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

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Classes of DAAs

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: 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

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 CTS-1027 Danoprevir GS 9256 IDX320 Vaniprevir BI Boceprevir Telaprevir TMC435 Nonnucleoside polymerase inhibitors BI IDX375 ABT-333 ABT-072 ANA598 BMS Filibuvir Tegobuvir VX-759 VX-222 Nucleoside polymerase inhibitors IDX184 PSI-7977 RG7128 NS5A inhibitorsA-831 PPI-461 BMS BMS CF102

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

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 PegIFN/RBV Protease inhibitor

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 Beyond PegIFN/RBV Protease inhibitor Nucleos(t)ide polymerase inhibitor Nonnucleoside polymerase inhibitor NS5A inhibitor

Activity of DAAs: Protease Inhibitors in Phase III Trials

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)

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:

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 SVR (%) Treatment-Naive Pts Treatment- Experienced [1-2] [3-4] Current Standard of Care SVR (%) [1-2] [3-4] SOC + Protease Inhibitors (Approval Anticipated in 2011) 1. Poordad F, et al. AASLD Abstract LB Jacobson IM, et al. AASLD Abstract Bacon BR, et al. AASLD Abstract Foster GR, et al. APASL Abstract Treatment-Naive Pts Treatment- Experienced

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 wks PR 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, % Relapse, %99 Adverse events more frequent in PI arms Rash, anemia, pruritus, nausea Anemia, dysgeusia 1. Jacobson IM, et al. AASLD Abstract Poordad F, et al. AASLD Abstract LB-4.

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

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 [1] SILEN-C2, IIRVR: (NR) EVR: (NR) Danoprevir (RG7227) [2] ATLAS, IIRVR: (7) cEVR: (43) TMC435 [3] PILLAR, IIbSVR4: (NR) SVR12: (NR) Vaniprevir (MK-7009) [4] Protocol 007, IIaRVR: (5)* cEVR: (47)* SVR: (63) *Significant difference. 1. Sulkowski M, et al. EASL Abstract Terrault N, et al. AASLD Abstract Fried M, et al. AASLD Abstract LB Manns MP, et al. AASLD Abstract 82.

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: (63) Filibuvir [2] IIRVR : (0) cEVR: (50) EOT: (50) SVR 12: (50) Relapse: (0) Nucleoside RG7128 [3] PROPEL, IIbcEVR: (49) 1. Lawitz E, et al. AASLD Abstract Jacobson I, et al. EASL Abstract Jensen DM, et al. AASLD Abstract 81.

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 [1] IIaRVR: (8) eRVR: (8) cEVR: (42) 1. Pol S, et al. EASL Abstract 1189.

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 [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 Abstract LB Pawlotsky JM, et al. Gastroenterology. 2011[epub ahead of print]. Abstract Jacobson IM, et al. AASLD Abstract Foster G, et al. EASL Abstract Sulkowski M, et al. EASL Abstract Terrault N, et al. AASLD Abstract Petry A, et al. AASLD Abstract Fried M, et al. AASLD Abstract LB Manns MP, et al. AASLD Abstract 82.

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 [5] 1+ (not fully pangenotypic) 1. Lawitz E, et al. AASLD Abstract Jacobson I, et al. EASL Abstract Standring DN, et al. EASL Abstract Jensen DM, et al. AASLD Abstract Pol S, et al. EASL Abstract 1189.

Adherence, Dosing, and Adverse Events

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: Mitra D, et al. Value Health. 2010;13: Raptopoulou M, et al. J Viral Hepat. 2005;12: Smith SR, et al. Ann Pharmacother. 2007;41:  Retrospective analysis of pegIFN alfa-2b/RBV trials (N = 511) [1] Adherence Rate (%) n = SVR (%)

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: Antiretroviral Pills Prescribed/Day, n Patients With Plasma HIV-1 RNA ≤ 50 copies/mL at 48 Wks (%) PI NRTI NNRTI

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 BMS TMC435 BID BI Telaprevir Danoprevir* Vaniprevir ANA598 RG7128 Filibuvir TID Boceprevir Telaprevir Danoprevir

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 [4] Gastrointestinal events, jaundice, and rash*5 (12) BMS [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 Abstract LB Jacobson IM, et al. AASLD Abstract Lawitz E, et al. AASLD Abstract Sulkowski M, et al. EASL Abstract Pol S, et al. EASL Abstract Terrault N, et al. AASLD Abstract Jacobson I, et al. EASL Abstract Jensen DM, et al. AASLD Abstract Fried M, et al. AASLD Abstract LB Manns MP, et al. AASLD Abstract 82. *Higher in BID dosing than QD.

Resistance

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

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: Ozeki I. J Hepatol. 2009;50:S McHutchison JG, et al. N Engl J Med. 2009;360: Kwo PY, et al. Lancet. 2010;376:

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: Zeuzem S, et al. AASLD Abstract 227.

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:

Looking Further Into the Future of HCV Therapy

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

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?

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

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 AI [2] (N = 21) IIaNull respondersxx GS Tegobuvir [3] (N = 46) IINaivexx SOUND C-1 [4] (N = 32) IINaivexx 1. Gane EJ, et al. Lancet. 2010;376: Lok A, et al. AASLD Abstract LB Zeuzem S, et al. AASLD Abstract LB Zeuzem S, et al. AASLD Abstract LB-7.

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: RG 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: Patients infected with GT1 HCV (N = 86)* Wk 48 PegIFN/RBV † Day 7Day 14 RG mg BID + Danoprevir 100 mg TID (n = 8 active, 2 placebo) RG mg BID + Danoprevir 200 mg TID (n = 8 active, 1 placebo) PegIFN/RBV † RG mg BID + Danoprevir 100 mg TID (n = 8 active, 1 placebo) PegIFN/RBV † RG mg BID + Danoprevir 200 mg TID (n = 8 active, 4 placebo) PegIFN/RBV † Treatment naive Previous nonresponders to IFN (excluding null responders) RG 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 mg/day. Previous null responders to IFN RG mg BID + Danoprevir 900 mg BID (n = 8 active, 2 placebo) PegIFN/RBV † RG mg BID + Danoprevir 900 mg BID (n = 8 active, 2 placebo) PegIFN/RBV † Day 4

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 /200 TID8Naive /100 TID7Naive /200 TID8Naive /900 BID8Naive /600 BID8Exp, non-null /900 BID8Exp, null Gane EJ, et al. Lancet. 2010;376: Gane EJ, et al. AASLD Abstract 193.

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 BMS Alone or With PR in GT1 Null Responders  Open-label, randomized, placebo-controlled phase IIa trial of BMS (NS5A inhibitor) and BMS (NS3 protease inhibitor) Lok A, et al. AASLD Abstract LB-8. Prior null responders with GT1 HCV (N = 21) BMS mg QD + BMS mg BID (n = 11) Wk 72 Wk 24 Follow-up BMS mg QD + BMS mg BID + PegIFN/RBV* (n = 10) Follow-up *PegIFN alfa-2a 180 µg/wk; weight-based RBV mg/day.

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 BMS 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 Abstract LB-8. BMS BMS BMS BMS PegIFN/RBV RVReRVRcEVR Patients (%) 7/116/10 4/115/119/10

clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C GS 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 Abstract LB-1. GS mg BID + Tegobuvir 40 mg BID (n = 16) † Wk 48 Wk 4 GS mg BID + Tegobuvir 40 mg BID + RBV* † (n = 15) PegIFN/RBV* (n = 16) PegIFN/RBV* (n = 15) GS 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 mg/day. † PegIFN/RBV started early if virologic breakthrough.

clinicaloptions.com/hepatitis Change Folio Title on Master /Arial 15pt /Unbold White clinicaloptions.com/hepatitis Future Generations: Direct-Acting Antivirals for Hepatitis C GS 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 Abstract LB-1. HCV RNA ResponseTegobuvir + GS (n = 15) Tegobuvir + GS RBV (n = 13) Tegobuvir + GS PegIFN/RBV (n = 14) Median maximal change from baseline, log 10 IU/mL Achieved nadir ≤ 25 IU/mL, % Day 14 HCV RNA ≤ 25 IU/mL, % Day 28 HCV RNA ≤ 25 IU/mL (RVR), %

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 BI and RBV in Naive GT1 Pts  Randomized, open-label trial of BI (NS5B nonnucleoside polymerase inhibitor) and BI (NS4 protease inhibitor) in an interferon-sparing strategy BI PegIFN/RBV † Wk 48 *RBV mg/day in 2 doses. † PegIFN alfa-2a 180 µg/wk; weight-based RBV mg/day. Wk 4 BI PegIFN/RBV † BI mg TID+ BI mg QD + RBV* (n = 15) Treatment- naive patients with GT1 HCV (N = 32) BI mg TID+ BI mg QD + RBV* (n = 17) Zeuzem S, et al. AASLD Abstract LB-7.

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 mg Day 15Day 22Day 29 BI mg 6/1514/1717/1710/1511/1517/17 Pts With HCV RNA < 25 IU/mL (%) Zeuzem S, et al. AASLD Abstract LB-7.

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

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