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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, - PowerPoint PPT Presentation
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
HCV SPRINT-1HCV SPRINT-1
Final Results SVR 24Final Results SVR 24 Boceprevir* plus PegIFN Boceprevir* plus PegIFN -2b/Ribavirin -2b/Ribavirin
HCV 1 Treatment Naïve PatientsHCV 1 Treatment Naïve PatientsPaul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff,Paul Kwo, Eric J Lawitz, Jonathan McCone, Eugene R Schiff,
John M Vierling, David Pound, Mitchell Davis, Joseph S Galati, John M Vierling, David Pound, Mitchell Davis, Joseph S Galati, Stuart C Gordon, Natarajan Ravendhran, Lorenzo Rossaro, Stuart C Gordon, Natarajan Ravendhran, Lorenzo Rossaro,
Frank H Anderson, Ira M Jacobson, Raymond Rubin,Frank H Anderson, Ira M Jacobson, Raymond Rubin, Kenneth Koury, Lisa Pedicone, Eirum Chaudhri, and Janice K Albrecht Kenneth Koury, Lisa Pedicone, Eirum Chaudhri, and Janice K Albrecht
EASL April 23, 2009
Copenhagen, Denmark* NS3 Protease Inhibitor
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
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
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
SPRINT-1 Study DesignWeek 4 Week 28 Week 48
Lead-inStrategy
Control
No Lead-inStrategy
Low DoseRBV Strategy
N=104
N=59
N=16
aPart two consisted of 75 patients in 10 US sites, 1:4 randomization.
N=103
N=107
N=103
N=103
Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg + Boceprevir 800 mg TID for 48 wks
Peg-IFN2b 1.5 μg/kg + RBV 400-1000 mg + Boceprevir 800 mg TID for 48 wks
Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg for 48 wks
Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg + Boceprevir 800 mg TID for 28 wks
Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg + Boceprevir 800 mg TID for 48 wks
24 wksFollow-up
24 wksFollow-up
24 wksFollow-up
44 wks Follow-up
24 wksFollow-up
Peg-IFN2b + RBV
800-1400 mg 44 wks
Follow-upPeg-IFN2b 1.5 μg/kg +
RBV 800-1400mg + Boceprevir 800 mg TID for 24 wks
Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg + Boceprevir 800 mg TID for 44 wks
Peg-IFN2b + RBV
800-1400 mg 24 wks
Follow-up
PAR
T 1
PAR
T 2a
4
Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
Baseline Characteristics
a Boceprevir added to treatment regimen after 4 week lead-in of Peg-IFN alpha-2b + RBV.
P/RControl 48 wksN=104
P/R/B28 wksN=107
P/R 4 wks P/R/B 24 wksN=103a
P/R/B48 wksN=103
P/R 4 wks P/R/B 44 wksN=103a
P/R/B48 wksN=16
P/low dose R/B
48 wksN=59
GenderMale (%) 67 59 50 61 56 56 69
RaceCaucasian (%) 80 80 83 84 83 75 73Black (%) 15 17 15 14 15 25 27
Mean age (years) 48.3 46.4 47.7 46.7 47.6 50.3 48.7Mean weight (kg) 83.4 83.4 79.9 80.0 78.4 81.4 88.5HCV subtype (%)
1a 51 63 51 53 58 44 661b 40 28 36 35 34 44 31
1 (no sub-type) 9 9 13 12 8 13 3
Viral load mean (log10 IU/mL) 6.53 6.64 6.53 6.54 6.53 6.43 6.47
HCV-RNA >600,000 IU/mL (%) 90 92 87 91 90 81 83
Cirrhosis (%) 8 7 7 9 6 0 7
PART 1 PART 2
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
Sustained Virologic Responsea
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.
Part 2
0
10
20
30
40
50
60
70
80
P/R/B 48 wks
50
P/low dose R/B 48 wks
36
N=16 N=59
Part 1
% P
atie
nts
HC
V N
egat
ive
% P
atie
nts
HC
V N
egat
ive
0
10
20
30
40
50
60
70
80
38
54b 56c
67d
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
75e
N=104 N=107N=103
N=103N=103
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
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
All Patients Patients with RVRb Patients with EVRc
SVRa by time to first PCR-negative HCV RNA
0
20
40
60
80
100
120
% o
f Pat
ient
s H
CV
Neg
ativ
e
P/R Control 48 wks
38
56
75
100
8294
86
68
91P = 0.005
P <0.0001
N= 104 103 103 8 66 66 37 85 85
P/R 4 wks P/R/B 24 wks P/R 4 wks P/R/B 44 wks
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
Predictability of SVR: RVR and EVRSustained 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)68
(58/85)
P/R/B 48 wks 67f
(69/103)84
(32/38)84
(68/81)P/R 4 wks P/R/B 44 wks
75g
(77/103)94
(62/66)91
(77/85)
P/R/B 48 wks 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 <0.0001 compared to P/R control
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
Effect of Treatment Duration on SVR
aTime after Peg-IFN alpha-2b +RBV in control; time after boceprevir dosing in treatment arms.
Time to first PCR-negative HCV-RNAa
P/R Control48 wks% (n/N)
P/R 4 wks P/R/B
24 wks% (n/N)
P/R 4 wks P/R/B
44 wks% (n/N)
≤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(0/1)
0(0/1)
Never negative 0(0/44)
0(0/17)
0(0/17)
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
Predictability of SVR Based onResponse 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/B24 wks%(n/N)
P/R 4 wks P/R/B44 wks%(n/N)
<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.
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
SVR Rates and AnemiaAnemia (Hgb <10 g/dL)No Anemia (Hgb ≥10 g/dL)
0
10
20
30
40
50
60
70
80
90
100
48
35
67
47
88
6458
30
P/R Control48 wksa
P/R 4 wks P/R/B 24 wksa
P/R 4 wks P/R/B 44 wks
P/low dose R/B48 wks
aOne patient in each group missing in-treatment hemoglobin values
n/N=
% o
f Pat
ient
s H
CV
Neg
ativ
e
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
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
45 46
10
0 0
23
50
27
0 0
25
46
27
20
4946
5
0 00
10
20
30
40
50
60
Hemoglobin: Nadir WHO Grade Category Observed During Treatment Period
% o
f Pat
ient
s
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)
Boceprevir added to treatment regimen after week 4 lead-in of Peg-IFN alpha-2b + RBV.
P/R Control 48 wksP/R 4 wks P/R/B 24 wksP/R 4 wks P/R/B 44 wksP/low dose R/B 48 wks
Grade 4 (6.5 – <g/dL)
12
Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
Overall Relapse and Relationship to RVROverall Relapse and Relationship to RVR
aP = 0.0079; bP = 0.0002 compared to P/R Control.
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
% R
elap
se%
Rel
apse
P/R/B
48 wks
P/low dose R/B 48 wks
Part 2
11
22
00
5
10
15
20
25
30
35
Part 1
24
30
24
7a
3b
00
5
10
15
20
25
30
35
Relapse overall
14
21
11
6
2
Relapse in RVR pts
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
Most Common Adverse Events*
aBased upon counts for all treatment groups combined, >30%
P/R Control 48 wks N=104
P/R/B28 wks N=107
P/R 4 wks P/R/B
24 wks N=103
P/R/B48 wks N=103
P/R 4 wks P/R/B
44 wks N=103
P/R/B48 wks N=16
P/low dose R/B
48 wksN=59
Fatigue 55 61 68 50 71 69 68
Anemia 34 56 53 52 56 63 24
Headache 43 49 40 43 52 81 49
Nausea 43 38 41 54 47 63 59
Insomnia 38 34 28 39 40 44 39
Pyrexia 34 26 26 40 34 44 44
Chills 34 29 30 32 34 31 44
Alopecia 26 34 29 29 34 31 32
Diarrhea 22 26 26 24 28 31 24
Dysgeusia 9 21 26 32 27 44 31
Neutropenia 12 23 17 25 30 19 32
Influenza like illness 24 22 20 18 15 38 19
Arthralgia 20 13 21 20 18 31 19
Dizziness 15 18 16 20 14 44 19
Vomiting 5 22 15 24 17 44 19
Decreased Appetite 12 7 14 17 12 38 27
Injection Site Reaction 10 8 5 9 11 25 36
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
Treatment Discontinuations (%)
P/R Control 48 wks
% (N=104)
P/R 4 wks P/R/B24 wks
% (N=103)c,d
P/R 4 wks P/R/B44 wks
% (N=103)c
P/low dose R/B48 wks
% (N=59)
EPOn = 27
No EPOn = 77
EPOn = 50
No EPOn = 53
EPOn = 53
No EPOn = 50
EPOn = 9
No EPOn = 50
Total 7 18 14 38 15 38 11 60
Adverse Events 4 9 2 26 8 10 0 14
Viral Breakthrougha 0 0 6 2 4 6 11 30
Otherb 4 9 6 9 4 22 0 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
15
Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
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
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Kwo P, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09
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