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Presentation on theme: "Clinicaloptions.com/hepatitis Highlights of AASLD 2012 Highlights of AASLD 2012 CCO Official Conference Coverage of the 2012 Annual Meeting of the American."— Presentation transcript:

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

2 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options ( Disclaimer The materials published on the Clinical Care Options Web site reflect the views of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 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 clinicaloptions.com/hepatitis Highlights of AASLD 2012 OPTIMIZE: Telaprevir BID vs Telaprevir q8h in Tx-Naive Pts With GT1 HCV Infection  Randomized, multicenter, open-label phase III noninferiority trial Buti M, et al. AASLD Abstract LB-8. Treatment- naive patients with chronic GT1 HCV infection (N = 740) Telaprevir 750 mg q8h + PegIFN/RBV (n = 371) Telaprevir 1125 mg BID + PegIFN/RBV (n = 369) PegIFN/RBV Stratified by fibrosis status (F0-F2 vs F3-F4), IL28B GT (CC, CT, TT) Wk 12Wk 24Wk 48 PegIFN/RBV RVR No RVR Follow-up PegIFN/RBV RVR No RVR Follow-up

7 clinicaloptions.com/hepatitis Highlights of AASLD 2012  SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups  Similar safety and tolerability profile in both treatment arms OPTIMIZE: Efficacy of Telaprevir BID vs Telaprevir q8h in GT1 HCV Infection Buti M, et al. AASLD Abstract LB-8. Reproduced with permission. TVR q8h/PR TVR BID/PR SVR12 (%) CCCTTT n/ N = / / / / / 57 38/ 58 F0-2F3/ / / / / 105 IL28B GT Liver Disease Status

8 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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) Gallegos-Orozco JF, et al. AASLD Abstract 53. Patients (%) Completed Treatment Discontinued Treatment On Treatment 100 Initiated TVR + PegIFN/RBV 50/ Completed > 12 Wks of Rx n/ N= 36/ 50 31/ 50 11/ 50 8/ 50

9 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Cheinquer H, et al. AASLD Abstract 156. 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 Wk 24Wk 48 Wk 72 *47 patients dropped out and did not reach randomization at Wk 24.

10 clinicaloptions.com/hepatitis Highlights of AASLD 2012 N-CORE: SVR24 Rates Comparable With 24 or 48 Wks of PegIFN alfa-2a/RBV  Higher incidence of AEs, SAEs, AE-related dose reductions in 48-wk arm Cheinquer H, et al. AASLD Abstract 156. Reproduced with permission. Odds Ratio % CI P Value / 95 57/ 93 49/ 95 51/ 81 49/ 90 46/ 63 SVR24 (%) 52 ITT (n = 188) Per Protocol (n = 176) Study Completer (n = 153) 24-wk pegIFN/RBV 48-wk pegIFN/RBV n/N =

11 Hepatitis C Current Therapy: Anemia Management

12 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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] Pts with Hb ≤10 g/dL* during BOC-based therapy (N = 500) Erythropoietin 40,000 IU/wk (n = 251) † RBV Dose Reduction (by mg/day) (n = 249) † Stratified by black vs nonblack, anemia onset ≤ 16 wks vs > 16 wks from initiation of lead-in 1. Poordad F, et al. AASLD Abstract Lawitz E, et al. AASLD Abstract 50. *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.  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

13 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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] 1. Poordad F, et al. EASL Abstract Poordad F, et al. AASLD Abstract 154. Reproduced with permission. SVR (%) 178/ / / / / / 121 n/N = All PtsUndetectableDetectable RBV dose reduction Erythropoietin

14 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Lawitz E, et al. AASLD Abstract 50. SVR, % (n/N)Noncirrhotic (n = 438) Cirrhotic (n = 48) RBV dose reduction73 (162/221)57 (13/23)* Erythropoietin72 (157/217)64 (16/25)* *P =.5966 for difference between arms among pts with cirrhosis.

15 HCV/HIV-Coinfected Patients

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

17 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Sulkowski MS, et al. AASLD Abstract 54. Reproduced with permission. Telaprevir + PR Placebo + PR Overall Population No ART EFV-Based ART ATV-Based ART / 38 10/ 22 5/ 7 2/ 6 11/ 16 4/ 8 12/ 15 4/ 8 SVR24 (%) n/N =

18 Novel DAAs + PegIFN/RBV

19 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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) Treatment- naive, noncirrhotic patients* (N = 332) SOF + PegIFN/RBV (n = 52) SOF + PegIFN/RBV (n = 125) SOF + PegIFN/RBV (n = 155) Wk 24 Wk 12 SOF (n = 75) SOF + RBV (n = 75) Hassanein T, et al. AASLD Abstract 230. *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.

20 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Hassanein T, et al. AASLD Abstract 230. EOT SVR HCV RNA < LOD (%) SOF + PR 12 wks SOF + PR 24 wks SOF + PR wks  11 patients (1 in 12-wk group) who attained SVR12 subsequently lost to follow-up  No relapse after SVR12 in any group GT4 HCV (n = 11) GT6 HCV (n = 5)  11/11 patients with genotype 4 HCV achieved RVR and EOT response –2 LTFU without posttreatment data  No relapse after SVR12 in either group EOT SVR12

21 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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) SOF + RBV Wk 12 Treatment naive (n = 25) SOF + RBV SOF + GS RBV Null responders (n = 10) Treatment naive (n = 25) Null responders (n = 9) Patients, % EOTSVR4SVR * Gane EJ, et al. AASLD Abstract 229. *Data reported for 3 pts only. Data collection ongoing.  No SAEs related to study drugs; AE profile consistent with RBV toxicity profile

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

23 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Feld JJ, et al. AASLD Abstract 81. 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) Wk 24 Danoprevir/RTV + Mericitabine + PegIFN/RBV (n = 50) Danoprevir/RTV + Mericitabine + RBV* (n = 77) Danoprevir/RTV + Mericitabine + PegIFN/RBV (n = 77) Noncirrhotic pts with GT1 HCV and previous null response to pegIFN/RBV (N = 228) Danoprevir/RTV + Mericitabine + PegIFN/RBV (n = 74) Wk 48 PegIFN/RBV *GT1a HCV pts added pegIFN/RBV due to high relapse rates and are excluded from this analysis.

24 clinicaloptions.com/hepatitis Highlights of AASLD 2012  Response rates highest with 4-drug therapy and lowest with pegIFN-free therapy in both cohorts MATTERHORN: Response to DNV/RTV, MCB, and PegIFN/RBV in GT1 HCV  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 Feld JJ, et al. AASLD Abstract 81. Reproduced with permission. DNV/RTV + MCB + RBV DNV/RTV + pegIFN/RBV DNV/RTV + MCB + pegIFN/RBV Response (%) 87 EOT SVR12EOTSVR12 20/ 23 n/N = 39 9/ / / 31 Prior Partial ResponsePrior Null Response 84 62/ / / / / / 48 8/ 27 SVR12 (%) 91 Partial / 21 n/N = GT1bGT1a / 26 30/ 30 18/ 24 32/ 44 Partial Null Partial

25 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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) Lok AS, et al. AASLD Abstract 79. Noncirrhotic pts with GT1 HCV and previous null response to pegIFN/RBV (N = 101) Daclatasvir 60 mg QD + Asunaprevir 200 mg BID* (n = 18) Daclatasvir 60 mg QD + Asunaprevir 200 mg QD* (n = 20) 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) Wk 24 *Only pts with GT1b HCV included in dual-therapy arms.

26 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Lok AS, et al. AASLD Abstract HCV RNA < LLOQ (%) / 21 EOT SVR24EOTSVR / 20 18/ 20 20/ 21 16/ 18 14/ 20 14/ 18 13/ 20 n/N = DCV + ASV (BID) + PR DCV + ASV (QD) + PR DCV + ASV (BID) DCV + ASV (QD)

27 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Poordad F, et al. AASLD Abstract 83. Reproduced with permission. SVR24 (%) 71 PILLAR Naive, F / 7 15/ 19 38/ 68 0/ 10 24/ ASPIRE Tx Exp’d, F3 + F4 ASPIRE Tx Exp’d, F4 Only Relapser / 10 17/ 26 14/ 21 0/ 3 7/ Partial Responder Null Responder Placebo + PR Simeprevir 150 mg QD + PR 1/ 10 SVR24 by METAVIR Score SVR24 by Prior IFN Response in Pts With F3/F4 1/ 23 SVR24 (%) n/N =

28 Novel DAAs + Ribavirin Interferon-Free Regimens

29 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 12Wk 8 Cohort 1: Treatment-naive GT1 HCV pts (N = 438) Kowdley KV, et al. AASLD Abstract LB-1. ABT-450/RTV 150/100 mg QD + ABT ABT RBV (n = 80) ABT-450/RTV 150/100 mg QD + ABT RBV (n = 41) ABT-450/RTV 100/100 mg QD or 200/100 mg QD + ABT RBV (n = 79) ABT-450/RTV 150/100 mg QD + ABT ABT-333 (n = 79) ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT ABT RBV (n = 79) ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT ABT RBV (n = 80)

30 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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) Kowdley KV, et al. AASLD Abstract LB-1. Cohort 2: Treatment-exp’d GT1 HCV pts with previous null response (N = 133) ABT-450/RTV 200/100 mg QD + ABT RBV (n = 45) ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT ABT RBV (n = 45) ABT-450/RTV 100/100 mg QD or 150/100 mg QD + ABT ABT RBV (n = 43) Wk 24Wk 12

31 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 8 wks12 wks SVR12 (%) Observed data (above bar) ITT (within bar) n = a1b1a1b1a1b1a1b1a1b1a1b1a1b 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 Treatment-Naive PatientsNull Responders Kowdley KV, et al. AASLD Abstract LB-1. Reproduced with permission.

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

33 clinicaloptions.com/hepatitis Highlights of AASLD 2012 SVR24  Similar high SVR4 rates with 12-wk regimens –SVR12 in all 68 pts who have reached time point SVR Rates With 12 or 24 Wks of Daclatasvir + Sofosbuvir ± RBV  Very high SVR24 rates with all 24-wk regimens across genotypes Sulkowski MS, et al. AASLD Abstract LB-2. SOF + DCV + RBV SOF LI + DCVSOF + DCV SOF + DCV (12 wk) SOF + DCV + RBV (12 wk) 93 GT2/ GT1 HCV RNA < LLOQ (%) EOT*SVR EOT*SVR24EOT* *EOT includes pts who discontinued early, with last visit considered EOT.

34 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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% Wk 24 SVR4 Osinusi A, et al. AASLD Abstract LB-4. Sofosbuvir 400 mg + RBV 1000/1200 mg (n = 10) Sofosbuvir 400 mg + RBV 1000/1200 mg (n = 25) Sofosbuvir 400 mg + RBV 600 mg (n = 25) Part 1 (early-stage fibrosis) SVR12 90 Part 2 (all stages of fibrosis) EOT Viral Response, %  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)

35 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Jacobson IM, et al. AASLD Abstract Di Bisceglie A, et al. EASL Abstract 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 12.

36 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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) Jacobson IM, et al. AASLD Abstract 231. Virologic Outcome, % (n/N)VX TVR + RBV in GT1b (n = 23) VX TVR + RBV in GT 1a (n = 23) SVR1270 (16/23)73 (17/23)  SVR12 with no pegIFN/RBV add on100 (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)  Wk 12 (cEVR)83 (19/23)  Wks 2 and 883 (19/23)65 (15/23) HCV RNA undetectable  Wk 4 (RVR)91 (21/23)57 (13/23)  Wk 12 (cEVR)83 (19/23)  Wks 2 and 822 (5/23)26 (6/23)

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

38 clinicaloptions.com/hepatitis Highlights of AASLD 2012  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 SOUND-C2: Final Efficacy Analysis of Faldaprevir + BI ± RBV in GT1 HCV Zeuzem S, et al. AASLD Abstract 232. Reproduced with permission SVR12 (%) PPITT PP n/N = 48/ 73 47/ 68 40/ 58 54/ 75 18/ 41 BI dosing Duration (wks) RBV TID 16 + TID 28 + TID 40 + BID 28 + TID 28 ‒ GT 1aGT 1b ITT n/N = 13/ 34 35/ 47 TID 16 + TID 28 + TID 40 + BID 28 + TID 28 ‒ 38 14/ 32 33/ 48 16/ 34 24/ 43 13/ 30 41/ 48 2/ 18 16/ Non-CCCC ITT n/N = 34/ 60 14/ 21 TID 16 + TID 28 + TID 40 + BID 28 + TID 28 ‒ 57 32/ 58 14/ 21 28/ 58 12/ 19 38/ 59 16/ 19 11/ 33 7/

39 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Soriano V, et al. AASLD Abstract 84. Reproduced with permission. BI Dosing Duration (wks) RBV SVR12 (%) / / 217 TID 16, 28, 40 + BID 28 + TID / / / / 43 CirrhosisNo cirrhosis GT1aGT1b SVR12 (%) / / 14 TID 16, 28, 40 + BID 28 + TID / / / / 25 CirrhosisNo Cirrhosis TID 16, 28, 40 + BID 28 + TID / / / / / / 124 n/ N =

40 Interferon- and Ribavirin-Free Regimens

41 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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) Everson GT, et al. AASLD Abstract LB-3. Treatment-naive noncirrhotic pts with GT1 HCV (N = 32) Daclatasvir 60 mg QD + Asunaprevir 200 mg BID + BMS mg BID (n = 16) Daclatasvir 60 mg QD + Asunaprevir 200 mg BID + BMS mg BID (n = 16) Wk 24 Stratification by HCV subgenotype (1a vs 1b) Wk 12

42 clinicaloptions.com/hepatitis Highlights of AASLD 2012 Response to Daclatasvir, Asunaprevir, and BMS 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 Everson GT, et al. AASLD Abstract LB-3. Reproduced with permission. HCV RNA < LLOQ TD or TND (%) 24-Wk Treatment (n = 16) Wk 4Wk 12EOTSVR Missing data HCV RNA < LLOQ TD or TND 12-Wk Treatment (n = 16) Wk 4Wk 12EOTSVR4SVR HCV RNA < LLOQ TD or TND (%)

43 New Peginterferons

44 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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) Vierling JM, et al. AASLD Abstract LB-9. Tx-naive pts with GT1 HCV (N = 119) Daclatasvir 60 mg QD + PegIFN lambda-1a 180 µg SC QW + RBV (n = 41) Asunaprevir 200 mg BID + PegIFN lambda-1a 180 µg SC QW + RBV (n = 38) No PDR*: PegIFN lambda-1a/RBV Stratified by HCV GT1 subgenotype, IL28B genotype PegIFN alfa-2a 180 µg SC QW + RBV (n = 40) Wk 24Wk 48 PDR: follow-up No PDR*: PegIFN lambda-1a/RBV PDR: follow-up *PDR: HCV RNA < LLOQ (-TD or -TND) at Wk 4, < LLOQ-TND at Wk 12.

45 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Vierling JM, et al. AASLD Abstract LB-9. Outcome, %PegIFN lamba-1a + RBV + Daclatasvir (n = 41) PegIFN lamba-1a + RBV + Asunaprevir (n = 38) PDR9084 PDR+ pts only(n = 37)(n = 32)  RVR73 91  cEVR100  eRVR7391  SVR47884  SVR SVR12 by HCV subtype, % (n/N)  1a65 (15*/23)67 (14 † /21)  1b93 (13*/14)91 (10*/11) SVR12 by IL28B genotype, % (n/N)  Non-CC75 (9/12)90 (9/10)  CC76 (19/25)68 (15/22) *6 IL28B CC; † 5 IL28B CC.

46 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Izumi N, et al. AASLD Abstract 234. Virologic Response PDREOTRSVR4 PDR+ Only 100 Patients (%) / 8 5/ 6 8/ 8 5/ 5 8/ 8 5/ PegIFN lambda-1a + RBV + daclatasvir PegIFN lambda-1a + RBV + asunaprevir n/ N =

47 Hepatitis B Treatment

48 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 < 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 Abstract Lau GK, et al. N Engl J Med. 2005;352: Janssen HL, et al. Lancet. 2005;365: Liaw YF, et al. Hepatology. 2011;54:

49 clinicaloptions.com/hepatitis Highlights of AASLD 2012 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 Sonneveld MJ, et al. AASLD Abstract 23. Reproduced with permission. PegIFN therapy GT A (n = 103) GT B (n = 205) GT C (n = 386) GT D (n = 110) EOTEOFBL Wks HBsAg Decline (log IU/mL) Outcome, % HBsAg Level at Wk 24, IU/mL < 1500 (n = 253) ,000 (n = 373) > 20,000 (n = 162) P Value HBeAg loss and HBV DNA < 2000 IU/mL 45163<.001 HBsAg loss1500<.001

50 Go Online for More CCO Coverage of AASLD 2012! 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/boston2012


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