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HCV SPRINT-1 Final Results SVR 24 Boceprevir

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Presentation on theme: "HCV SPRINT-1 Final Results SVR 24 Boceprevir"— Presentation transcript:

1 HCV SPRINT-1 Final Results SVR 24 Boceprevir
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, 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 1

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 mg/d to mg/d 2

3 SPRINT-1 Study Design PART 1 PART 2a Week 4 Week 28 Week 48
Peg-IFN2b 1.5 μg/kg + RBV mg for 48 wks 24 wks Follow-up PART 1 Control N=104 Peg-IFN2b + RBV mg Peg-IFN2b 1.5 μg/kg + RBV mg + Boceprevir 800 mg TID for 24 wks 44 wks Follow-up N=103 Lead-in Strategy Peg-IFN2b + RBV mg Peg-IFN2b 1.5 μg/kg + RBV mg + Boceprevir 800 mg TID for 44 wks 24 wks Follow-up N=103 Peg-IFN2b 1.5 μg/kg + RBV mg + Boceprevir 800 mg TID for 28 wks 44 wks Follow-up No Lead-in Strategy N=107 Peg-IFN2b 1.5 μg/kg + RBV mg + Boceprevir 800 mg TID for 48 wks 24 wks Follow-up N=103 PART 2a Peg-IFN2b 1.5 μg/kg + RBV mg + Boceprevir 800 mg TID for 48 wks 24 wks Follow-up Low Dose RBV Strategy N=16 Peg-IFN2b 1.5 μg/kg + RBV 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 Baseline Characteristics
PART 1 PART 2 P/R Control 48 wks N=104 P/R/B 28 wks N=107 P/R 4 wks  24 wks N=103a N=103 44 wks N=16 P/low dose R/B N=59 Gender Male (%) 67 59 50 61 56 69 Race Caucasian (%) 80 83 84 75 73 Black (%) 15 17 14 25 27 Mean age (years) 48.3 46.4 47.7 46.7 47.6 50.3 48.7 Mean weight (kg) 83.4 79.9 80.0 78.4 81.4 88.5 HCV subtype (%) 1a 51 63 53 58 44 66 1b 40 28 36 35 34 31 1 (no sub-type) 9 13 12 8 3 Viral load mean (log10 IU/mL) 6.53 6.64 6.54 6.43 6.47 HCV-RNA >600,000 IU/mL (%) 90 92 87 91 81 Cirrhosis (%) 7 6 a Boceprevir added to treatment regimen after 4 week lead-in of Peg-IFN alpha-2b + RBV. 4

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

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
Sustained Virologic Responsea % (n/N) Treatment Arm All Patients Patients with RVRb Patients with EVRc P/R Control 48 wks 38 (39/104) 100 (8/8) 86 (32/37) P/R/B 28 wks 54d (58/107) 74 (32/43) 68 (58/85) P/R 4 wks  P/R/B 24 wks 56e (58/103) 82 (54/66) P/R/B 48 wks 67f (69/103) 84 (32/38) 84 (68/81) P/R/B 44 wks 75g (77/103) 94 (62/66) 91 (77/85) 50 (8/16) 86 (6/7) 73 (8/11) P/low dose R/B 48 wks 36 (21/59) 75 (12/16) 60 (21/35) 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 < compared to P/R control

8 Effect of Treatment Duration on SVR
Time to first PCR-negative HCV-RNAa P/R Control 48 wks % (n/N) P/R 4 wks  P/R/B 24 wks 44 wks ≤4 wks 100 (8/8) 82 (54/66) 94 (62/66) >4 wks – ≤12 wks 83 (24/29) 21 (4/19) 79 (15/19) >12 wks 30 (7/23) (0/1) Never negative (0/44) (0/17) aTime after Peg-IFN alpha-2b +RBV in control; time after boceprevir dosing in treatment arms.

9 Predictability of SVR Based on Response During 4 Week P/R Lead-in
Log10 viral load decrease after 4 wks of P/R lead-in SVRa P/R 4 wks  P/R/B 24 wks %(n/N) 44 wks <0.5 29 (2/7) 44 (4/9) 0.5 < 1.0 24 (5/21) 62 (8/13) 1.0 < 1.5 30 (3/10) 65 (11/17) 1.5 < 2.0 73 (8/11) 80 (8/10) 2.0 < 3.0 67 (14/21) 79 (11/14) 3.0 < 4.0 83 (10/12) 82 (14/17) ≥4.0 100 (11/11) 92 (11/12) Undetectable 100 (3/3) 100 (9/9) 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 SVR Rates and Anemia % of Patients HCV Negative 88 67 64 58 48 47 35
Anemia (Hgb <10 g/dL) 88 No Anemia (Hgb ≥10 g/dL) 67 64 58 48 % of Patients HCV Negative 47 35 30 P/R Control 48 wksa P/R 4 wks  P/R/B 24 wksa P/R/B 44 wks P/low dose R/B 48 wks n/N= 12/25 27/78 34/51 24/51 42/48 35/55 7/12 14/47 Epo Use n/N= 19/25 8/78 41/51 9/51 43/48 10/55 9/12 0/47 aOne patient in each group missing in-treatment hemoglobin values

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

13 Most Common Adverse Events*
P/R Control 48 wks N=104 P/R/B 28 wks N=107 P/R 4 wks  P/R/B 24 wks N=103 48 wks N=103 P/R 4 wks  44 wks N=103 48 wks N=16 P/low dose R/B 48 wks N=59 Fatigue 55 61 68 50 71 69 Anemia 34 56 53 52 63 24 Headache 43 49 40 81 Nausea 38 41 54 47 59 Insomnia 28 39 44 Pyrexia 26 Chills 29 30 32 31 Alopecia Diarrhea 22 Dysgeusia 9 21 27 Neutropenia 12 23 17 25 19 Influenza like illness 20 18 15 Arthralgia 13 Dizziness 16 14 Vomiting 5 Decreased Appetite 7 Injection Site Reaction 10 8 11 36 aBased upon counts for all treatment groups combined, >30%

14 Treatment Discontinuations (%)
P/R Control 48 wks % (N=104) P/R 4 wks  P/R/B 24 wks % (N=103)c,d 44 wks % (N=103)c P/low dose R/B % (N=59) EPO n = 27 No EPO n = 77 EPO n = 50 No EPO n = 53 EPO n = 53 No EPO n = 50 EPO n = 9 Total 7 18 14 38 15 11 60 Adverse Events 4 9 2 26 8 10 Viral Breakthrougha 6 30 Otherb 22 16 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 14

15 Mutations Observed by Population Sequencing in SPRINT-1 Trial
Major (≥25%) Less Common (≥5% to <25%) Infrequent (<5%) V36M V36A, V36L T54S T54A V55A R155K R155T A156S V158I V170A I170T

16 Summary Boceprevir significantly improves SVR Safety
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 16

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