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Paul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff,

HCV SPRINT-1 Final Results SVR 24 Boceprevir* plus PegIFN  -2b/Ribavirin HCV 1 Treatment Naïve Patients. Paul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff, John M Vierling, David Pound, Mitchell Davis, Joseph S Galati, Stuart C Gordon, Natarajan Ravendhran, Lorenzo Rossaro,

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Paul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff,

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  1. HCV SPRINT-1Final Results SVR 24 Boceprevir* plus PegIFN -2b/Ribavirin HCV 1 Treatment Naïve Patients Paul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff, John M Vierling, David Pound, Mitchell Davis, Joseph S Galati, Stuart C Gordon, Natarajan Ravendhran, Lorenzo Rossaro, Frank H Anderson, Ira M Jacobson, Raymond Rubin, Kenneth Koury, Lisa Pedicone, Eirum Chaudhri, and Janice K Albrecht EASL April 23, 2009 Copenhagen, Denmark * NS3 Protease Inhibitor

  2. Aims of the Study • Evaluate safety/efficacy of Peg-IFN alfa-2b 1.5 µg/kg plus RBV in combination with boceprevir • Assess impact on SVR • RVR and EVR • Effect of the 4-week lead-in which allows • Achievement of steady-state drug levels • Alpha interferon-mediated immune system activation • Lower HCV burden • Potentially decreased pool of pre-existing viral quasi-species • 28 vs. 48 week treatment duration • Decreased ribavirin from 800-1400 mg/d to 400-1000 mg/d

  3. PART 1 PART 2a SPRINT-1 Study Design Week 28 Week 4 Week 48 Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg for 48 wks 24 wks Follow-up N=104 Control 44 wks Follow-up Peg-IFN2b + RBV 800-1400 mg Peg-IFN2b 1.5 μg/kg + RBV 800-1400mg + Boceprevir 800 mg TID for 24 wks N=103 Lead-in Strategy Peg-IFN2b + RBV 800-1400 mg Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg + Boceprevir 800 mg TID for 44 wks 24 wks Follow-up N=103 Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg + Boceprevir 800 mg TID for 28 wks 44 wks Follow-up N=107 No Lead-in Strategy Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg + Boceprevir 800 mg TID for 48 wks 24 wks Follow-up N=103 Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg + Boceprevir 800 mg TID for 48 wks 24 wks Follow-up N=16 Low Dose RBV Strategy Peg-IFN2b 1.5 μg/kg + RBV 400-1000 mg + Boceprevir 800 mg TID for 48 wks 24 wks Follow-up N=59 aPart two consisted of 75 patients in 10 US sites, 1:4 randomization.

  4. PART 1 PART 2 Baseline Characteristics a Boceprevir added to treatment regimen after 4 week lead-in of Peg-IFN alpha-2b + RBV.

  5. Part 2 80 80 70 70 60 60 50 50 50 % Patients HCV Negative 40 40 36 30 30 20 20 10 10 0 0 P/low dose R/B 48 wks P/R/B 48 wks N=16 N=59 Sustained Virologic Responsea Part 1 75e 67d 56c 54b 38 P/R Control 48 wks P/R/B 28 wksf P/R 4 wks P/R/B 24 wks P/R/B 48 wks P/R 4 wks  P/R/B 44 wks N=104 N=103 N=107 N=103 N=103 aRoche COBAS TaqMan LLD <15 IU/mL; bP = 0.013; cP = 0.005; dP <0.0001; eP <0.0001 compared to P/R Control; f1 late relapser after follow-up week 24, not included n SVR.

  6. Predictability of SVR: RVR and EVR SVRa by time to first PCR-negative HCV RNA P/R Control 48 wks P/R 4 wks  P/R/B 24 wks P <0.0001 P/R 4 wks  P/R/B 44 wks 100 94 91 P = 0.005 86 82 75 68 % of Patients HCV Negative 56 38 N= 104 103 103 8 66 66 37 85 85 All Patients Patients with RVRb Patients with EVRc aRoche COBAS TaqMan LLD <15 IU/mL; bRVR: undetectable HCV-RNA on or before 4 wks of boceprevir treatment; undetectable HCV-RNA on or on before 4 weeks for P/R control cEVR:undetectable HCV-RNA on or before 12 wks of boceprevir treatment; undetectable HCV-RNA on or before 12 weeks for P/R control

  7. Predictability of SVR: RVR and EVR aRoche COBAS TaqMan LLD <15 IU/mL; bRVR: undetectable HCV-RNA on or before 4 wks of boceprevir treatment; undetectable HCV-RNA on or on before 4 weeks for P/R control cEVR:undetectable HCV-RNA on or before 12 wks of boceprevir treatment; undetectable HCV-RNA on or before 12 weeks for P/R control; dP = 0.013; eP = 0.005; fP <0.0001; gP <0.0001 compared to P/R control

  8. Effect of Treatment Duration on SVR aTime after Peg-IFN alpha-2b +RBV in control; time after boceprevir dosing in treatment arms.

  9. Predictability of SVR Based onResponse During 4 Week P/R Lead-in aUndetectable HCV-RNA using Roche COBAS TaqMan with LLD <15 IU/mL; 7 and 2 patients were missing week 4 virology in 28 and 48 wk groups, respectively.

  10. 9/12 7/12 0/47 14/47 43/48 42/48 35/55 10/55 19/25 12/25 8/78 27/78 41/51 34/51 9/51 24/51 P/R 4 wks  P/R/B 44 wks P/R 4 wks  P/R/B 24 wksa P/low dose R/B 48 wks P/R Control 48 wksa Epo Use n/N= SVR Rates and Anemia Anemia (Hgb <10 g/dL) No Anemia (Hgb ≥10 g/dL) 88 67 64 58 48 47 % of Patients HCV Negative 35 30 n/N= aOne patient in each group missing in-treatment hemoglobinvalues

  11. Hemoglobin: Nadir WHO Grade Category Observed During Treatment Period P/R Control 48 wks P/R 4 wks  P/R/B 24 wks P/R 4 wks  P/R/B 44 wks P/low dose R/B 48 wks % of Patients Grade 0 (≥11 g/dL) Grade 1 (9.5 – <11.0 g/dL) Grade 2 (8.0 – <9.5 g/dL) Grade 3 (6.5 – <8.0 g/dL) Grade 4 (6.5 – <g/dL) Boceprevir added to treatment regimen after week 4 lead-in of Peg-IFN alpha-2b + RBV.

  12. Part 1 Part 2 Relapse in RVR pts 35 30 21 25 22 20 14 11 15 11 6 10 2 5 0 0 P/R/B 48 wks P/low dose R/B 48 wks Overall Relapse and Relationship to RVR Relapse overall 35 30 30 24 24 25 % Relapse 20 15 10 7a 5 3b 0 0 P/R Control 48 wks P/R/B 28 wks P/R 4 wks  P/R/B 24 wks P/R/B 48 wks P/R 4 wks  P/R/B 44 wks aP = 0.0079; bP = 0.0002 compared to P/R Control.

  13. Most Common Adverse Events* aBased upon counts for all treatment groups combined, >30%

  14. Treatment Discontinuations (%) aPersistent ≥2 log10 increase from nadir and ≥50,000 IU/mL; bLost to follow-up, subject did not wish to continue, non-compliance with protocol; cBoceprevir added to treatment regimen after 4 wk lead-in of Peg-IFN alpha-2b + RBV; d6 patients discontinued during lead-in period prior to Boceprevir

  15. Mutations Observed by Population Sequencing in SPRINT-1 Trial

  16. Summary • Boceprevir significantly improves SVR • Boceprevir with SOC for 48 weeks nearly doubles SVR • Week 4 P/R response, RVR, and EVR all show promise for response guided therapy • Anemia appears to be a surrogate for response • Full dose RBV required • Safety • Boceprevir is well-tolerated for up to 48 weeks • No boceprevir-defining toxicity responsible for treatment discontinuation • Boceprevir is associated with ~1 g/dL incremental hemoglobin decrease • Anemia management with EPO is associated with increased completion rates

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