Highlights of AASLD 2012 CCO Official Conference Coverage of the 2012 Annual Meeting of the American Association for the Study of Liver Diseases

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1 Highlights of AASLD 12 CCO Official Conference Coverage of the 12 Annual Meeting of the American Association for the Study of Liver Diseases November 9-13, 12 Boston, 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 Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options ( Disclaimer The materials published on the Clinical Care Options Web site reflect the views of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, PhD Professor of Hepatology The Liver Unit Consultant Hepatologist Queen Marys University of London London, United Kingdom Paul Y. Kwo, MD Professor of Medicine Medical Director of Transplantation Division of Medicine/Gastroenterology/Hepatology Indiana University School of Medicine Indianapolis, Indiana

4 Faculty Disclosures Graham R. Foster, FRCP, PhD, has disclosed that he has received consulting fees and fees for non-cme services from Boehringer Ingelheim, 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 C Current 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), IL28B GT (CC, CT, TT) Wk 12 Wk 24 Wk 48 Treatmentnaive patients with chronic GT1 HCV infection (N = 7) Telaprevir 750 mg q8h + PegIFN/RBV (n = 371) Telaprevir 1125 mg BID + PegIFN/RBV (n = 369) PegIFN/RBV PegIFN/RBV RVR No RVR RVR No RVR Follow-up PegIFN/RBV Follow-up PegIFN/RBV Buti M, et al. AASLD 12. 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 SVR12 (%) TVR q8h/pr TVR BID/PR n/ N = 92/ / / 8 139/ 6 37/ 57 CC CT TT 38/ 58 9/ / / / 105 F0-2 F3/4 IL28B GT Liver Disease Status Buti M, et al. AASLD 12. 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/ 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) Patients (%) n/ N= 0 50/ / / / / 50 Gallegos-Orozco JF, et al. AASLD 12. 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 24 Wk 48 Wk 72 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; 48-wk follow-up (n = 95) Stop therapy; 24-wk follow-up *47 patients dropped out and did not reach randomization at Wk 24. Cheinquer H, et al. AASLD 12. Abstract 156.

10 N-CORE: SVR24 Rates Comparable With 24 or 48 Wks of PegIFN alfa-2a/rbv SVR24 (%) wk pegifn/rbv 48-wk pegifn/rbv n/n = 0 49/ 95 57/ 93 ITT (n = 188) 49/ 95 51/ 81 Per Protocol (n = 176) 49/ 90 Odds Ratio % CI P Value / 63 Study Completer (n = 153) Higher incidence of AEs, SAEs, AE-related dose reductions in 48-wk arm Cheinquer H, et al. AASLD 12. Abstract 156. Reproduced with permission.

11 Hepatitis C Current Therapy: Anemia Management

12 Anemia Management in HCV Pts Treated With BOC: Erythropoietin vs 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 0-0 mg/day) Pts with Hb 10 g/dl* (n = 249) during BOC-based therapy (N = 500) Erythropoietin,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: g/dl for women, g/dl for men. RBV Dose Reduction included 23 pts with cirrhosis; Erythropoietin included 25 pts with cirrhosis. 1. Poordad F, et al. AASLD 12. Abstract Lawitz E, et al. AASLD 12. Abstract 50.

13 SVR Rates With RBV Dose Reduction or Erythropoietin for 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] RBV dose reduction Erythropoietin SVR (%) n/n = 0 178/ / / 129 All Pts Undetectable Detectable 1. Poordad F, et al. EASL 12. Abstract Poordad F, et al. AASLD 12. Abstract 154. Reproduced with permission. 107/ / 1 71/ 121

14 SVR Rates With RBV Dose Reduction or Erythropoietin in 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 SVR, % (n/n) Noncirrhotic (n = 438) Cirrhotic (n = 48) RBV dose reduction 73 (162/221) 57 (13/23)* Erythropoietin 72 (157/217) 64 (16/25)* *P =.5966 for difference between arms among pts with cirrhosis. Lawitz E, et al. AASLD 12. 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 12 Wk 48 Wk 60 (SVR12) WK 72 (SVR24) Part A: No Current ART HCV/HIV-coinfected patients, CD4+ cell count 500 cells/mm 3, HIV-1 RNA,000 copies/ml (N = 13) TVR 750 mg q8h + PegIFN/ RBV Placebo + PegIFN/RBV PegIFN/RBV (n = 7) PegIFN/RBV (n = 6) Follow-up Part B: Stable ART HCV/HIV-coinfected patients on stable ART,* CD4+ cell count 300 cells/mm 3, HIV-1 RNA 50 copies/ml (N = 47) TVR 750 mg q8h + PegIFN/ RBV Placebo + PegIFN/RBV PegIFN/RBV (n = 31) PegIFN/RBV (n = 16) Follow-up *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 12. Abstract 54.

17 SVR24 (%) Highlights of AASLD 12 Study 110: SVR24 With TVR + PegIFN/RBV in HCV GT1/HIV-Coinfected Patients n/n = 0 Higher SVR24 rate with TVR-based therapy / 38 10/ 22 5/ / 6 11/ 16 Telaprevir + PR Placebo + PR / 8 12/ 15 4/ 8 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 Sulkowski MS, et al. AASLD 12. 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 12 Wk 24 SOF + PegIFN/RBV (n = 52) Treatmentnaive, noncirrhotic patients* (N = 332) SOF + PegIFN/RBV (n = 155) SOF + PegIFN/RBV (n = 125) SOF (n = 75) 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 12. 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 HCV RNA < LOD (%) EOT SVR12 SOF + PR 12 wks SOF + PR 24 wks SOF + PR wks EOT SVR12 GT4 HCV (n = 11) GT6 HCV (n = 5) 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 12. 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) Wk 12 Patients, % EOT SVR4 SVR12 Treatment naive (n = 25) Null responders (n = 10) SOF + RBV SOF + RBV Treatment naive (n = 25) Null responders (n = 9) SOF + GS RBV SOF + GS RBV * 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 12. 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 Wk 12 SVR, % (n = 10) SOF + PegIFN + RBV (SVR24) (n = 10) SOF + PegIFN + RBV SOF + RBV (SVR24) Treatment-naive, GT2/3 HCV (N = 95) (n = 9) (n = 11) (n = 10) SOF + PegIFN + RBV SOF + RBV SOF + RBV SOF + Reduced-Dose RBV (800 mg/day) (SVR24) (SVR24) 60 (SVR8) (n = 10) SOF 60 (SVR24) (n = 25) SOF + RBV 64 (SVR12) Treatmentexperienced, GT2/3 HCV (n = 10) (n = 25) SOF + PegIFN + RBV SOF + RBV (SVR24) 68 (SVR12) Gane EJ, et al. AASLD 12. 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 Noncirrhotic pts with GT1 HCV and previous partial response to pegifn/ RBV (N = 151) Danoprevir/RTV + Mericitabine + RBV* (n = 52) Danoprevir/RTV + PegIFN/RBV (n = 49) Danoprevir/RTV + Mericitabine + PegIFN/RBV (n = 50) Noncirrhotic pts with GT1 HCV and previous null response to pegifn/rbv (N = 228) Danoprevir/RTV + Mericitabine + RBV* (n = 77) 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 12. 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 DNV/RTV + MCB + RBV DNV/RTV + pegifn/rbv All regimens generally well tolerated 3 potentially treatment-related SAEs DNV/RTV + MCB + pegifn/rbv 5 discontinuations due to AEs Prior Partial Response Prior Null Response GT1b GT1a Response (%) n/n = / 23 46/ 49 EOT 47/ / / / / 32 73/ / / 74 SVR12 EOT SVR12 SVR12 (%) n/n = / / 26 30/ / / 24 32/ 44 Feld JJ, et al. AASLD 12. Abstract 81. Reproduced with permission.

25 Daclatasvir and Asunaprevir in GT1 HCV Previous Null Responders AI : randomized, open-label phase IIa study with daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) Noncirrhotic pts with GT1 HCV and previous null response to pegifn/rbv (N = 101) Lok AS, et al. AASLD 12. Abstract 79. Daclatasvir 60 mg QD + Asunaprevir 0 mg BID* (n = 18) Daclatasvir 60 mg QD + Asunaprevir 0 mg QD* (n = ) Daclatasvir 60 mg QD + Asunaprevir 0 mg BID + PegIFN/RBV (n = ) Daclatasvir 60 mg QD + Asunaprevir 0 mg QD + PegIFN/RBV (n = 21) Daclatasvir 60 mg QD + Asunaprevir 0 mg BID + RBV (n = 22) *Only pts with GT1b HCV included in dual-therapy arms. Wk 24

26 Outcomes With Daclatasvir + Asunaprevir ± PegIFN or RBV in Null Responders HCV RNA < LLOQ (%) n/n = 0 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 0 mg BID vs ASV 0 mg QD DCV + ASV (BID) + PR DCV + ASV (QD) + PR DCV + ASV (BID) 95 DCV + ASV (QD) / 21/ 21 EOT 90 18/ / 21 Lok AS, et al. AASLD 12. Abstract / / 78 14/ 18 SVR24 EOT SVR / 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

27 PILLAR/ASPIRE: Simeprevir + PegIFN/RBV in Pts With GT1 HCV, F3/4 Fibrosis SVR24 (%) 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 71 SVR24 by METAVIR Score Placebo + PR Simeprevir 150 mg QD + PR 4 5/ 15/ 1/ 38/ 0/ 24/ n/n = n/n = 0 0 PILLAR ASPIRE ASPIRE Tx Relapser Naive, F3 Tx Exp d, Exp d, F3 + F4 F4 Only Poordad F, et al. AASLD 12. Abstract 83. Reproduced with permission. 62 SVR24 (%) SVR24 by Prior IFN Response in Pts With F3/F4 0/ / / / 21 Partial Responder 0/ / 21 Null Responder

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 8 Wk 12 Wk 24 ABT-450/RTV 150/ mg QD + ABT ABT RBV (n = 80) ABT-450/RTV 150/ mg QD + ABT RBV (n = 41) Cohort 1: Treatment-naive GT1 HCV pts (N = 438) ABT-450/RTV / mg QD or 0/ mg QD + ABT RBV (n = 79) ABT-450/RTV 150/ mg QD + ABT ABT-333 (n = 79) Kowdley KV, et al. AASLD 12. Abstract LB-1. ABT-450/RTV / mg QD or 150/ mg QD + ABT ABT RBV (n = 79) ABT-450/RTV / mg QD or 150/ mg QD + ABT ABT RBV (n = 80)

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 RTVboosted ABT-450 (protease inhibitor), ABT-267 (NS5A inhibitor), and ABT-333 (nonnucleoside polymerase inhibitor) Wk 12 Wk 24 Cohort 2: Treatment-exp d GT1 HCV pts with previous null response (N = 133) ABT-450/RTV 0/ mg QD + ABT RBV (n = 45) ABT-450/RTV / mg QD or 150/ mg QD + ABT ABT RBV (n = 45) ABT-450/RTV / mg QD or 150/ mg QD + ABT ABT RBV (n = 43) Kowdley KV, et al. AASLD 12. 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 SVR12 (%) n = a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 89 Observed data (above bar) ITT (within bar) ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 ABT-450 ABT-267 ABT-333 RBV ABT-450 ABT-267 RBV ABT-450 ABT-267 ABT-333 RBV 8 wks 12 wks 12 wks Kowdley KV, et al. AASLD 12. Abstract LB-1. Reproduced with permission.

32 Daclatasvir + Sofosbuvir ± RBV in Treatment-Naive Patients With GT1-3 HCV AI444-0: 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) Treatment-naive noncirrhotic patients with GT1 HCV (N = 126) SOF + DCV (n = 41) SOF + DCV (n = 14) SOF + DCV + RBV (n = 15) SOF + DCV + RBV (n = 41) Treatment-naive noncirrhotic patients with GT2/3 HCV (N = 44) SOF SOF + DCV (n = 16) SOF + DCV (n = 14) SOF + DCV+ RBV (n = 14) Sulkowski MS, et al. AASLD 12. Abstract LB-2.

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

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% Part 1 (early-stage fibrosis) Wk 24 Viral Response, % EOT SVR4 SVR12 Sofosbuvir 0 mg + RBV 0/10 mg (n = 10) Part 2 (all stages of fibrosis) Sofosbuvir 0 mg + RBV 600 mg (n = 25) Sofosbuvir 0 mg + RBV 0/10 mg (n = 25) 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 log 10 IU/mL by Day 7 Both regimens well tolerated and resulted in significant improvement of hepatic inflammation (P <.0001) Osinusi A, et al. AASLD 12. Abstract LB-4.

35 ZENITH: VX 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 TVR), but 4-drug therapy (VX TVR + pegifn/rbv) associated with SVR12 rates of 83% to 90% with no virologic breakthrough [2] Wk 12 Wk 36 Tx-naive noncirrhotic pts with GT1a HCV VX mg BID + Telaprevir 1125 mg BID + RBV (n = 23) End treatment if HCV RNA undetectable at Wks 2 and 8 (n = 6) PegIFN/RBV for 24 wks if HCV RNA detectable at Wk 2 or 8 (n = 14*) Tx-naive noncirrhotic pts with GT1b HCV VX mg BID + Telaprevir 1125 mg BID + RBV (n = 23) End treatment if HCV RNA undetectable at Wks 2 and 8 (n = 5) 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 Jacobson IM, et al. AASLD 12. Abstract Di Bisceglie A, et al. EASL 11. Abstract 1363.

36 ZENITH: Response to VX 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) Virologic Outcome, % (n/n) Jacobson IM, et al. AASLD 12. Abstract 231. VX TVR + RBV in GT1b (n = 23) VX TVR + RBV in GT 1a (n = 23) SVR12 70 (16/23) 73 (17/23) SVR12 with no pegifn/rbv add on (5/5) 67 (4/6) SVR12 with pegifn/rbv add on (48 wks) 85 (11/13) 93 (13/14) HCV RNA < 25 IU/mL Wk 4 (RVR) 91 (21/23) 91 (21/23) Wk 12 (cevr) 83 (19/23) 83 (19/23) Wks 2 and 8 83 (19/23) 65 (15/23) HCV RNA undetectable Wk 4 (RVR) 91 (21/23) 57 (13/23) Wk 12 (cevr) 83 (19/23) 83 (19/23) Wks 2 and 8 22 (5/23) 26 (6/23)

37 SOUND-C2: Faldaprevir + BI 7127 ± RBV in Tx-Naive Pts With GT1 HCV Randomized, open-label phase IIb trial of faldaprevir (NS3/4A protease inhibitor) with BI 7127 (nonnucleoside polymerase inhibitor) Stratified by HCV subgenotype and IL28B genotype Tx-naive pts with GT1 HCV (N = 362) Zeuzem S, et al. AASLD 12. Abstract 232. Faldaprevir 1 mg QD + BI mg TID + RBV (n = 81) Wk 16 Faldaprevir 1 mg QD + BI mg TID + RBV (n = 80) Faldaprevir 1 mg QD + BI mg TID + RBV (n = 77) Faldaprevir 1 mg QD + BI mg BID + RBV (n = 78) Faldaprevir 1 mg QD + BI mg TID, no RBV (n = 46) Wk 28 Wk Randomization to this arm stopped early due to FDA concerns regarding lack of RBV

38 SOUND-C2: Final Efficacy Analysis of Faldaprevir + BI 7127 ± 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 SVR12 (%) PP ITT GT 1a GT 1b Non-CC CC PP n/n = 48/ 73 47/ 68 / 58 54/ 75 18/ 41 0 ITT n/n = 13/ 34 35/ 47 14/ 32 33/ 48 16/ 34 24/ 43 13/ 30 41/ 48 2/ 18 16/ 28 0 ITT n/n = 34/ 60 14/ 21 32/ 58 14/ 21 28/ 58 12/ 19 38/ 59 16/ 19 11/ / BI 7127 dosing Duration (wks) RBV TID 16 + TID 28 + TID + BID 28 + TID 28 TID 16 + TID 28 + TID + BID 28 + TID 28 TID 16 + TID 28 + TID + BID 28 + TID 28 Zeuzem S, et al. AASLD 12. Abstract 232. Reproduced with permission.

39 SOUND-C2 Subanalysis: Efficacy of Treatment in Patients With Cirrhosis Among 33 cirrhotic patients, outcomes with faldaprevir + BI RBV similar to noncirrhotic patients SVR12 rates higher in GT1b vs GT1a HCV Higher rate of discontinuations and SAEs with TID dosing SVR12 (%) n/ N = BI 7127 Dosing Duration (wks) RBV 52 11/ / 217 TID 16, 28, + Cirrhosis No cirrhosis GT1a GT1b 67 6/ 9 BID / 69 Soriano V, et al. AASLD 12. Abstract 84. Reproduced with permission. 33 1/ 3 TID 28-17/ 43 SVR12 (%) n/ N = 43 3/ / 14 TID 16, 28, / / 5 Cirrhosis BID / 0 33 TID 28-1/ 3 43 / / 124 No Cirrhosis TID 16, 28, / / 43 BID / / 25 TID 28 -

40 Interferon- and Ribavirin-Free Regimens

41 Daclatasvir, Asunaprevir, and BMS in Treatment-Naive Patients With GT1 HCV Interim analysis of Part 1 of AI : randomized, open-label, phase IIa study with daclatasvir (NS5A inhibitor), asunaprevir (NS3 protease inhibitor), and BMS (nonnucleoside polymerase inhibitor) Stratification by HCV subgenotype (1a vs 1b) Wk 12 Wk 24 Treatment-naive noncirrhotic pts with GT1 HCV (N = 32) Daclatasvir 60 mg QD + Asunaprevir 0 mg BID + BMS mg BID (n = 16) Daclatasvir 60 mg QD + Asunaprevir 0 mg BID + BMS mg BID (n = 16) Everson GT, et al. AASLD 12. Abstract LB-3.

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

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) Stratified by HCV GT1 subgenotype, IL28B genotype Daclatasvir 60 mg QD + PegIFN lambda-1a 180 µg SC QW + RBV (n = 41) Wk 24 Wk 48 PDR: follow-up No PDR*: PegIFN lambda-1a/rbv Tx-naive pts with GT1 HCV (N = 119) Asunaprevir 0 mg BID + PegIFN lambda-1a 180 µg SC QW + RBV (n = 38) PDR: follow-up No PDR*: PegIFN lambda-1a/rbv PegIFN alfa-2a 180 µg SC QW + RBV (n = ) *PDR: HCV RNA < LLOQ (-TD or -TND) at Wk 4, < LLOQ-TND at Wk 12. Vierling JM, et al. AASLD 12. 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 Outcome, % PegIFN lamba-1a + RBV + Daclatasvir (n = 41) PegIFN lamba-1a + RBV + Asunaprevir (n = 38) PDR PDR+ pts only (n = 37) (n = 32) RVR cevr ervr SVR SVR SVR12 by HCV subtype, % (n/n) 1a 65 (15*/23) 67 (14 /21) 1b 93 (13*/14) 91 (10*/11) SVR12 by IL28B genotype, % (n/n) Non-CC 75 (9/12) 90 (9/10) CC 76 (19/25) 68 (15/22) Vierling JM, et al. AASLD 12. Abstract LB-9. *6 IL28B CC; 5 IL28B CC.

46 Patients (%) D-LITE: Substudy in Japanese Patients With GT1 HCV In small Japanese substudy, % SVR4 rates in both arms 0 PegIFN lambda-1a + RBV + daclatasvir PegIFN lambda-1a + RBV + asunaprevir n/ N = 8/ / 6 Virologic Response 8/ 8 5/ 5 PDR EOTR SVR4 PDR+ Only Izumi N, et al. AASLD 12. Abstract / 8 5/ 5 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

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 study [3] Neptune study [4] Response observed in 23% with HBeAg loss with HBV DNA < 00 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 >,000 IU/mL at Wk 24 in all genotypes 1. Sonneveld MJ, et al. AASLD 12. Abstract Lau GK, et al. N Engl J Med. 05;352: Janssen HL, et al. Lancet. 05;365: Liaw YF, et al. Hepatology. 11;54:

49 HBsAg Decline During PegIFN Therapy Varies According to HBV Genotype HBsAg Decline (log IU/mL) HBsAg decline differed by HBV genotype Sustained HBsAg decrease seen in pts with response to pegifn but typically not in nonresponders BL GT A (n = 103) GT C (n = 386) PegIFN therapy GT D (n = 110) GT B (n = 5) EOT EOF Wks Sonneveld MJ, et al. AASLD 12. Abstract 23. Reproduced with permission. Outcome, % HBeAg loss and HBV DNA < 00 IU/mL Wk 24 HBsAg level predicted response at 6 mos posttreatment, regardless of genotype < 1500 (n = 253) HBsAg Level at Wk 24, IU/mL 1500-,0 00 (n = 373) >,000 (n = 162) P Value <.001 HBsAg loss <.001

50 Go Online for More CCO Coverage of AASLD 12! Capsule Summaries of all the key data Expert Analysis panel discussion exploring the clinical implications Downloadable Slideset: download your own copy of this slideset clinicaloptions.com/boston12