-790052 60 mg QD +BMS-650032 600 mg BID(n = 11) Follow-up Prior null responders with GT1 HCV (N = 21) BMS-790052 60 mg QD +BMS-650032 600 mg BID + PR*(n = 10) Follow-up *PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. Lok A, et al. AASLD 2010. Abstract LB-8.

  19. BMS-790052 + BMS-650032 Alone or With PegIFN/RBV: Wk 12 Interim Analysis • All viral breakthroughs occurred in patients with GT1a BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PR 100 90 80 64 60 60 60 46 Patients (%) 36 40 20 7/11 6/10 4/11 6/10 5/11 9/10 0 RVR eRVR cEVR Lok A, et al. AASLD 2010. Abstract LB-8.

  20. PILLAR: TMC435 + PegIFN/RBV in GT1 Tx-Naive Patients: 24-Wk Interim Analysis • Randomized, double-blind, placebo-controlled phase IIb trial • TMC435: NS3/4A protease inhibitor administered once daily Wk 72 Wk 12 Wk 24 Wk 48 Follow-up TMC435 75 mg + PR(n = 78) PR(n = 78) Follow-up* or PR(n = 78) TMC435 75 mg + PR(n = 75) Follow-up* or PR (n = 75) Treatment-naive patients with GT1HCV (N = 386) PR(n = 77) Follow-up* or PR (n = 77) TMC435 150 mg + PR(n = 77) TMC435 150 mg + PR(n = 79) Follow-up* or PR (n = 79) PR(n = 77) PR (n = 77) *Treatment ended at Wk 24 if HCV RNA < 25 IU/mL at Wks 4, 12, 16, and 20; all others continued on PR. Fried M, et al. AASLD 2010. Abstract LB-5.

  21. PILLAR: Undetectable HCV RNA at Wks 4 and 12 After EOT at Wk 24 • 79% to 86% of patients able to stop therapy at Wk 24 • Adverse events leading to discontinuation observed in < 10% of all study arms • TMC435 75 mg did not totally abrogate graded response due to IL28B genotype TMC12 + PR24 75 mg (n = 78) TMC12 + PR24 150 mg (n = 77) TMC24 + PR24 75 mg (n = 75) TMC24 + PR24 150 mg (n = 79) 97 100 93 93 93 91 91 89 88 80 60 Patients (%) 40 20 n/N = 59/65 56/60 57/61 27/29 62/68 32/33 32/36 28/32 0 SVR4 SVR12 Fried M, et al. AASLD 2010. Abstract LB-5.

  22. New Data on Other HCV Protease Inhibitors in Development • Danoprevir (RG7227): phase II study (ATLAS) in GT1 naive patients[1] • 88% to 92% of patients achieved cEVR when combined with pegIFN/RBV vs 43% with SOC • Vaniprevir (MK-7009): phase IIa study (Protocol 007) in GT1 naive patients without cirrhosis[2] • Significantly higher early response rates when combined with pegIFN/RBV vs SOC • RVR: 67% to 84% vs 5%; cEVR: 74% to 85% vs 47% • SVR rates in higher-dose arms numerically, but not significantly, higher vs control • SVR: 61% to 84% vs 63% • Highest 2 doses allow for once-daily dosing • MK-5172: phase I study in GT1 and GT3 patients without cirrhosis[3] • Potent activity against GT1 and GT3 over 7-day dosing period • Active against known resistance mutants in healthy persons[4] 1. Terrault N, et al. AASLD 2010. Abstract 32. 2. Manns MP, et al. AASLD 2010. Abstract 82. 3. Petry A, et al. AASLD 2010. Abstract 807. 4. Brainard DM, et al. AASLD 2010. Abstract 1885.

  23. New Data on Other HCV Polymerase Inhibitors in Development • ANA598 (nonnucleoside): phase II study in GT1 naive patients[1] • ANA598 200 or 400 mg BID + pegIFN/RBV given for 12 wks before response-guided pegIFN/RBV • 73% to 75% of patients achieved cEVR when combined with pegIFN/RBV vs 63% with SOC • RG7128 (nucleoside): phase IIb PROPEL study in GT1 and GT4 naive patients[2] • RG7128 500 or 1000 mg + pegIFN/RBV given for 8 or 12 wks before response-guided pegIFN/RBV • 80% to 88% of patients in arms receiving 12 wks of RG7128 combined with pegIFN/RBV achieved cEVR vs 49% with SOC 1. Lawitz E, et al. AASLD 2010. Abstract 31. 2. Jensen DM, et al. AASLD 2010. Abstract 81.

  24. PegIFN Lambda for Treatment-Naive GT1, 2, 3, or 4 HCV Patients • Phase IIa study • High rates of HCV RNA undetectability at 3 highest pegIFN lambda levels, comparable to pegIFN alfa-2a controls[1] • RVR: 80% to 100% • cEVR: 80% to 100% • HCV RNA response rates lower with genotype 1/4 vs 2/3 • Response rates numerically higher with IL28B CC vs non-CC genotype[1] • Fewer hematologic AEs at Wk 12 with pegIFN lambda than pegIFN alfa-2a 1. Muir AJ, et al. AASLD 2010. Abstract 821. 2. Thompson AJ, et al. Gastroenterology. 2010;139:120-129.

  25. Regional Distribution of IL28B rs12979860 CC Genotype Thomas DL, et al. Nature. 2009;461:798-801. Reprinted by permission from Macmillan Publishers Ltd:

  26. IL28B Associations in Patients With Chronic Hepatitis C • IL28B polymorphisms associated with • Higher SVR rates[1] • Higher RVR rates[2] • Higher HCV RNA[3] • Higher LDL levels[4] • Higher baseline ALT levels[5] • Higher rate of spontaneous viral clearance[6] • Modeling study supports IL28B genotype stratification (CC vs non-CC) in HCV clinical trials of pegIFN/RBV + DAAs[7] 1. Ge D, et al. Nature. 2009;461:399-401. 2. Mangia A, et al. AASLD 2010. Abstract 897. 3. Liu L, et al. AASLD 2010. Abstract 231. 4. Saito H, et al. AASLD 2010. Abstract 732. 5. Thompson AJ, et al. AASLD 2010. Abstract 1893. 6. Thomas DL, et al. Nature. 2009;461:798-801. 7. Thompson AJ, et al. AASLD 2010. Abstract 810.

  27. Predictors of Response to Hepatitis C Treatment 1. Ge D, et al. Nature. 2009;461:399-401. 2. Freedman ND, et al. AASLD 2010. Abstract 224. 3. Harrison SA, et al. Hepatology. 2010;52:864-874. 4. Mouch AS, et al. AASLD 2010. Abstract 809. 5. Sulkowski MS, et al. AASLD 2010. Abstract 816.

  28. Advances in HBV Therapy

  29. Vertical HBV Transmission in Mothers Treated With Telbivudine in Late Pregnancy • Prospective, nonrandomized, case-controlled, open-label study Pan C, et al. AASLD 2010. Abstract 212.

  30. Mode of Delivery and Risk of Perinatal HBV Transmission in HBeAg+ Mothers • Retrospective, observational study • 556 mothers; 569 infants • Immunoprophylaxis schedule (standard of care) • 200 IU HBIG and HB vaccine 10 µg within 6 hrs after birth • 200 IU HBIG 2 wks postpartum • HB vaccine 10 µg at 1 and 6 mos Vaginal delivery (n = 286) Elective cesarean (n = 189) 25 Emergency cesarean (n = 94) 19 20 15 P = .384 14 13 HBV Infection in Infant (%) P = .047 P = .028 10 9 6 5 2 0 At Birth* At 7-12 Mos of Age† *HBsAg+ or HBV DNA detectable in umbilical cord blood. † HBsAg+. Zou H, et al. AASLD 2010. Abstract 235.

  31. NEPTUNE: PegIFN alfa-2a Dosed at 90 vs 180 µg/wk in HBeAg+ Patients • PegIFN alfa-2a 90 µg/wk inferior to 180 µg/wk, regardless of treatment duration, in randomized, double-blind phase IV study *For noninferiority; ie, nonsignificance = not noninferior. Liaw Y-F, et al. AASLD 2010. Abstract 215.

  32. NEPTUNE: PegIFN alfa-2a Administered for 24 vs 48 Wks in HBeAg+ Patients • 24 wks inferior to 48 wks of pegIFN alfa-2a therapy, regardless of dose, in randomized, double-blind phase IV study *For noninferiority; ie, nonsignificance = not noninferior. Liaw Y-F, et al. AASLD 2010. Abstract 215.

  33. PegIFN alfa-2b Administered for 24 vs 48 Wks in HBeAg+ Patients • Patients recruited from 25 centers in China, Malaysia, Taiwan, and Singapore in prospective, randomized phase IV trial 100 EOT 24 Wks After EOT 80 60 HBeAg Seroconversion (%) P = .001 40 29.9 17.9 16.9 16.3 20 13.8 12.2 0 PegIFN alfa-2b 1.0 µg/kg/wk for 24 wks PegIFN alfa-2b 1.5 µg/kg/wk for 24 wks PegIFN alfa-2b 1.5 µg/kg/wk for 48 wks Fan X, et al. AASLD 2010. Abstract 133.

  34. Safety of Extending PegIFN alfa-2a From 48 to 96 Wks in Genotype D HBeAg- Pts • PegBeLiver: higher virologic/serologic response rates observed 1 yr posttreatment in HBeAg-negative pts (94% genotype D) treated with pegIFN alfa-2a for 96 vs 48 wks[1] 1. Lampertico P, et al. EASL 2010. Abstract 98. 2. Lampertico P, et al. AASLD 2010. Abstract 135.

  35. Entecavir in Previously NA-Naive HBV Patients With Partial Virologic Response • PVR: HBV DNA > 80 IU/mL at Wk 48 of therapy but > 1 log IU/mL decrease from baseline • Majority of previously NA-naive pts with PVR and HBV DNA < 1000 IU/mL achieved HBV DNA < 80 IU/mL at Wk 96 without modifying treatment • However, pts with HBV DNA ≥ 1000 IU/mL at Wk 48 did not achieve HBV DNA < 80 IU/mL at Wk 96 except when treatment modified • 1 added tenofovir, 2 switched to tenofovir/emtricitabine Zoutendijk R, et al. AASLD 2010. Abstract 448. Table used with permission.

  36. Rates of HBsAg Loss With Longer Duration of Tenofovir • 192-wk results of Study 103: randomized, double-blind phase III trial TDF-TDF 0.12 ADV-TDF 10.8% 0.10 8.5% 0.08 Switch to open-label TDF Cumulative Probability of HBsAg Loss 0.06 0.04 0.02 0 0 12 24 36 48 64 80 92 108 120 132 144 156 168 180 192 Wks on Study Heathcote EJ, et al. AASLD 2010. Abstract 477. Graphic used with permission.

  37. TDF Monotherapy vs TDF/FTC for HBV Patients Viremic After Adefovir Therapy • At Wk 48, 81% of patients initially given TDF or TDF/FTC had HBV DNA < 400 copies/mL[1] • 13/13 patients with baseline LAM resistance and 9/10 with baseline ADV resistance had HBV DNA < 400 copies/mL at Wk 168 Wk 96 Wk 24* Wk 48 Wk 168 Chronic HBV patients with incomplete suppression on ≥ 6 mos adefovir (N = 105) TDF 300 mg(n = 53) TDF/FTC 300/200 mg(n = 52) *After Wk 24, patients with detectable HBV DNA on TDF could receive open-label TDF/FTC. 1. Berg T, et al. Gastroenterology. 2010;139:1207-1217. 2. Berg T, et al. AASLD 2010. Abstract 136.

  38. Correlates of Severe Liver Disease Outcomes in HBV Patients • Retrospective, longitudinal cohort study of the Kaiser Permanente Medical Care Program of Northern California Viral Hepatitis Registry *Nonsignificant correlations. Manos MM, et al. AASLD 2010. Abstract 175.

  39. Go Online for More CCO Coverage of AASLD 2010! Capsule Summariesof key studies plusExpert Analysespanel discussions exploring the clinical implications Expert Highlights:download mp3 files and listen to our experts review the highlights of this conference clinicaloptions.com/Boston2010

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