1. Sunday, October 31, 2010 Sheraton Boston Hotel Boston, Massachusetts Debating Key Concepts in HCV Management With New HCV Therapies This program is supported by an educational grant from

2. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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 Debating Key Concepts in HCV Management With New HCV Therapies Faculty Disclosures Jean-Michel Pawlotsky, MD, PhD, has disclosed that he has received contracted research support from Gilead Sciences and has received consulting fees from Abbott, Biotica, Boehringer Ingelheim, Bristol-Myers Squibb, Debiopharm, GenMab, Gilead Sciences, GlaxoSmithKline, Idenix, Janssen-Cilag, Madaus-Rottapharm, Merck, Novartis, Ono, Pfizer, Roche, Schering-Plough, Tibotec, Vertex, and Virco. Fred Poordad, MD, has disclosed that he has received consulting fees from Abbott, Genentech, Gilead Sciences, Merck, Roche, Salix, Schering-Plough, Tibotec, and Vertex; fees for non-CME/CE services from Genentech, Gilead Sciences, and Salix; and contracted research support from Abbott, Achillion, Bristol-Myers Squibb, Gilead Sciences, Genentech, Human Genome Sciences, Novartis, Pfizer, Salix, Schering-Plough/Merck, Tibotec, and Vertex. Mark S. Sulkowski, MD, has disclosed that he has received consulting fees from Abbott, Achillion, Boehringer-Ingelheim, Genentech, Gilead Sciences, Human Genome Sciences, Merck, Pfizer, Tibotec, and Vertex and contracted research support from Abbott Laboratories, Boehringer-Ingelheim, Genentech, Gilead Sciences, Merck, Pharmasset, Tibotec, and Vertex.

4. Mark S. Sulkowski, MD Associate Professor of Medicine Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/Hepatology Johns Hopkins University School of Medicine Baltimore, Maryland Current and Anticipated Burden of the HCV Epidemic

5. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Estimated 170 Million Persons With HCV Infection Worldwide  3-4 million newly infected each yr worldwide World Health Organization 2008. Available at: http://www.who.int/ith/es/index.html. > 10% 2.5% to 10.0% 1.0% to 2.5% Prevalence of infection NA * * *

6. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Persons (n) Peak incidence Peak cirrhosis Reprinted from Gastroenterology, 138, Davis GL, et al, Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression, 513-521, Copyright 2010, with permission from Elsevier. The Changing Face of HCV in the US Yr 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 0 195019601970198019902000201020302020 Ever HCV infected All chronic HCV Acute HCV infection Cirrhosis

7. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies SVR Associated With Improved Outcome  SVR –Durable –Leads to improved histology –Leads to clinical benefits –Decreases decompensation –Prevents de novo esophageal varices –Decreases risk of hepatocellular carcinoma –Decreases mortality Bruno S, et al. Hepatology. 2010;51:2069-2076. Veldt BJ, et al. Ann Intern Med. 2007;147:677-684. Maylin S, et al. Gastroenterology. 2008;135:821-829.

8. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies 40 38 41 0 20 40 SVR Patients (%) PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1400 mg/day PegIFN alfa-2b 1.0 µg/kg/wk + RBV 800-1400 mg/day PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day McHutchison JG, et al. N Engl J Med. 2009;361:580-593. Intent-to-treat analysis IDEAL Study: PegIFN alfa-2a vs PegIFN alfa-2b in Treatment-Naive GT1 HCV Pts 60 80 100

9. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Strategies to Impact the HCV Epidemic  Develop novel treatments that achieve higher SVR rates in all patients –Overcome host factors –Shorten therapy  Increase rate of HCV diagnosis and treatment –Enhance screening –Enhance treatment delivery

10. Jean-Michel Pawlotsky, MD, PhD Professor, Department of Virology Henri Mondor Hospital Université Paris Est Créteil, France How Will New HCV Therapies Change the Management of Treatment-Naive Patients?

11. What Will Be the Standard of Care for Genotype 1 Patients?

12. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Phase III SPRINT-2: BOC + PegIFN/RBV in Treatment-Naive Patients Treatment-naive patients with genotype 1 HCV (2 cohorts: N = 938 nonblack and 159 black) PR* (n = 316, 52) PR* (n = 311 nonblack, 52 black) Wk 72 Wk 48 Follow-up Wk 28 Follow-up Wk 4 BOC/PR* (n = 316 nonblack, 52 black) BOC/PR* (n = 311 nonblack, 55 black) PR* (n = 311, 55) PR* *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 Week 8) and at all subsequent assays. Poordad F, et al. AASLD 2010. Abstract LB-4. Follow-up RVR † No RVR  Randomized, placebo-controlled trial

13. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies SPRINT-2: Overall SVR Rates 0 20 40 60 80 100 4-Wk PR + Response- Guided BOC/PR SVR (%) 63 4-Wk PR + 44-Wk BOC/PR 48-Wk PR 66 38 P <.0001 for both treatment arms vs control These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data. n/N =233/368242/366137/363

14. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies SPRINT-2: Response Rates According to Race 0 20 40 60 80 100 Patients (%) SVR Relapse 4-wk PR + 44 weeks BOC/PR4-wk PR + response-guided BOC/PR48-wk PR 67 68 40 8 23 9 0 20 40 60 80 100 Patients (%) SVRRelapse 42 53 23 17 14 12 Nonblack Patients Black Patients P <.0001 P =.044 P =.004 Poordad F, et al. AASLD 2010. Abstract LB-4. n =211 213125 21 183722 2912 362

15. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies SPRINT-2: SVR Rates in Patients Who Qualified For 28 Weeks of Therapy  44% of patients qualified for 28 weeks of therapy (assessment at Week 4 of BOC, ie Week 8 of therapy) in response-guided arm 0 20 40 60 80 100 Non-blacks SVR (%) Blacks 87 97 n/N = 143/147 13/15 Poordad F, et al. AASLD 2010. Abstract LB-4.

16. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Phase III ADVANCE: TVR + PegIFN/RBV in Treatment-Naive Patients Treatment-naive patients with genotype1 HCV (N = 1088) Wk 12 TVR/P/R* (n = 364) TVR/P/R* (n = 363) PR* (n = 361) eRVR † : PR* Wk 72 Wk 48 Wk 8 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. Wk 24 PR* eRVR † : P/R* PR* Follow-up  Randomized, placebo-controlled trial

17. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies ADVANCE: Overall SVR and Relapse Rates 0 20 40 60 80 100 Patients (%) 69 SVR 75 44 P <.0001 for both treatment arms vs control 12-wk TVR/PR + 12/36-wk PR (n = 363) 48-wk PR (n = 361) 8-wk TVR/PR + 16/40-wk PR (n = 364) n = 250 271 158 Relapse 99 28 n =28 27 64 Jacobson IM, et al. AASLD 2010. Abstract 211.

18. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies ADVANCE: SVR Rates in Patients Who Qualified For 24 Weeks of Therapy  57% and 58% of patients qualified for 24 weeks of therapy (assessment at Week 4) in 8-wk and 12-wk TVR arms, respectively 0 20 40 60 80 100 8-wk TVR/PR + 16/40-wk PR SVR (%) 12-wk TVR/PR + 12/36-wk PR 89 83 n/N =171/207189/212 Jacobson IM, et al. AASLD 2010. Abstract 211.

19. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies ADVANCE: Response Rates According to Race/Cirrhosis 12-wk TVR/PR + 12/36-wk PR 48-wk PR 8-wk TVR/PR + 16/40-wk PR 0 20 40 60 80 100 SVR (%) Blacks 58 62 25 0 20 40 60 80 100 SVR (%) Bridging fibrosis/cirrhosis 53 62 33 n/N = 23/40 16/267/28n/N = 45/85 45/7324/73 Jacobson IM, et al. AASLD 2010. Abstract 211.

20. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Phase III ILLUMINATE: Response-Guided TVR + PegIFN/RBV in Tx-Naive GT1 Pts Treatment- naive patients with genotype 1 HCV (N = 540) PR* (n = 162) PR* (n = 160) Wk 72Wk 48Wk 24 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. Follow-up  Open-label, randomized trial Wk 20 eRVR † No eRVR † PR* (n = 218) TVR/PR* Wk 12 PR*

21. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies ILLUMINATE: Overall SVR Rates 0 20 40 60 80 100 24-wk therapy SVR (%) 92 48-wk therapy 88 Overall 72 Patients With eRVR n/N = 388/540 149/162 140/160 Sherman KE, et al. AASLD 2010. Abstract LB-2.

22. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Boceprevir: Adverse Events and Discontinuations Poordad F, et al. AASLD 2010. Abstract LB-4.  Anemia and dysgeusia reported more frequently in BOC arms vs control in SPRINT-2 Outcome4-Wk PR + Response- Guided BOC/PR (n = 368) 4-Wk PR + 44-Wk BOC/PR (n = 366) 48-Wk PR (n = 363) Adverse event, %  Anemia49 29 EPO use43 24  Dysgeusia374318 Discontinuations due to adverse events, % 1216  Anemia221

23. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Telaprevir: Adverse Events and Discontinuations Outcome, %8-wk TVR/PR + 16/40-wk PR (n = 364) 12-wk TVR/PR + 12/36-wk PR (n = 363) 48-wk PR (n = 361) Adverse event, %  Pruritus455036  Rash353724  Anemia393719 Discontinuation of TVR/placebo due to rash 571 Discontinuation of all drugs due to rash events 0.51.40  Pruritus, rash, and anemia reported more frequently in TVR arms vs control in ADVANCE Jacobson IM, et al. AASLD 2010. Abstract 211.

24. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies  Standard-of-care first-line treatment of HCV genotype 1 may be triple combination  More data needed for special populations that may be difficult to treat or raise complex drug-drug interaction issues and were not included in phase II and III trials BOC or TVR RBVPegIFN Take-Home Messages: First-line Treatment of Genotype 1 HCV

25. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies  Advanced liver disease  Liver transplantation  HIV coinfected  Hemodialysis  Immunosuppressed patients  Others Other Populations?

26. Which Predictors of Treatment Failure Will Be Useful With the New Standard Therapy for Genotype 1 HCV?

27. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies What Do We Currently Know About Resistance to Protease Inhibitors?  Minor resistant populations pre-exist at baseline in virtually all HCV-infected patients [1]  Resistant variants rapidly selected with monotherapy [2]  Emergence of resistance reduced when protease inhibitor combined with potent antivirals without cross-resistance, such as IFN, or IFN plus ribavirin [3,4]  Failure to achieve SVR during triple combination therapy associated with selection of resistant HCV variants [3] 1. Bartenschlager R, et al. J Gen Virol. 2000;81:1631-1648. 2. Ozeki I. J Hepatol. 2009;50:S350. 3. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 4. Kwo PY, et al. Lancet. 2010;376:705-716.

28. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Treatment Failures on Triple Combination With a DAA  Insufficient response to pegIFN and RBV  Growth of uncontrolled DAA-resistant HCV variants

29. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies 0 20 40 60 80 100 37 55 75 97 59 SVR (%) TotalPrior Null Response Prior Partial Response Prior Breakthrough Prior Relapse Berg T, et al. EASL 2010. Abstract 4. Graphic reproduced with permission. Study 107: TVR/PR Retreatment of Pts With PR Failure in PROVE 1/2/3 Trials N = 177n = 51n = 29n = 8n = 29

30. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Predicting Treatment Failure (IFN and RBV Nonresponsiveness)  Lead-in phase with pegIFN and RBV alone  Baseline predictors

31. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies SVR According to Week 4 Response to PR Lead-in in Non-Black Patients Poordad F, et al. AASLD 2010. Abstract LB-4. Graphic reproduced with permission. 0 20 40 60 80 100 48 P/RBOC RGTBOC/PR48 SVR (%) 52 82 29 39 5 121 234 187 228 178 218 31 79 21 73 3/62 ≥ 1 log 10 HCV RNA decline from baseline < 1 log 10 HCV RNA decline from baseline

32. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies IDEAL Trial: SVR Rates According to IL28B SNP rs12979860 0 20 40 60 80 100 TTCTCC SVR (%) Ge D, et al. Nature. 2009;461:399-401. n = 186n = 559n = 392

33. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies  ITT analysis of patients from IDEAL study who consented to genetic testing, regardless of adherence level (n = 1604) plus 67 patients from another trial –Race based on self-report, similar to clinical practice setting Thompson AJ, et al. Gastroenterology. 2010;139:120-129. PredictorAdjusted Odds Ratio (95% CI)P Value rs12979860 CC5.2 (4.1-6.7)<.0001 HCV RNA level ≤ 600,000 IU/mL3.1 (2.3-4.1)<.0001 White vs black2.8 (2.0-4.0)<.0001 Hispanic vs black2.1 (1.3-3.6).0041 METAVIR F0-F22.7 (1.8-4.0)<.0001 Fasting blood sugar < 5.6 mmol/L1.7 (1.3-2.2)<.0001 Multivariate Analysis of Baseline Predictors of SVR (Genotype 1 HCV)

34. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Take-Home Messages: Baseline Predictors of Response  Treatment failure with pegIFN/RBV + protease inhibitor for genotype 1 likely due to an insufficient response to pegIFN and RBV antiviral activity  Therefore, predictors of treatment failure will likely be the same as those with current treatment using pegIFN/RBV

35. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Take-Home Messages: Baseline Predictors of Response  Lead-in phase of 4 wks with pegIFN/RBV alone prior to starting protease inhibitor is one way to –Help assess pegIFN/RBV responsiveness –Guide treatment decision (pending additional analyses of phase III trial data)  Algorithms using baseline factors to predict response are expected to be inferred from future Phase III trial data analyses –Algorithms likely to include IL28B genotype determination, but other parameters may need to be included to improve the individual predictive value

36. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Boceprevir or Telaprevir RibavirinPegIFN-α First-line Treatment for Genotype 1 HCV

37. Fred Poordad, MD Chief of Hepatology Cedars-Sinai Medical Center Associate Professor of Medicine David Geffen School of Medicine University of California, Los Angeles Los Angeles, California What New Approaches Will Be Possible for Treatment-Experienced Patients?

38. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Introduction  With current standard of care, ~ 60% of genotype 1 patients will be nonresponders or relapsers  Successful retreatment of this “experienced” population is suboptimal with current therapeutic options  Emerging therapies offer possibility of higher response rates Fried MW, et al. N Engl J Med. 2002;347:975-982. Manns MP, et al. Lancet. 2001;358:958-965.

39. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Null response Suboptimal Virologic Responses Relapse Breakthrough PegIFN/RBV Partial response 2 log 10 decline Limit of detection Wks 0412182430364248546066728 78 HCV RNA (log 10 IU/mL) 0 1 2 3 4 5 6 7 8 Incomplete treatment McHutchison JG, et al. N Engl J Med. 2009;361:580-593.

40. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Relative Proportions of HCV Patients Eligible for Treatment in United States Treatment naive Nonresponders Relapsers Ineligible (comorbidities, etc) Treatment naive

41. Retreatment of Treatment Failures With PegIFN/RBV or cIFN/RBV

42. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Retreatment of PegIFN/RBV Nonresponders Yields Low SVR Rates 1. Jensen D, et al. Ann Intern Med. 2009;150:528-540. 2. Poynard T, et al. Gastroenterology. 2009;136:1618-1628. 3. Bacon BR, et al. Hepatology. 2009;49:1838-1846. 8.0 PegIFN alfa-2a/RBV for 48 Wks in PegIFN alfa-2b/RBV Nonresponders SVR (%) 0 20 40 60 80 100 6.3 PegIFN alfa-2b/RBV for 48 Wks in PegIFN/RBV Nonresponders SVR (%) 0 20 40 60 80 100 10.7 cIFN for 48 Wks in PegIFN/RBV Nonresponders SVR (%) 0 20 40 60 80 100 REPEAT [1] EPIC3 [2] DIRECT [3]

43. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Retreatment of PegIFN/RBV Relapsers 1. McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303. 2. Poynard T, et al. Gastroenterology. 2009;136:1618-1628. PegIFN alfa-2a/RBV for 48 Wks in PegIFN/RBV Relapsers 33 PegIFN alfa-2b/RBV for 48 Wks in PegIFN/RBV Relapsers 20 McHutchison et al [1] SVR (%) 0 20 40 60 80 100 SVR (%) 0 20 40 60 80 100 EPIC3 [2]

44. Retreatment of Treatment Failures With HCV Protease Inhibitors

45. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Boceprevir Clinical Trials in Prior Nonresponders to PegIFN/RBV Wk 48Wk 72Wk 4Wk 36 RESPOND-1* (N = 357) Follow-up BOC † 400 mg + PR Follow-up 4 arms: BOC † 100, 200, 400 (x 2) ‡ + P PR Follow-up Wk 12 Follow-up *All patients switched to BOC 800 mg + P/R at Wk 24 upon DSMB review. † TID dosing. ‡ One of the 400-mg arms was nonrandomized. BOC 400 mg † + PR PR RESPOND-2 (N = 403) PR BOC † + PR PR BOC † + PR If detectable at Wk 8 Follow-up PR If detectable at Wk 12 BOC † 800 mg + P Wk 24 Follow-up

46. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies RESPOND-1: EOT and SVR Rates According to Treatment Arm Schiff E, et al. EASL 2008. Abstract 104. PR for 48 wks (n = 49) BOC + P 100 mg (n = 48) BOC + P 200 mg (n = 49) BOC + PR 400 mg (n = 49) BOC + P 400 mg (n = 97) BOC + P 800 mg (n = 65) PR for 12 wks → BOC + PR 400 mg for 24 wks (n = 44) 8 2 32 7 6 2 16 12 20 14 13 5 21 4 0 10 20 30 40 EOT Response SVR Response Rate (%) 50 60 70 80 90 100

47. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Lessons Learned From RESPOND-1 Results  800 mg TID optimal dosing of BOC  RBV of great importance to optimize SVR and decrease breakthrough events  Optimal BOC regimen for treatment-experienced patients not evaluated in this trial

48. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies RESPOND-2: SVR Rates According to Treatment Arm and Prior Response 0 20 40 60 80 100 Overall SVR (%) [1] 4-wk PR + 44-wk BOC + PR (n = 161) 59* Prior Nonresponders Prior Relapsers 48-wk PR (n = 80) 4-wk PR + response-guided BOC + PR (n = 162) 66 21 40 52 7 75 29 69 P <.0001 vs control (both arms) *46% of patients in response-guided arm eligible for shorter duration of therapy, with 86% SVR rate. [2] Bacon BR, et al. AASLD 2010. Abstract 216.

49. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies RESPOND-2: SVR Rates According to Virologic Response by Wk 4 < 1 log Response at Wk 4 33 ≥ 1 log Response at Wk 4 34 0 73 79 25 P <.0001 vs control (both arms) Bacon BR, et al. AASLD 2010. Abstract 216. Graphic reproduced with permission. P <.0001 vs control (both arms) 0 20 40 60 80 100 SVR (%) 4-wk PR + 44-wk BOC + PR (n = 161) 48-wk PR (n = 80) 4-wk PR + response-guided BOC + PR (n = 162)

50. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies TVR Clinical Trials in Prior Nonresponders to PegIFN/RBV PROVE 3 (N = 453) PR TVR + PRPR Follow-up TVR + P Follow-up TVR + PRPR Follow-up Wk 48Wk 24Wk 12Wk 72 Wk 4 Wk 16 REALIZE (N = 662) PR Follow-up TVR + PRPR TVR + PRPR Follow-up Study 107* † (N = 117) TVR + PRPR Follow-up *Study enrolled nonresponders in control arms of PROVE 1, 2, and 3. † Protocol amended to tailor pegIFN/RBV duration: (a) pegIFN/RBV extended for total of 48 wks in pts not attaining RVR with triple therapy and all previous null responders (n = 34); (b) pegIFN/RBV shortened to 24 wks in pts attaining eRVR (undetectable at Wks 4 and 12) with triple therapy

51. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies PROVE 3: SVR Rates According to Prior Response 0 20 40 60 80 100 SVR (%) McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303. 24-wk TVR + P (n = 111) 24-wk TVR + PR + 24-wk PR (n = 113) 12-wk TVR + PR + 12-wk PR (n = 115) 48-wk PR (n = 114) Prior Nonresponders 39 Prior Relapsers Prior Breakthrough 38 9 11 69 76 20 42 57 36 62 40 Overall 51* 14 24 † 53* *P <.001 vs control. † P =.02 vs control.

52. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies PROVE 3: Breakthrough Events  Most breakthrough events observed during first 12 wks of treatment and associated with TVR resistance mutations  Breakthrough more common with HCV GT 1a vs 1b (24% vs 11%) McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303. 20 2 22 0 45 13 3 2 0 20 40 60 80 100 Cumulative Breakthrough at Wk 24 (%) Prior Nonresponders Prior Relapsers 24-wk TVR + P (n = 111) 24-wk TVR + PR + 24-wk PR (n = 113) 12-wk TVR + PR + 12-wk PR (n = 115) 48-wk PR (n = 114)

53. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Study 107: TVR Retreatment of Pts With PegIFN/RBV Failure in PROVE 1/2/3 Trials Berg T, et al. EASL 2010. Abstract 4. RelapseSVRRVR 0 20 40 60 80 100 Prior Null Responders* (n = 51) Patients (%) 41 Prior Partial Responders † (n = 29) Prior Virologic Breakthrough (n = 8) 37 24 86 55 26 88 0 75 93 3 (1/29) 97 Prior Relapsers (n = 29) *Null responders: Wk 4 HCV RNA reduced by < 1 log 10 IU/mL; Wk 12 HCV RNA reduced by < 2 log 10 IU/mL. † Partial responders: HCV RNA reduced by ≥ 2 log 10 IU/mL at Wk 12, but HCV RNA detectable at Wk 24. n= 2119 6/ 25 25 16 6/ 23 7 62728

54. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Lessons Learned From Phase II Telaprevir Studies  Optimal duration –12 wks of TVR –48 wks of pegIFN/RBV  RBV critically important to decrease breakthrough and relapse  Activity demonstrated in null responders, breakthrough patients, and relapsers

55. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies REALIZE: SVR Rates According to Treatment Arm and Prior Response 0 20 40 60 80 100 Overall SVR (%) 4-wk PR + 12-wk TVR + PR + 32-wk PR (n ~ 265) 64 Prior Relapsers Prior Partial Responders Prior Null Responders 48-wk PR (n = 132) 12-wk TVR + PR + 36-wk PR (n ~ 265) 66 17 83 88 24 54 15 5 29 33 59 P <.0001 P <.001 These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.

56. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Similarities and Differences Between REALIZE and RESPOND-2 Trial Designs  Both explore lead-in of 4 wks of pegIFN/RBV –May help early identification of patients intolerant to therapy and those less likely to respond  Prior null responders excluded in RESPOND-2 –However, lead-in identified that 28% of patients had < 1 log decline after 4 wks of pegIFN/RBV, with ~ 34% SVR rate  Response-guided paradigm studied in RESPOND-2 with BOC allows shorter duration of 36 wks –46% (74/162) of patients met early response criteria, with 86% SVR rate

57. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies RESPOND-2: Adverse Events Over Entire Treatment Course Outcome4-Wk PR + Response- Guided BOC + PR (n = 162) 4-Wk PR + 44-Wk BOC + PR (n = 161) 48-Wk PR (n = 114) Adverse event, %  Anemia434620  Dysgeusia434511  Adverse events more common in BOC arms vs control –Anemia and dysgeusia Bacon BR, et al. AASLD 2010. Abstract 216.

58. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies REALIZE: Adverse Events During TVR Dosing Period These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.  Adverse events more common in TVR arms vs control –Fatigue, pruritus, rash, flu-like symptoms, nausea, and anemia

59. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Remaining Issues for Use of Protease Inhibitors in Treatment-Experienced Pts  Null responders not optimally served by either regimen  Better understanding of resistance  Will baseline predictors of response, including IL28B, factor into decisions to treat?

60. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Summary  2 viable new therapies that will set the new standard of care for treatment-experienced patients –SVR in BOC arms of Phase III trial: 59% to 66% –SVR in TVR arms of Phase III trial: 64% to 66%  Complexities with each regimen and some differences –Response-guided therapy vs fixed duration –46% of patients receiving response-guided BOC therapy eligible for 36 weeks of therapy –Different adverse event profiles

61. Mark S. Sulkowski, MD Associate Professor of Medicine Medical Director, Viral Hepatitis Center Divisions of Infectious Diseases and Gastroenterology/Hepatology Johns Hopkins University School of Medicine Baltimore, Maryland How Will On-Treatment Management Differ in the Setting of New HCV Therapies?

62. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies The Case of the “Naive” Treatment-Naive Patient  32-yr-old law student who acquired hepatitis C after very brief injection drug use in high school but is otherwise healthy  She was recently diagnosed after donating blood and has never seen a specialist  Her primary doctor ordered some laboratory tests –Genotype 1a HCV –HCV RNA 540,000 IU/mL –ALT 31 U/L

63. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies The Case of the “Naive” Treatment-Naive Patient  She has 1 visit with her gastroenterologist –No biopsy since she wants to “get rid” of her HCV infection –They decide to initiate treatment with protease inhibitor plus pegIFN/RBV

64. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies The Case of the “Naive” Treatment-Naive Patient  What education should she receive before starting therapy? –Response –Side effects  How will you monitor her during treatment? –Frequency of office visits and HCV RNA monitoring

65. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies The Case of the “Naive” Treatment-Naive Patient  Early in the course of treatment, she has a follow-up visit and laboratory tests –Hemoglobin 8.7 g/dL –HCV RNA < 25 IU/mL –Reports experiencing increasing fatigue, depression, and difficulty concentrating while studying for her bar exam

66. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies The Case of the “Naive” Treatment-Naive Patient: Discussion and Debate  How will anemia be managed in the setting of protease inhibitors?  What are the consequences if she decides to stop therapy?

67. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies The Case of the Busy Sales Executive  53-yr-old man with chronic hepatitis C was diagnosed ~ 7 yrs ago after a life insurance exam –Genotype 1a; HCV RNA 2.3 million IU/mL –Liver biopsy several yrs ago revealed portal fibrosis with few septae  He is receiving no medications except a multivitamin that he often forgets to take  He wants to get rid of hepatitis but has been “too busy” to commit to a year of therapy

68. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies The Case of the Busy Sales Executive: Discussion and Debate  Is he a candidate for 24-28 wks of therapy?  How would you apply “response-guided therapy”? –What if he does not achieve an early response?

69. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies The Case of the Highly Motivated Nonresponder  48-yr-old black man has failed previous treatment  He presents 1 day after the approval of a protease inhibitor with the intent of starting treatment as soon as possible –Genotype 1b; HCV RNA 7.4 million IU/mL –Liver biopsy 5 yrs ago revealed METAVIR stage 2 fibrosis  He was a null responder (< 2 log IU/mL reduction at Week 12) to pegIFN alfa-2a 180 µg/wk SC plus RBV 600 mg BID

70. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies The Case of the Highly Motivated Nonresponder: Discussion and Debate  Would IL28B testing help?  Does the finding of genotype 1b HCV influence your decision?  Does the patient’s liver disease stage influence the decision to treat?  If he starts protease-inhibitor-based therapy, is there a new “stopping rule” for viral nonresponse?

71. clinicaloptions.com/hepatitis Debating Key Concepts in HCV Management With New HCV Therapies Summary  Protease inhibitor + pegIFN/RBV expected to be the next standard of care for most patients with HCV genotype 1  Treatment-naive patients can anticipate SVR rates ranging from 63%-75% –Shorter duration for many patients (response-guided therapy)  Treatment-experienced patients can anticipate SVR rates ranging from 29%-88% depending on response to pegIFN/RBV  New issues will emerge with PI-based therapy –Resistance –Side effects: rash, anemia, dysgeusia

72. Go Online for More on Debating Key Concepts in HCV Management! Interactive Virtual Presentation Expert faculty members who have experience with novel targeted anti-HCV discuss areas of ongoing debate and highlight areas of consensus, providing a better understanding of the potential changes forthcoming in hepatitis C treatment. clinicaloptions.com/hepatitis