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November 9-13, 2012 Boston, Massachusetts

Highlights of AASLD 2012 CCO Official Conference Coverage of the 2012 Annual Meeting of the American Association for the Study of Liver Diseases. November 9-13, 2012 Boston, Massachusetts. In partnership with. This program is supported by educational grants from.

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November 9-13, 2012 Boston, Massachusetts

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  1. Highlights of AASLD 2012CCO Official Conference Coverage of the 2012 Annual Meeting of the American Association for the Study of Liver Diseases November 9-13, 2012Boston, Massachusetts In partnership with This program is supported by educational grants from This program is supported by an educational grant from

  2. About These Slides • 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 Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) DisclaimerThe materials published on the Clinical Care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 Graham R. Foster, FRCP, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Marys University of LondonLondon, United Kingdom Paul Y. Kwo, MDProfessor of MedicineMedical Director of TransplantationDivision of Medicine/Gastroenterology/HepatologyIndiana University School of MedicineIndianapolis, Indiana

  4. Faculty Disclosures Graham R. Foster, FRCP, PhD, has disclosed that he has received consulting fees and fees for non-CME services from BoehringerIngelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Novartis, Roche, and Vertex; and grants for research support from Janssen and Roche. Paul Y. Kwo, MD, has disclosed that he has received consulting fees from Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck, Novartis, and Vertex; fees for non-CME services from Bristol-Myers Squibb, Merck, and Vertex; grants for research support from Abbott, Bristol-Myers Squibb, Gilead Sciences, Merck, Roche, and Vertex.

  5. Hepatitis CCurrent Therapy

  6. OPTIMIZE: Telaprevir BID vs Telaprevir q8h in Tx-Naive Pts With GT1 HCV Infection • Randomized, multicenter, open-label phase III noninferiority trial Stratified by fibrosis status (F0-F2 vs F3-F4), IL28BGT (CC, CT, TT) Wk 12 Wk 24 Wk 48 RVR Follow-up PegIFN/RBV Telaprevir 750 mg q8h + PegIFN/RBV (n = 371) Treatment-naive patients with chronic GT1 HCV infection (N = 740) PegIFN/RBV NoRVR RVR Follow-up PegIFN/RBV Telaprevir 1125 mg BID + PegIFN/RBV (n = 369) PegIFN/RBV NoRVR Buti M, et al. AASLD 2012. Abstract LB-8.

  7. OPTIMIZE: Efficacy of Telaprevir BID vs Telaprevir q8h in GT1 HCV Infection • SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups • Similar safety and tolerability profile in both treatment arms TVR q8h/PR TVR BID/PR 100 92 87 81 78 80 68 68 65 66 59 58 60 SVR12 (%) 40 20 n/N = 92/106 97/105 141/208 139/206 37/57 38/58 209/268 213/264 61/103 61/105 0 CC CT TT F0-2 F3/4 Liver Disease Status IL28B GT Buti M, et al. AASLD 2012. Abstract LB-8. Reproduced with permission.

  8. Retrospective Analysis of TVR in Pts With GT1 HCV and Compensated Cirrhosis • Retrospective study from single liver transplantation clinic • eRVR: 35% (14/40 pts) • EOT response: 75% (6/8 pts) • Reasons for discontinuation • SAE (n = 12) • Lack of viral response (n = 11) • Pt preference (n = 6) • Loss of insurance (n = 2) 100 100 80 72 62 60 Patients (%) 40 22 16 20 50/ 50 36/ 50 31/ 50 11/ 50 8/ 50 n/ N= 0 CompletedTreatment Initiated TVR+ PegIFN/RBV DiscontinuedTreatment On Treatment Completed > 12 Wks of Rx Gallegos-Orozco JF, et al. AASLD 2012. Abstract 53.

  9. N-CORE: 24 vs 48 Wks of PegIFN alfa-2a + RBV in GT2/3 Patients Without RVR • Multicenter, international, randomized, open-label phase IIIb trial Wk 72 Wk 24 Wk 48 Stop therapy; 48-wk follow-up(n = 95) Tx-naive patients with chronic GT2/3 HCV infection who initiated pegIFN/RBV therapy and did not achieve RVR but did achieve EVR(N = 235)* Continue PegIFN/RBV (n = 93) Stop therapy; 24-wk follow-up *47 patients dropped out and did not reach randomization at Wk 24. Cheinquer H, et al. AASLD 2012. Abstract 156.

  10. N-CORE: SVR24 Rates Comparable With 24 or 48 Wks of PegIFN alfa-2a/RBV 100 • Higher incidence of AEs, SAEs, AE-related dose reductions in 48-wk arm 24-wk pegIFN/RBV 80 48-wk pegIFN/RBV 73 63 61 60 54 52 52 SVR24 (%) 40 20 49/ 95 57/ 93 49/ 95 51/ 81 49/ 90 46/ 63 n/N = 0 ITT (n = 188) Per Protocol(n = 176) Study Completer(n = 153) Cheinquer H, et al. AASLD 2012. Abstract 156.Reproduced with permission.

  11. Hepatitis C Current Therapy:Anemia Management

  12. Anemia Management in HCV Pts Treated With BOC: Erythropoietinvs RBV Reduction • Subanalysis within randomized trial of GT1 HCV therapy–naive pts receiving 4 wks of lead-in, then either 44 wks of triple therapy or RGT (24-44 wks)[1,2] Stratified by black vs nonblack, anemia onset ≤ 16 wks vs > 16 wks from initiation of lead-in RBV Dose Reduction (by 200-400 mg/day)(n = 249)† Pts with Hb ≤10 g/dL* during BOC-based therapy(N = 500) Erythropoietin 40,000 IU/wk(n = 251)† • Secondary anemia management with RBV dose reduction, erythropoietin administration, or transfusion, allowed if Hb ≤ 8.5 g/dL • Patients discontinued if Hb ≤ 7.5 g/dL *Baseline Hb requirements: 12-15 g/dL for women, 13-15 g/dL for men. †RBV Dose Reduction included 23 pts with cirrhosis; Erythropoietin included 25 pts with cirrhosis. 1. Poordad F, et al. AASLD 2012. Abstract 154. 2. Lawitz E, et al. AASLD 2012. Abstract 50.

  13. SVR Rates With RBV Dose Reduction or Erythropoietinfor Anemia Management • Similar SVR rates (71%) with both strategies[1,2] • Similar SVR rates regardless of timing of anemia management, number of RBV dose reductions, or lowest RBV dose received • Lower SVR rates if < 50% of per protocol total RBV dose received • Higher SVR rate if anemia management initiated with undetectable HCV RNA[2] 100 86 86 RBV dose reductionErythropoietin 80 71 71 56 56 60 SVR (%) 40 20 178/ 249 178/ 251 111/ 129 107/ 124 67/ 120 71/ 121 n/N = 0 All Pts Undetectable Detectable 1. Poordad F, et al. EASL 2012. Abstract 1419. 2 Poordad F, et al. AASLD 2012. Abstract 154.Reproduced with permission.

  14. SVR Rates With RBV Dose Reduction or Erythropoietinin Cirrhotics • SVR rates similar with each anemia management strategy in both cirrhotic and noncirrhotic patients • Higher proportion of cirrhotic patients received secondary anemia management (44% vs 26%; P = .009) • RBV dose reduction should be primary strategy for managing anemia, but erythropoietin may be strongly considered as secondary treatment *P = .5966 for difference between arms among pts with cirrhosis. Lawitz E, et al. AASLD 2012. Abstract 50.

  15. HCV/HIV-Coinfected Patients

  16. Study 110: Telaprevir + PegIFN/RBV in GT1 HCV Tx-Naive HCV/HIV Coinfection • Multicenter, randomized, double-blind, placebo-controlled phase II trial Wk 60(SVR12) WK 72(SVR24) Wk 12 Wk 48 TVR† 750 mg q8h + PegIFN/RBV PegIFN/RBV(n = 7) Part A: No Current ART HCV/HIV-coinfected patients, CD4+ cell count ≥ 500 cells/mm3,HIV-1 RNA ≤ 100,000 copies/mL (N = 13) Follow-up Placebo +PegIFN/RBV PegIFN/RBV(n = 6) TVR† 750 mg q8h + PegIFN/RBV PegIFN/RBV(n = 31) Part B: Stable ART HCV/HIV-coinfected patients on stable ART,*CD4+ cell count ≥ 300 cells/mm3,HIV-1 RNA ≤ 50 copies/mL (N = 47) Follow-up Placebo +PegIFN/RBV PegIFN/RBV(n = 16) *Either EFV/TDF/FTC or ATV/RTV + TDF + (FTC or 3TC).†TVR dose increased to 1125 mg q8h with EFV. Sulkowski MS, et al. AASLD 2012. Abstract 54.

  17. Study 110: SVR24 With TVR + PegIFN/RBV in HCV GT1/HIV-Coinfected Patients • Higher SVR24 rate with TVR-based therapy • No significant drug–drug interactions with TVR and ART • TVR plasma levels similar in patients with or without ART • EFV and ATV/RTV plasma levels similar in patients with or without TVR • No HIV breakthroughs in patients using ART during HCV treatment • Safety and tolerability similar to treatment in patients with HCV monoinfection Telaprevir + PR 100 Placebo + PR 80 80 74 71 69 60 50 50 SVR24 (%) 45 40 33 20 5/ 7 2/ 6 11/ 16 4/ 8 12/ 15 4/ 8 28/ 38 10/ 22 n/N = 0 No ART EFV-Based ART ATV-Based ART Overall Population Sulkowski MS, et al. AASLD 2012. Abstract 54. Reproduced with permission.

  18. Novel DAAs + PegIFN/RBV

  19. ATOMIC: Sofosbuvir (GS-7977) Plus PR in Treatment-Naive Genotype 1 Patients • Interim analysis of randomized, open-label phase IIb study with sofosbuvir (nucleoside polymerase inhibitor) Wk 24 Wk 12 SOF + PegIFN/RBV(n = 52) Treatment-naive, noncirrhotic patients*(N = 332) SOF + PegIFN/RBV(n = 125) SOF (n = 75) SOF + PegIFN/RBV(n = 155) SOF + RBV(n = 75) *All infected with GT1 HCV, except for 11 patients with GT4 HCV and 5 with GT6 HCV in 24-wk arm of SOF + pegIFN/RBV. Hassanein T, et al. AASLD 2012. Abstract 230.

  20. ATOMIC: Sofosbuvir (GS-7977) Plus PR in Treatment-Naive Genotype 1 Patients • SVR12 in ~ 90% patients with 12 or 24 wks of treatment • High rates of SVR12 in genotype 4/6 with 24 wks of treatment • Sofosbuvir well tolerated up to 24 wks 100 100 100 99 99 98 100 100 91 92 90 82 80 80 SOF + PR 12 wks GT4 HCV (n = 11) GT6 HCV (n = 5) 60 60 HCV RNA < LOD (%) SOF + PR 24 wks 40 40 SOF + PR 12 + 12 wks 20 20 0 0 EOT SVR12 EOT SVR12 • 11 patients (1 in 12-wk group) who attained SVR12 subsequently lost to follow-up • No relapse after SVR12 in any group • 11/11 patients with genotype 4 HCV achieved RVR and EOT response • 2 LTFU without posttreatment data • No relapse after SVR12 in either group Hassanein T, et al. AASLD 2012. Abstract 230.

  21. ELECTRON: Sofosbuvir, GS-5885, and RBV in Noncirrhotic Pts With GT1 HCV • Interim analysis of nonrandomized phase II study with sofosbuvir (nucleoside polymerase inhibitor) ± GS-5885 (NS5A inhibitor) Patients, % Wk 12 SOF + RBV Treatment naive (n = 25) SOF + RBV Null responders (n = 10) SOF + GS-5885 + RBV Treatment naive (n = 25) SOF + GS-5885 + RBV Null responders (n = 9) • No SAEs related to study drugs; AE profile consistent with RBV toxicity profile *Data reported for 3 pts only. Data collection ongoing. Gane EJ, et al. AASLD 2012. Abstract 229.

  22. ELECTRON: Sofosbuvir in Patients With GT2/3 HCV • Interim analysis of nonrandomized phase II study with SOF (nucleoside polymerase inhibitor) ± GS-5885 (NS5A inhibitor) Wk 4 Wk 8 SVR, % Wk 12 100 (SVR24) SOF + PegIFN + RBV (n = 10) 100 (SVR24) SOF + PegIFN + RBV SOF + RBV (n = 10) 100 (SVR24) SOF + PegIFN + RBV SOF + RBV (n = 9) Treatment-naive, GT2/3 HCV(N = 95) 100 (SVR24) SOF + RBV (n = 11) 60 (SVR8) SOF + Reduced-Dose RBV (800 mg/day) (n = 10) 60 (SVR24) SOF (n = 10) 64 (SVR12) SOF + RBV (n = 25) 100 (SVR24) SOF + PegIFN + RBV (n = 10) Treatment-experienced, GT2/3 HCV 68 (SVR12) SOF + RBV (n = 25) Gane EJ, et al. AASLD 2012. Abstract 229. Reproduced with permission.

  23. MATTERHORN: Danoprevir/RTV, Mericitabine, and PegIFN/RBV in GT1 HCV • Randomized, open-label phase II trial of RTV-boosted danoprevir (protease inhibitor), mericitabine (nucleoside polymerase inhibitor), and pegIFN/RBV Wk 24 Wk 48 Danoprevir/RTV + Mericitabine + RBV* (n = 52) Noncirrhotic pts withGT1 HCV and previous partial response to pegIFN/RBV(N = 151) Danoprevir/RTV + PegIFN/RBV (n = 49) Danoprevir/RTV + Mericitabine + PegIFN/RBV (n = 50) Danoprevir/RTV + Mericitabine + RBV* (n = 77) Noncirrhotic pts with GT1 HCV and previous null response to pegIFN/RBV(N = 228) Danoprevir/RTV + Mericitabine+ PegIFN/RBV (n = 77) Danoprevir/RTV + Mericitabine+ PegIFN/RBV (n = 74) PegIFN/RBV *GT1a HCV pts added pegIFN/RBV due to high relapse rates and are excluded from this analysis. Feld JJ, et al. AASLD 2012. Abstract 81.

  24. MATTERHORN: Response to DNV/RTV, MCB, and PegIFN/RBV in GT1 HCV • Response rates highest with 4-drug therapy and lowest with pegIFN-free therapy in both cohorts • Higher response with pegIFN-containing regimens in GT1b vs 1a • Less relapse with addition of MCB • All regimens generally well tolerated • 3 potentially treatment-related SAEs • 5 discontinuations due to AEs DNV/RTV + MCB + RBV DNV/RTV + pegIFN/RBV DNV/RTV + MCB + pegIFN/RBV Prior Partial Response Prior Null Response GT1b GT1a 96 100 94 94 96 100 88 87 100 86 91 84 80 75 80 73 55 56 60 60 Response (%) 39 SVR12 (%) 40 40 30 20 20 20/ 23 46/ 49 47/ 50 9/ 23 27/ 48 43/ 50 28/ 32 73/ 76 17/ 31 62/ 74 19/ 21 25/ 26 30/ 30 8/ 27 18/ 24 32/ 44 n/N = n/N = 0 0 EOT SVR12 EOT SVR12 Partial Partial Null Partial Null Partial Feld JJ, et al. AASLD 2012. Abstract 81.Reproduced with permission.

  25. Daclatasvir and Asunaprevir in GT1 HCV Previous Null Responders • AI447-011: randomized, open-label phase IIa study with daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) Wk 24 Daclatasvir 60 mg QD + Asunaprevir 200 mg BID* (n = 18) Daclatasvir 60 mg QD + Asunaprevir 200 mg QD* (n = 20) Noncirrhotic pts with GT1 HCV and previous null response to pegIFN/RBV(N = 101) Daclatasvir 60 mg QD + Asunaprevir 200 mg BID + PegIFN/RBV (n = 20) Daclatasvir 60 mg QD + Asunaprevir 200 mg QD + PegIFN/RBV (n = 21) Daclatasvir 60 mg QD + Asunaprevir 200 mg BID + RBV (n = 22) *Only pts with GT1b HCV included in dual-therapy arms. Lok AS, et al. AASLD 2012. Abstract 79.

  26. Outcomes With Daclatasvir + Asunaprevir ± PegIFN or RBV in Null Responders • High response rates with 4-drug regimen of DCV + ASV + pegIFN/RBV • Lower response rates with 2-drug regimen (all GT1b pts) • Better response with ASV 200 mg BID vs ASV 200 mg QD • SVR data from 3-drug arm not reported due to high rate of virologic breakthrough in GT1a but not in GT1b • 10 GT1a pts with virologic breakthrough • All triple-therapy pts offered pegIFN • No virologic breakthrough with addition of pegIFN • Virologic breakthrough in 8 pts in 2-drug arms but none in 4-drug arm • 3 relapses • 1 with DCV + ASV QD • 2 with DCV + ASV + PR • All regimens generally well tolerated, with no discontinuations due to toxicity DCV + ASV (BID) + PR DCV + ASV (QD) + PR DCV + ASV (BID) DCV + ASV (QD) 100 100 95 100 90 89 78 80 70 65 60 HCV RNA < LLOQ (%) 40 20 20/ 20 21/ 21 18/ 20 20/ 21 16/ 18 14/ 20 14/ 18 13/ 20 n/N = 0 EOT SVR24 EOT SVR12 Lok AS, et al. AASLD 2012. Abstract 79.

  27. PILLAR/ASPIRE: Simeprevir + PegIFN/RBV in Pts With GT1 HCV, F3/4 Fibrosis • Subanalysis of randomized, placebo-controlled phase IIb trials of simeprevir (protease inhibitor) • Relatively high SVR24 rates in pts with advanced fibrosis • In ASPIRE, 4/13 (31%) F4 null responders achieved SVR24 Placebo + PR Simeprevir 150 mg QD + PR SVR24 by METAVIR Score SVR24 by Prior IFN Response in Pts With F3/F4 100 100 79 80 80 71 67 65 62 56 60 60 SVR24 (%) SVR24 (%) 33 10 40 40 4 20 20 5/ 7 15/ 19 38/ 68 0/ 10 24/ 39 0/ 10 17/ 26 14/ 21 0/ 3 7/ 21 1/ 23 1/ 10 n/N = n/N = 0 0 PILLAR Naive, F3 ASPIRE Tx Exp’d, F3 + F4 ASPIRE Tx Exp’d,F4 Only Relapser Partial Responder Null Responder Poordad F, et al. AASLD 2012. Abstract 83.Reproduced with permission.

  28. Novel DAAs + Ribavirin Interferon-Free Regimens

  29. AVIATOR: IFN-Free Regimens With ABT-450/RTV, ABT-267, ABT-333, and RBV • Interim analysis of randomized, open-label, phase II study with RTV-boosted ABT-450 (protease inhibitor), ABT-267 (NS5A inhibitor), and ABT-333 (nonnucleoside polymerase inhibitor) Wk 24 Wk 8 Wk 12 ABT-450/RTV 150/100 mg QD + ABT-267 + ABT-333 + RBV (n = 80) ABT-450/RTV 150/100 mg QD +ABT-333 + RBV (n = 41) Cohort 1: Treatment-naive GT1 HCV pts (N = 438) ABT-450/RTV 100/100 mg QD or 200/100 mg QD + ABT-267 + RBV (n = 79) ABT-450/RTV 150/100 mg QD +ABT-267 + ABT-333 (n = 79) ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT-267 + ABT-333 + RBV (n = 79) ABT-450/RTV 100/100 mg QD or 150/100 mg QD +ABT-267 + ABT-333 + RBV (n = 80) Kowdley KV, et al. AASLD 2012. Abstract LB-1.

  30. AVIATOR: IFN-Free Regimens With ABT-450/RTV, ABT-267, ABT-333, and RBV • Interim analysis of randomized, open-label, phase II study with RTV-boosted ABT-450 (protease inhibitor), ABT-267 (NS5A inhibitor), and ABT-333 (nonnucleoside polymerase inhibitor) Wk 12 Wk 24 ABT-450/RTV 200/100 mg QD +ABT-267 + RBV (n = 45) Cohort 2: Treatment-exp’d GT1 HCV pts with previous null response(N = 133) ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT-267 + ABT-333 + RBV (n = 45) ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT-267 + ABT-333 + RBV(n = 43) Kowdley KV, et al. AASLD 2012. Abstract LB-1.

  31. AVIATOR: SVR12 Rates With ABT-450/RTV, ABT-267, ABT-333, and RBV • SVR12 rates higher in pts with GT1b HCV but also high in pts with GT1a HCV • 12-wk regimen with all 3 DAAs + RBV produced highest SVR12 rates • No drug-related SAEs reported; 2 pts discontinued tx due to drug-related AEs Treatment-Naive Patients Null Responders 100 100 100 100 100 100 100 98 Observed data (above bar) 96 80 89 88 88 86 81 100 100 100 82 100 100 96 96 96 60 89 ITT (within bar) 85 84 83 81 SVR12 (%) 79 40 20 0 56 24 29 12 52 27 52 25 54 25 26 18 28 17 n = 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b ABT-450ABT-267ABT-333RBV ABT-450ABT-333RBV ABT-450ABT-267RBV ABT-450ABT-267ABT-333 ABT-450ABT-267ABT-333RBV ABT-450ABT-267RBV ABT-450ABT-267ABT-333RBV 8 wks 12 wks 12 wks Kowdley KV, et al. AASLD 2012. Abstract LB-1.Reproduced with permission.

  32. Daclatasvir + Sofosbuvir ± RBV in Treatment-Naive Patients With GT1-3 HCV AI444-040: interim analysis of randomized, open-label phase IIa trial of daclatasvir (NS5A inhibitor) and sofosbuvir (nucleotide polymerase inhibitor) Wk 1 Wk 12 Wk 24 SOF SOF + DCV (n = 15) SOF + DCV (n = 14) Treatment-naive noncirrhotic patients with GT1 HCV (N = 126) SOF + DCV + RBV (n = 15) SOF + DCV (n = 41) SOF + DCV + RBV (n = 41) SOF SOF + DCV (n = 16) Treatment-naive noncirrhotic patients with GT2/3 HCV (N = 44) SOF + DCV (n = 14) SOF + DCV+ RBV (n = 14) Sulkowski MS, et al. AASLD 2012. Abstract LB-2.

  33. SVR Rates With 12 or 24 Wks of Daclatasvir + Sofosbuvir ± RBV • Similar high SVR4 rates with 12-wk regimens • SVR12 in all 68 pts who have reached time point • Very high SVR24 rates with all 24-wk regimens across genotypes GT1 GT2/3 100 100 100 100 100 100 100 100 100 100 98 95 100 100 94 93 93 88 80 80 60 60 HCV RNA < LLOQ (%) 40 40 20 20 0 0 EOT* SVR24 EOT* SVR24 EOT* SVR4 SOF + DCV (12 wk) SOF LI + DCV SOF + DCV SOF + DCV + RBV SOF + DCV + RBV (12 wk) *EOT includes pts who discontinued early, with last visit considered EOT. Sulkowski MS, et al. AASLD 2012. Abstract LB-2.

  34. NIH SPARE: Interim Data on Sofosbuvir and RBV in Difficult-to-Treat GT1 Pts • Subjects primarily GT1a (70%), male (63%), black (83%), IL28B CT/TT (80%) • BMI > 30: 48%; advanced liver disease: 23%; HCV RNA > 800,000 IU/mL: 62% Viral Response, % Wk 24 Part 1 (early-stage fibrosis) EOT SVR4 SVR12 Sofosbuvir400 mg + RBV 1000/1200 mg (n = 10) 90 90 Part 2 (all stages of fibrosis) Sofosbuvir 400 mg + RBV 600 mg(n = 25) 88 56 Sofosbuvir 400 mg + RBV 1000/1200 mg (n = 25) 72 96 • In viral kinetic study involving 10 low-dose and 15 full-dose RBV subjects, HCV RNA decrease was rapid with median HCV RNA reduction of 4.14 log10 IU/mL by Day 7 • Both regimens well tolerated and resulted in significant improvement of hepatic inflammation (P < .0001) Osinusi A, et al. AASLD 2012. Abstract LB-4.

  35. ZENITH: VX-222 + Telaprevir + RBV in Tx-Naive Pts With GT1a or GT1b HCV • Interim analysis of triple-therapy arm of randomized phase II study with VX-222 (nonnucleoside polymerase inhibitor) and BID telaprevir[1] • Previous report demonstrated high rate of virologic breakthrough with dual therapy (VX-222 + TVR), but 4-drug therapy (VX-222 + TVR + pegIFN/RBV) associated with SVR12 rates of 83% to 90% with no virologic breakthrough[2] Wk 12 Wk 36 End treatment if HCV RNAundetectable at Wks 2 and 8 (n = 6) VX-222 400 mg BID + Telaprevir 1125 mg BID + RBV(n = 23) Tx-naive noncirrhotic pts with GT1a HCV PegIFN/RBV for 24 wks if HCV RNA detectable at Wk 2 or 8 (n = 14*) End treatment if HCV RNAundetectable at Wks 2 and 8 (n = 5) VX-222 400 mg BID + Telaprevir 1125 mg BID + RBV(n = 23) Tx-naive noncirrhotic pts with GT1b HCV PegIFN/RBV for 24 wks if HCV RNA detectable at Wk 2 or 8 (n = 13*) *3 pts in the GT1a arm and 5 pts in the GT1b arm discontinued treatment at or before Wk 12. 1. Jacobson IM, et al. AASLD 2012. Abstract 231. 2. Di Bisceglie A, et al. EASL 2011. Abstract 1363.

  36. ZENITH: Response to VX-222 + TVR + RBV in Patients With GT1a and GT1b HCV • Comparable SVR12 rates in GT 1a and 1b • No SAEs; safety and tolerability better than previously observed with 4-drug regimen (with pegIFN) Jacobson IM, et al. AASLD 2012. Abstract 231.

  37. SOUND-C2: Faldaprevir + BI 207127 ± RBV in Tx-Naive Pts With GT1 HCV • Randomized, open-label phase IIb trial of faldaprevir (NS3/4A protease inhibitor) with BI 207127 (nonnucleoside polymerase inhibitor) Wk 16 Wk 40 Wk 28 Stratified by HCV subgenotype and IL28B genotype Faldaprevir 120 mg QD + BI 207127 600 mg TID + RBV (n = 81) Faldaprevir 120 mg QD + BI 207127 600 mg TID + RBV (n = 80) Tx-naive pts with GT1 HCV(N = 362) Faldaprevir 120 mg QD + BI 207127 600 mg TID + RBV (n = 77) Faldaprevir 120 mg QD + BI 207127 600 mg BID + RBV (n = 78) Faldaprevir 120 mg QD + BI 207127 600 mg TID, no RBV (n = 46) Randomization to this arm stopped early due to FDA concerns regarding lack of RBV Zeuzem S, et al. AASLD 2012. Abstract 232.

  38. SOUND-C2: Final Efficacy Analysis of Faldaprevir + BI 207127 ± RBV in GT1 HCV • Higher SVR in pts with GT1b HCV and in pts with IL28B genotype CC • Favorable safety/tolerability with low rate of discontinuation with BID dosing GT 1a Non-CC GT 1b CC PP ITT 100 100 100 85 84 75 80 80 80 72 69 69 69 67 67 66 64 63 58 57 57 56 60 55 60 69 60 48 47 59 59 44 44 SVR12 (%) 43 52 38 40 40 40 33 39 20 20 20 11 0 0 0 ITTn/N = 34/60 14/21 32/58 14/21 28/58 12/19 38/59 16/19 11/33 7/12 ITTn/N = 13/34 35/47 14/32 33/48 16/34 24/43 13/30 41/48 2/18 16/28 PPn/N = 48/73 47/68 40/58 54/75 18/41 TID16 + TID28 + TID40+ BID28 + TID28 ‒ TID16 + TID28 + TID40+ BID28 + TID28 ‒ BI 207127 dosingDuration (wks)RBV TID16 + TID28 + TID40+ BID28 + TID28 ‒ Zeuzem S, et al. AASLD 2012. Abstract 232.Reproduced with permission.

  39. SOUND-C2 Subanalysis: Efficacy of Treatment in Patients With Cirrhosis • Among 33 cirrhotic patients, outcomes with faldaprevir + BI 207217 + RBV similar to noncirrhotic patients • SVR12 rates higher in GT1b vs GT1a HCV • Higher rate of discontinuations and SAEs with TID dosing GT1a GT1b Cirrhosis No cirrhosis 100 100 86 80 80 80 70 68 67 60 57 57 60 60 52 50 43 43 42 SVR12 (%) SVR12 (%) 40 33 40 40 33 11 2/ 18 20 20 124/217 17/43 11/21 6/ 9 48/69 1/ 3 3/ 7 8/ 14 2/ 4 4/ 5 0/ 0 1/ 3 40/93 84/124 11/26 37/43 15/25 n/ N = n/ N = 0 0 Cirrhosis No Cirrhosis BI 207127 Dosing Duration (wks) RBV TID16, 28, 40+ BID28+ TID28- TID16, 28, 40+ BID28+ TID28- TID16, 28, 40+ BID28+ TID28- Soriano V, et al. AASLD 2012. Abstract 84. Reproduced with permission.

  40. Interferon- and Ribavirin-Free Regimens

  41. Daclatasvir, Asunaprevir, and BMS-791325 in Treatment-Naive Patients With GT1 HCV • Interim analysis of Part 1 of AI443-014: randomized, open-label, phase IIa study with daclatasvir (NS5A inhibitor), asunaprevir (NS3 protease inhibitor), and BMS-791325 (nonnucleoside polymerase inhibitor) Stratification by HCV subgenotype (1a vs 1b) Wk 12 Wk 24 Daclatasvir 60 mg QD + Asunaprevir 200 mg BID + BMS-791325 75 mg BID (n = 16) Treatment-naive noncirrhotic pts with GT1 HCV(N = 32) Daclatasvir 60 mg QD + Asunaprevir 200 mg BID + BMS-791325 75 mg BID (n = 16) Everson GT, et al. AASLD 2012. Abstract LB-3.

  42. Response to Daclatasvir, Asunaprevir, and BMS-791325 in Modified ITT Analysis • Both regimens generally well tolerated, with no discontinuations due to AEs • Infrequent SAEs, grade 3/4 AEs, or grade 3/4 lab abnormalities 24-Wk Treatment(n = 16) 12-Wk Treatment(n = 16) HCV RNA < LLOQTD or TND Missing data 100 94 94 100 88 100 94 94 94 100 100 80 80 60 60 HCV RNA < LLOQTD or TND (%) HCV RNA < LLOQTD or TND (%) 40 40 20 20 0 0 Wk 4 Wk 12 EOT SVR4 Wk 4 Wk 12 EOT SVR4 SVR12 Everson GT, et al. AASLD 2012. Abstract LB-3.Reproduced with permission.

  43. New Peginterferons

  44. D-LITE: PegIFN lambda-1a + RBV + Daclatasvir or Asunaprevir in GT1 HCV • Interim analysis of randomized, double-blind phase IIb study with pegIFN lamba-1a (a type III IFN) plus daclatasvir (NS5A inhibitor), asunaprevir (NS3 protease inhibitor) Wk 24 Wk 48 Stratified by HCV GT1 subgenotype, IL28B genotype Daclatasvir 60 mg QD + PegIFN lambda-1a 180 µg SC QW + RBV (n = 41) PDR: follow-up No PDR*: PegIFN lambda-1a/RBV Asunaprevir 200 mg BID + PegIFN lambda-1a 180 µg SC QW + RBV (n = 38) Tx-naive pts with GT1 HCV(N = 119) PDR: follow-up No PDR*: PegIFN lambda-1a/RBV PegIFN alfa-2a 180 µg SC QW + RBV (n = 40) *PDR: HCV RNA < LLOQ (-TD or -TND) at Wk 4, < LLOQ-TND at Wk 12. Vierling JM, et al. AASLD 2012. Abstract LB-9.

  45. D-LITE: Virologic Outcomes in Patients With Protocol-Defined Response • Most patients achieved PDR, qualified for shortened therapy • Higher SVR12 rates in GT1b HCV, but high response rates regardless of IL28B genotype *6 IL28B CC; †5 IL28B CC. Vierling JM, et al. AASLD 2012. Abstract LB-9.

  46. D-LITE: Substudy in Japanese Patients With GT1 HCV • In small Japanese substudy, 100% SVR4 rates in both arms • In asunaprevir arm, the 1 patient without PDR discontinued due to AE at Wk 3 • Daclatasvir arm better tolerated than asunaprevir arm • 1 SAE in asunaprevir arm • More grade 3/4 AEs with asunaprevir (80% vs 13%) • More grade 3/4 lab abnormalities with asunaprevir PegIFN lambda-1a + RBV + daclatasvirPegIFN lambda-1a + RBV + asunaprevir Virologic Response 100 100 100 100 100 100 83 80 60 Patients (%) 40 20 8/8 5/6 8/8 5/5 8/ 8 5/5 n/ N = 0 PDR EOTR SVR4 PDR+ Only Izumi N, et al. AASLD 2012. Abstract 234.

  47. Hepatitis B Treatment

  48. Response-Guided PegIFN-Based Therapy in HBeAg-Positive Patients • Pooled analysis of 3 global randomized studies (N = 803)[1] • Phase III study of pegIFN[2] • HBV 99-01 study[3] • Neptune study[4] • Response observed in • 23% with HBeAg loss with HBV DNA < 2000 IU/mL (n = 182) • 5% with HBsAg loss at 6 mos posttreatment (n = 39) • HBsAg levels at Wks 12 and 24 predicted response to therapy • HBV genotypic–specific stopping rules proposed • Low response rates if HBsAg > 20,000 IU/mL at Wk 24 in all genotypes 1. Sonneveld MJ, et al. AASLD 2012. Abstract 23. 2. Lau GK, et al. N Engl J Med. 2005;352:2682-2695.3. Janssen HL, et al. Lancet. 2005;365:123-129. 4. Liaw YF, et al. Hepatology. 2011;54:1591-1599.

  49. HBsAg Decline During PegIFN Therapy Varies According to HBV Genotype • HBsAg decline differed by HBV genotype • Sustained HBsAg decrease seen in pts with response to pegIFN but typically not in nonresponders • Wk 24 HBsAg level predicted response at 6 mos posttreatment, regardless of genotype 0.0 GT D (n = 110) -0.5 GT C (n = 386) HBsAg Decline (log IU/mL) -1.0 GT B (n = 205) -1.5 GT A (n = 103) PegIFN therapy -2.0 BL 12 24 EOT EOF Wks Sonneveld MJ, et al. AASLD 2012. Abstract 23.Reproduced with permission.

  50. Go Online for More CCO Coverage of AASLD 2012! Capsule Summariesof all the key data Expert Analysispanel discussion exploring the clinical implications Downloadable Slideset: download your own copy of this slideset clinicaloptions.com/boston2012

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