1. Stefan Zeuzem, MD Professor of Medicine Chief, Department of Medicine JW Goethe University Hospital Frankfurt, Germany Future Generations: Understanding the Similarities and Differences Among Direct-Acting Antivirals for Hepatitis C This program is supported by an educational grant from

2. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C 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 Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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. Classes of DAAs

4. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C HCV Life Cycle and DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside *Role in HCV life cycle not well defined NS5A* inhibitors

5. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Select DAAs in Clinical Development Phase IPhase IIPhase III Protease InhibitorsABT-450 ACH-1625 GS 9451 MK-5172 VX-985 BMS-650032 CTS-1027 Danoprevir GS 9256 IDX320 Vaniprevir BI 201335 Boceprevir Telaprevir TMC435 Nonnucleoside polymerase inhibitors BI 207127 IDX375 ABT-333 ABT-072 ANA598 BMS-791325 Filibuvir Tegobuvir VX-759 VX-222 Nucleoside polymerase inhibitors IDX184 PSI-7977 RG7128 NS5A inhibitorsA-831 PPI-461 BMS-790052 BMS-824393 CF102

6. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Evolution of HCV Therapy 2001 PegIFN/RBV

7. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Evolution of HCV Therapy 20012011 PegIFN/RBV Protease inhibitor

8. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Evolution of HCV Therapy 20012011Beyond PegIFN/RBV Protease inhibitor Nucleos(t)ide polymerase inhibitor Nonnucleoside polymerase inhibitor NS5A inhibitor

9. Activity of DAAs: Protease Inhibitors in Phase III Trials

10. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Boceprevir and Telaprevir  Boceprevir, a potent inhibitor of HCV NS3/4A protease  Telaprevir, a potent inhibitor of HCV NS3/4A protease  Both being tested in combination with standard-of- care pegIFN alfa-2/RBV in phase III studies in chronic HCV infection Boceprevir –SPRINT-2: naive GT1 patients –RESPOND-2: nonresponder GT1 patients (partial responders and relapsers) Telaprevir –ADVANCE: naive GT1 patients –ILLUMINATE: response-guided therapy in naive GT1 paitents –REALIZE: nonresponder GT1 patients (null responders, partial responders, relapsers)

11. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Evolving Response Definitions in Patients Receiving HCV Therapy With DAAs TermTime PointHCV RNA Level RVRWk 4 of therapy NEW: Wk 4 of triple therapy Undetectable NEW: eRVRWk 4 and later time point Undetectable EVRWk 12 of therapyUndetectable (complete EVR) ≥ 2 log decrease from baseline (partial EVR) ETREnd of therapyUndetectable SVR6 mos posttherapyUndetectable Adapted from Ghany MG, et al. Hepatology. 2009;49:1335-1374.

12. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C SVR Rates With BOC and TPV in GT1 Treatment-Naive and -Experienced Pts 0 20 40 60 80 100 SVR (%) Treatment-Naive Pts Treatment- Experienced 38-44 [1-2] 17-21 [3-4] Current Standard of Care 0 20 40 60 80 100 SVR (%) 63-75 [1-2] 59-66 [3-4] SOC + Protease Inhibitors (Approval Anticipated in 2011) 1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3. Bacon BR, et al. AASLD 2010. Abstract 216. 4. Foster GR, et al. APASL 2011. Abstract 1529. Treatment-Naive Pts Treatment- Experienced

13. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Similarities and Differences in Phase III Studies of TVR and BOC in GT1 Naive Pts ParameterTVR [1] BOC [2] PR lead-in?NoYes: 4 wks PegIFN alfa formulation2a2b PI dosing requirements TID; administer with fatty meal TID Duration of PI triple therapy 8-12 wks followed by 12-40 wks PR 24-44 wks after 4 wks PR lead-in Qualification for shortened therapy (response guided) Undetectable HCV RNA until Wk 12 of triple therapy Undetectable HCV RNA until Wk 24 of triple therapy Qualified for shortened therapy, %58 (24 wks)44 (28 wks) SVR, %69-7563-66 Relapse, %99 Adverse events more frequent in PI arms Rash, anemia, pruritus, nausea Anemia, dysgeusia 1. Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. AASLD 2010. Abstract LB-4.

14. Activity of Other DAAs Combined With PR in Triple Therapy in Treatment-Naive Patients

15. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Activity of Other Protease Inhibitors Combined With PR in Phase II Studies Protease InhibitorTrial, PhasePatients Meeting Efficacy Measure, % (SOC) BI 201335 [1] SILEN-C2, IIRVR: 62-69 (NR) EVR: 54-59 (NR) Danoprevir (RG7227) [2] ATLAS, IIRVR: 73-86 (7) cEVR: 88-92 (43) TMC435 [3] PILLAR, IIbSVR4: 91-93 (NR) SVR12: 88-97 (NR) Vaniprevir (MK-7009) [4] Protocol 007, IIaRVR: 67-84 (5)* cEVR: 74-85 (47)* SVR: 61-84 (63) *Significant difference. 1. Sulkowski M, et al. EASL 2010. Abstract 1190. 2. Terrault N, et al. AASLD 2010. Abstract 32. 3. Fried M, et al. AASLD 2010. Abstract LB-5. 4. Manns MP, et al. AASLD 2010. Abstract 82.

16. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Activity of Polymerase Inhibitors Combined With PR in Phase II Studies Polymerase InhibitorTrial, PhasePatients Meeting Efficacy Measure, % (SOC) Nonnucleoside ANA 598 [1] IIcEVR: 73-75 (63) Filibuvir [2] IIRVR : 60-75 (0) cEVR: 63-88 (50) EOT: 60-75 (50) SVR 12: 30-50 (50) Relapse: 20-50 (0) Nucleoside RG7128 [3] PROPEL, IIbcEVR: 80-88 (49) 1. Lawitz E, et al. AASLD 2010. Abstract 31. 2. Jacobson I, et al. EASL 2010. Abstract 2088. 3. Jensen DM, et al. AASLD 2010. Abstract 81.

17. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Activity of NS5A Inhibitors Combined With PR in Phase II Studies Polymerase InhibitorTrial, PhasePatients Meeting Efficacy Measure, % (SOC) BMS-790052 [1] IIaRVR: 42-92 (8) eRVR: 42-83 (8) cEVR: 58-83 (42) 1. Pol S, et al. EASL 2010. Abstract 1189.

18. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Activity of DAAs by HCV Genotype AgentPotential Activity Protease Inhibitors Boceprevir [1,2] 1, 2 Telaprevir [3,4] 1, 2 BI 201335 [5] 1, 2? Danoprevir [6] 1, 2? MK-5172 [7] 1-6 TMC435 [8] 1, 2, 4, 5, 6 Vaniprevir [9] 1, 2? 1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Pawlotsky JM, et al. Gastroenterology. 2011[epub ahead of print]. Abstract 820. 3. Jacobson IM, et al. AASLD 2010. Abstract 211. 4. Foster G, et al. EASL 2010. Abstract 57. 5. Sulkowski M, et al. EASL 2010. Abstract 1190. 6. Terrault N, et al. AASLD 2010. Abstract 32. 7. Petry A, et al. AASLD 2010. Abstract 807. 8. Fried M, et al. AASLD 2010. Abstract LB-5. 9. Manns MP, et al. AASLD 2010. Abstract 82.

19. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Activity of DAAs by HCV Genotype AgentPotential Activity Polymerase Inhibitors Nonnucleoside ANA598 [1] 1 Filibuvir [2] 1 Nucleoside IDX184 [3] 1-4 (5, 6?) RG7128 [4] 1-6 NS5A Inhibitors BMS -790052 [5] 1+ (not fully pangenotypic) 1. Lawitz E, et al. AASLD 2010. Abstract 31. 2. Jacobson I, et al. EASL 2010. Abstract 2088. 3. Standring DN, et al. EASL 2009. Abstract 91. 4. Jensen DM, et al. AASLD 2010. Abstract 81. 5. Pol S, et al. EASL 2010. Abstract 1189.

20. Adherence, Dosing, and Adverse Events

21. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Adherence to PegIFN/RBV: Essential but Challenging  Only ~ 60% of US patients adhere to HCV therapy [2]  Drug exposure correlates with SVR; ≥ 80% adherence correlates with SVR [1,3]  Patient self-report overestimates adherence [4]  Adherence wanes over time [4] 1. McHutchison JG, et al. Gastroenterology. 2002;123:1061-1069. 2. Mitra D, et al. Value Health. 2010;13:479-486. 3. Raptopoulou M, et al. J Viral Hepat. 2005;12:91-95. 4. Smith SR, et al. Ann Pharmacother. 2007;41:1116-1123.  Retrospective analysis of pegIFN alfa-2b/RBV trials (N = 511) [1] Adherence Rate (%) 0 20 40 60 80 100 35 10 n = SVR (%) 24 17 307050 72 54 75 53 90 305 63

22. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Treatment Complexity and Adherence  Data from HIV field illustrates virologic suppression as a function of daily pill burden [1]  Investigational HCV triple therapy involves multiple daily pills plus injection drug –BOC TID: 12 pills/day –TPV TID: 6 pills/day –RBV BID: 4-6 pills/day –PegIFN: injection QW Virologic Response by Daily Pill Burden 1. Bartlett JA, et al. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV- 1 infected adults. AIDS. 2001;15:1369-1377. Antiretroviral Pills Prescribed/Day, n Patients With Plasma HIV-1 RNA ≤ 50 copies/mL at 48 Wks (%) 0 5 10 20 30 40 50 60 70 80 90 100 101520 PI NRTI NNRTI

23. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Dosing Frequency of DAAs (All Plus PegIFN/RBV) in Current Trials in Naive Pts *With RTV boosting. QD BI 201335 BMS-790052 TMC435 BID BI 201335 Telaprevir Danoprevir* Vaniprevir ANA598 RG7128 Filibuvir TID Boceprevir Telaprevir Danoprevir

24. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Common AEs of DAAs in Current Trials in Naive Pts AgentAEs More Frequent in Experimental Arm vs PR Discontinuations due to AEs, % (Wk) Boceprevir [1] Anemia, dysgeusia14 (48) Telaprevir [2] Rash, anemia, pruritus, nausea10 (48) ANA598 [3] Rash incidence and severity increased with 400-mg dose2 (12) BI 201335 [4] Gastrointestinal events, jaundice, and rash*5 (12) BMS-790052 [5] None reported8 (12) Danoprevir [6] ALT elevation, neutropenia, nausea diarrhea4 (12) Filibuvir [7] None reported0 (4) RG7128 [8] None reported2 (12) TMC435 [9] Mild bilirubin increases in first 2 wks of therapy7 (24) Vaniprevir [10] Vomiting with 600-mg dose0 (6) 1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3.Lawitz E, et al. AASLD 2010. Abstract 31. 4. Sulkowski M, et al. EASL 2010. Abstract 1190. 5. Pol S, et al. EASL 2010. Abstract 1189. 6. Terrault N, et al. AASLD 2010. Abstract 32. 7. Jacobson I, et al. EASL 2010. Abstract 2088. 8. Jensen DM, et al. AASLD 2010. Abstract 81. 9. Fried M, et al. AASLD 2010. Abstract LB-5. 10. Manns MP, et al. AASLD 2010. Abstract 82. *Higher in BID dosing than QD.

25. Resistance

26. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Development of Viral Resistance Treatment begins Viral LoadTime Selection of resistant quasispecies Incomplete suppression  Inadequate potency  Inadequate drug levels  Inadequate adherence  Preexisting resistance Drug-susceptible quasispecies Drug-resistant quasispecies

27. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C What Do We Currently Know About Resistance to Protease Inhibitors?  Minor resistant populations preexist at baseline in virtually all HCV-infected patients [1]  Resistant variants rapidly selected with monotherapy [2] –R155K requires 1 nucleotide change in GT1a but 2 nucleotide changes in GT1b; virtually all resistance has been seen in GT1a [3]  Emergence of resistance reduced when protease inhibitor combined with potent antivirals without cross-resistance, such as pegIFN, or pegIFN plus RBV [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 Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Cross-Resistance and Persistence of Mutations With Protease Inhibitors  Geometry of active site increases potential for cross- resistance among NS3 protease inhibitors  Hallmark resistance mutations A156V/T, R155K/T confer cross-resistance –Other: D168V/E/T  Ongoing studies into persistence of resistance –Boceprevir mutations can persist at least 3 yrs after exposure –However, telaprevir resistance mutations undetectable 2 yrs after treatment discontinuation in 89% of patients in EXTEND study [2] 1. Wyles DL. Top HIV Med. 2010;18:132-136. 2. Zeuzem S, et al. AASLD 2010. Abstract 227.

29. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C What Do We Know About Resistance to Polymerase Inhibitors? Nonnucleoside analogues  Resistance emerges rapidly and is often present before therapy Nucleoside analogues  Resistant variants have markedly reduced replication fitness due to highly conserved active site of polymerase  Resistance not seen in 14-day monotherapy studies and takes months to develop in vitro  High barrier to resistance makes combination of nucleoside analogues with other DAAs attractive Wyles DL. Top HIV Med. 2010;18:132-136.

30. Looking Further Into the Future of HCV Therapy

31. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Treat Pros and Cons of Treating vs Deferring Therapy Once PIs Are Available  Protease inhibitors substantially increase chance of SVR  Successful treatment may arrest progression of liver disease (including potential for cirrhosis, HCC, etc)  Many patients already “warehoused” awaiting DAAs, but when is the right time to exit the warehouse?  Current regimens complex, challenging adverse events  Potential for better treatment options in future, eg, better response rates, fewer adverse events, shorter duration  Risk of resistance if therapy fails; impact on future options? Defer

32. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C How Will We Use DAAs in the Future to Treat HCV Infection?  Initial paradigm to be approved will be addition of DAA to pegIFN/RBV –Will substantially improve therapeutic possibilities for many GT1 patients  However, challenging patient scenarios will remain, including –Previous null responders and other patients with adverse prognostic factors: is the improvement in SVR rate with telaprevir or boceprevir “good enough”? –Patients who cannot tolerate pegIFN, RBV, and/or the adverse events associated with telaprevir or boceprevir –Patients who cannot adhere to complex regimens for 6-12 mos; risk of resistance with suboptimal adherence –Others: Patients with end-stage renal disease, HCV/HIV coinfection, transplants  For some of these patients, will future DAA regimens represent better options?

33. Early Studies of Combinations of DAAs ± PegIFN and/or RBV

34. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Selected Trials Investigating Combinations of DAAs TrialPhasePopulationDAA Classes Included PINucNon Nuc NS5A Inh INFORM [1] (N = 88) II Naive and nonresponders xx AI447011 [2] (N = 21) IIaNull respondersxx GS-9256 + Tegobuvir [3] (N = 46) IINaivexx SOUND C-1 [4] (N = 32) IINaivexx 1. Gane EJ, et al. Lancet. 2010;376:1467-1475. 2. Lok A, et al. AASLD 2010. Abstract LB-8. 3. Zeuzem S, et al. AASLD 2010. Abstract LB-1. 4. Zeuzem S, et al. AASLD 2010. Abstract LB-7.

35. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C INFORM-1: RG7128 + Danoprevir + PegIFN/RBV in GT1 Patients  Phase II study of RG7128, a nucleoside NS5B polymerase inhibitor, and danoprevir, an NS3/4A protease inhibitor as part of HCV therapy Gane EJ, et al. Lancet. 2010;376:1467-1475. Patients infected with GT1 HCV (N = 86)* Wk 48 PegIFN/RBV † Day 7Day 14 RG7128 500 mg BID + Danoprevir 100 mg TID (n = 8 active, 2 placebo) RG7128 500 mg BID + Danoprevir 200 mg TID (n = 8 active, 1 placebo) PegIFN/RBV † RG7128 1000 mg BID + Danoprevir 100 mg TID (n = 8 active, 1 placebo) PegIFN/RBV † RG7128 1000 mg BID + Danoprevir 200 mg TID (n = 8 active, 4 placebo) PegIFN/RBV † Treatment naive Previous nonresponders to IFN (excluding null responders) RG7128 1000 mg BID + Danoprevir 600 mg BID (n = 8 active, 2 placebo) PegIFN/RBV † *2 additional arms not included in current analysis. † PegIFN alfa-2a 180  g/wk; RBV 1000-1200 mg/day. Previous null responders to IFN RG7128 1000 mg BID + Danoprevir 900 mg BID (n = 8 active, 2 placebo) PegIFN/RBV † RG7128 1000 mg BID + Danoprevir 900 mg BID (n = 8 active, 2 placebo) PegIFN/RBV † Day 4

36. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C INFORM-1: 14-Day Response Rates in Tx-Naive and Tx-Experienced HCV GT1 Pts  No serious adverse events, treatment-related discontinuations, or grade 3/4 laboratory abnormalities observed in any treatment arm  No evidence of emergent drug resistance during treatment RG7128/ Danoprevir Doses, mg n Pt Population HCV RNA Median Change From Baseline, log 10 IU/mL < LLOQ, % < 40 IU/mL< 15 IU/mL 500/100 TID8Naive-3.913 500/200 TID8Naive-5.26325 1000/100 TID7Naive-4.87129 1000/200 TID8Naive-4.86325 1000/900 BID8Naive-5.18863 1000/600 BID8Exp, non-null-4.05013 1000/900 BID8Exp, null-4.95025 Gane EJ, et al. Lancet. 2010;376:1467-1475. Gane EJ, et al. AASLD 2009. Abstract 193.

37. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C AI447011: BMS-790052 + BMS-650032 Alone or With PR in GT1 Null Responders  Open-label, randomized, placebo-controlled phase IIa trial of BMS- 790052 (NS5A inhibitor) and BMS-650032 (NS3 protease inhibitor) Lok A, et al. AASLD 2010. Abstract LB-8. Prior null responders with GT1 HCV (N = 21) BMS-790052 60 mg QD + BMS-650032 600 mg BID (n = 11) Wk 72 Wk 24 Follow-up BMS-790052 60 mg QD + BMS-650032 600 mg BID + PegIFN/RBV* (n = 10) Follow-up *PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day.

38. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C AI447011: BMS-790052 + BMS-650032 Alone or With PR: Wk 12 Interim Analysis  All viral breakthroughs occurred in patients with GT1a  No serious adverse events, or treatment-related discontinuations of DAAs –6/21 patients experienced transient transaminitis that improved or resolved without discontinuation of drug Lok A, et al. AASLD 2010. Abstract LB-8. BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PegIFN/RBV 64 36 46 60 90 0 20 40 60 80 100 RVReRVRcEVR Patients (%) 7/116/10 4/115/119/10

39. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C GS-9256 + Tegobuvir Alone, With RBV, or With PegIFN/RBV in GT1 Tx-Naive Patients  Phase II study of tegobuvir (GS-9190), an NS5B nonnucleoside polymerase inhibitor, and GS-9256, an NS3 protease inhibitor as part of HCV therapy Zeuzem S, et al. AASLD 2010. Abstract LB-1. GS-9256 75 mg BID + Tegobuvir 40 mg BID (n = 16) † Wk 48 Wk 4 GS-9256 75 mg BID + Tegobuvir 40 mg BID + RBV* † (n = 15) PegIFN/RBV* (n = 16) PegIFN/RBV* (n = 15) GS-9256 75 mg BID + Tegobuvir 40 mg BID + PegIFN/RBV* (n = 15) PegIFN/RBV* (n = 15) Part A Part B (nonrandomized) Treatment-naive patients with GT1 HCV *PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. † PegIFN/RBV started early if virologic breakthrough.

40. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C GS-9256 + Tegobuvir Alone, With RBV, or With PegIFN/RBV: Virologic Response  2 serious AEs reported (vasovagal collapse and bursitis of knee)  1 patient discontinued study drug due to AEs Zeuzem S, et al. AASLD 2010. Abstract LB-1. HCV RNA ResponseTegobuvir + GS- 9256 (n = 15) Tegobuvir + GS- 9256 + RBV (n = 13) Tegobuvir + GS-9256 + PegIFN/RBV (n = 14) Median maximal change from baseline, log 10 IU/mL -4.1-5.1-5.7 Achieved nadir ≤ 25 IU/mL, % 1362100 Day 14 HCV RNA ≤ 25 IU/mL, % 74671 Day 28 HCV RNA ≤ 25 IU/mL (RVR), % 738100

41. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C SOUND C1: BI 207127 + BI 201335 and RBV in Naive GT1 Pts  Randomized, open-label trial of BI 207127 (NS5B nonnucleoside polymerase inhibitor) and BI 201335 (NS4 protease inhibitor) in an interferon-sparing strategy BI 201335 + PegIFN/RBV † Wk 48 *RBV 1000-1200 mg/day in 2 doses. † PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. Wk 4 BI 201335 + PegIFN/RBV † BI 207127 400 mg TID+ BI 201335 120 mg QD + RBV* (n = 15) Treatment- naive patients with GT1 HCV (N = 32) BI 207127 600 mg TID+ BI 201335 120 mg QD + RBV* (n = 17) Zeuzem S, et al. AASLD 2010. Abstract LB-7.

42. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C SOUND C1: Week 4 Results  1 viral breakthrough in 400-mg arm  GT1a pts had lower response rate in low- dose arm  AEs: mild GI events, rash, photosensitivity  No severe AEs and no tx discontinuations in first 4 wks BI 207127 400 mg 40 67 73 82 100 0 20 40 60 80 100 Day 15Day 22Day 29 BI 207127 600 mg 6/1514/1717/1710/1511/1517/17 Pts With HCV RNA < 25 IU/mL (%) Zeuzem S, et al. AASLD 2010. Abstract LB-7.

43. clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C Summary  2 new protease inhibitors, boceprevir and telaprevir, with activity against GT1 HCV in combination with pegIFN/RBV are expected to become available in 2011 –Substantial increases in SVR rates in naive and previous nonresponder GT1 patients –Require pegIFN/RBV, increased adverse events, risk of resistance. adherence challenges  HCV therapy expected to continue to evolve during coming yrs –Potential for different patterns of adverse events, dosing, duration of therapy, barrier to resistance; wider genotypic efficacy; potential to eliminate pegIFN and/or RBV

44. Go Online to Access More Information on Direct-Acting Antivirals Downloadable PowerPoint slideset with speaker notes to use in your own noncommercial presentations clinicaloptions.com/future