Transcript Source doc - HIVandHepatitis.com

1
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
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
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
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
3
SPRINT-1 Study Design
Week 4
PART 1
PART 2a
No
Lead-in
Strategy
Week 48
Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg for 48 wks
Control
Lead-in
Strategy
Week 28
Peg-IFN2b
Peg-IFN2b 1.5 μg/kg +
+ RBV
RBV 800-1400mg +
800-1400 mg Boceprevir 800 mg TID for 24 wks
Peg-IFN2b
+ RBV
800-1400 mg
Low
Dose
RBV
Strategy
aPart
44 wks
Follow-up
Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg
+ Boceprevir 800 mg TID for 44 wks
Peg-IFN2b 1.5 μg/kg + RBV 800-1400 mg
+ Boceprevir 800 mg TID for 28 wks
24 wks
Follow-up
N=104
N=103
24 wks
Follow-up
44 wks
Follow-up
N=103
N=107
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
Peg-IFN2b 1.5 μg/kg + RBV 400-1000 mg
+ Boceprevir 800 mg TID for 48 wks
24 wks
Follow-up
N=59
two consisted of 75 patients in 10 US sites, 1:4 randomization.
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
4
Baseline Characteristics
PART 2
PART 1
P/R
Control
48 wks
N=104
P/R/B
28 wks
N=107
P/R 4 wks 
P/R/B
24 wks
N=103a
P/R/B
48 wks
N=103
P/R 4 wks 
P/R/B
44 wks
N=103a
P/R/B
48 wks
N=16
P/low dose
R/B
48 wks
N=59
67
59
50
61
56
56
69
Caucasian (%)
80
80
83
84
83
75
73
Black (%)
15
17
15
14
15
25
27
Mean age (years)
48.3
46.4
47.7
46.7
47.6
50.3
48.7
Mean weight (kg)
83.4
83.4
79.9
80.0
78.4
81.4
88.5
1a
51
63
51
53
58
44
66
1b
40
28
36
35
34
44
31
1 (no sub-type)
9
9
13
12
8
13
3
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
Gender
Male (%)
Race
HCV subtype (%)
Viral load mean
(log10 IU/mL)
a Boceprevir
added to treatment regimen after 4 week lead-in of Peg-IFN alpha-2b + RBV.
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
5
Sustained Virologic Responsea
% Patients HCV Negative
Part 1
Part 2
75e
80
67d
70
54b
60
70
56c
60
50
50
40
80
38
50
36
40
30
30
20
20
10
10
0
P/R Control
48 wks
P/R/B
28 wksf
N=104
N=107
P/R 4 wks 
P/R/B
24 wks
N=103
0
P/R/B
48 wks
N=103
P/R 4 wks 
P/R/B
44 wks
P/R/B
48 wks
P/low dose R/B
48 wks
N=16
N=59
N=103
aRoche
f1
COBAS TaqMan LLD <15 IU/mL; bP = 0.013; cP = 0.005; dP <0.0001; eP <0.0001 compared to P/R Control;
late relapser after follow-up week 24, not included n SVR.
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
6
Predictability of SVR: RVR and EVR
SVRa by time to first PCR-negative HCV RNA
P/R Control 48 wks
% of Patients HCV Negative
120
N=
P/R 4 wks  P/R/B 24 wks
P <0.0001
P/R 4 wks  P/R/B 44 wks
100
100
94
P = 0.005
80
91
86
82
75
68
56
60
40
38
20
0
104
103
103
All Patients
8
66
66
Patients with
RVRb
37
85
85
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
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
7
Predictability of SVR: RVR and EVR
Sustained Virologic Responsea % (n/N)
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)
56e
(58/103)
82
(54/66)
68
(58/85)
67f
(69/103)
84
(32/38)
84
(68/81)
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)
Treatment Arm
P/R 4 wks 
P/R/B 24 wks
P/R/B 48 wks
P/R 4 wks 
P/R/B 44 wks
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
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
8
Effect of Treatment Duration on SVR
P/R Control
48 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)
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)
Time to first PCRnegative HCV-RNAa
≤4 wks
aTime
after Peg-IFN alpha-2b +RBV in control; time after boceprevir dosing in treatment arms.
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
9
Predictability of SVR Based on
Response During 4 Week P/R Lead-in
SVRa
Log10 viral load decrease after
4 wks of P/R lead-in
P/R 4 wks  P/R/B
24 wks
%(n/N)
P/R 4 wks  P/R/B
44 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.
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
10
SVR Rates and Anemia
% of Patients HCV Negative
100
88
90
80
67
70
64
58
60
50
40
48
47
35
30
30
20
10
0
P/R Control
48 wksa
n/N=
Epo Use
n/N=
aOne
Anemia (Hgb <10 g/dL)
No Anemia (Hgb ≥10 g/dL)
P/R 4 wks 
P/R/B 24 wksa
P/R 4 wks 
P/R/B 44 wks
P/low dose R/B
48 wks
12/25 27/78
34/51
24/51
42/48
35/55
7/12 14/47
19/25 8/78
41/51
9/51
43/48
10/55
9/12 0/47
patient in each group missing in-treatment hemoglobin values
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
11
Hemoglobin: Nadir WHO Grade Category
Observed During Treatment Period
P/R Control 48 wks
P/R 4 wks  P/R/B 24 wks
60
% of Patients
50
46
45
P/R 4 wks  P/R/B 44 wks
P/low dose R/B 48 wks
50
49
46 46
40
30
23
27 27
25
20
10
10
0
5
0
Grade 0
(≥11 g/dL)
Grade 1
Grade 2
(9.5 – <11.0 g/dL) (8.0 – <9.5 g/dL)
0
2
0
Grade 3
(6.5 – <8.0 g/dL)
0
0
0
0
Grade 4
(6.5 – <g/dL)
Boceprevir added to treatment regimen after week 4 lead-in of Peg-IFN alpha-2b + RBV.
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
12
Overall Relapse and Relationship to RVR
Part 1
Part 2
Relapse overall
Relapse in RVR pts
35
35
30
% Relapse
30
25
30
24
24
25
20
20
15
15
11
10
14
11
7a
10
6
5
3b
2
5
0
0
0
0
P/R Control
48 wks
aP
22
21
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
P/R/B
48 wks
P/low dose R/B
48 wks
= 0.0079; bP = 0.0002 compared to P/R Control.
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
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
P/R/B
48 wks
N=103
P/R 4 wks 
P/R/B
44 wks
N=103
P/R/B
48 wks
N=16
P/low dose
R/B
48 wks
N=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
aBased
upon counts for all treatment groups combined, >30%
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
14
Treatment Discontinuations (%)
P/R
Control
48 wks
% (N=104)
P/R 4 wks  P/R/B
24 wks
% (N=103)c,d
P/R 4 wks  P/R/B
44 wks
% (N=103)c
P/low dose R/B
48 wks
% (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
No EPO
n = 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
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
15
Mutations Observed by Population
Sequencing in SPRINT-1 Trial
Major
(≥25%)
Less Common
(≥5% to <25%)
V36M
T54S
Infrequent
(<5%)
V36A, V36L
T54A
V55A
R155K
R155T
A156S
V158I
V170A
I170T
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
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
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