Transcript Slide 1

SPRINT-2/RESPOND-2
Boceprevir Plus Standard of Care
Phase 3 Clinical Trials
Analysis of Resistance Associated Variants by
HCV Genotype 1 subtypes 1a and 1b
Background
►
Nearly 170 million people worldwide are chronically infected with
Hepatitis C virus (HCV)
– HCV genotype 1 is the most common and least responsive to
peginterferon alfa and ribavirin with geographic differences in HCV
genotype 1 subtypes:
• Genotype 1a is predominant in Northern Europe and North America
• Genotype 1b is predominant in Southern and Eastern Europe and
Japan
– Leading indication for liver transplantation in Europe and United
States and is major etiologic factor in hepatocellular carcinoma
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Boceprevir - binds to the active site of the HCV NS3 protease
– VictrelisTM (Boceprevir) approved by FDA for treatment use in
combination with peginterferon alfa and ribavirin in adult patients
(≥18 years of age) with compensated liver disease, including
cirrhosis, who are previously untreated or who have failed previous
interferon and ribavirin therapy.
Objectives
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To compare the rate of sustained virologic response (SVR)
of Boceprevir (BOC) dosed in combination with Peginterferon alfa-2b (P) plus ribavirin (R) standard of care
therapy in patients with Genotype 1a (G1a) and Genotype
1b (G1b) in the SPRINT-2 and RESPOND-2 clinical trials.
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To compare the frequency of Resistance Associated amino
acid Variants (RAVs) between G1a and G1b viruses
among non-SVR patients enrolled in SPRINT-2 and
RESPOND-2
SPRINT-2/RESPOND-2 Phase 3 Trials
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SPRINT-2
- 1,097 previously untreated patients (two cohorts enrolled
and analyzed separately)
• Cohort 1: 938 (86%) non-Black patients
• Cohort 2: 159 (14%) Black patients
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RESPOND-2
– 403 prior treatment failures to P/R (patients failing to attain sustained
virologic response after an adequate course of therapy)
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Patient characteristics common to both studies
– Patients mono-infected with chronic hepatitis C genotype 1
– Co-infection with HIV or HBV excluded
– Adult (≥18 years) patients
– Compensated liver disease with all degrees of fibrosis
– Studies conducted primarily in North America and Western Europe
SPRINT-2/RESPOND-2 Phase 3 Trials
– Double-blind for BOC
– 3 treatment arms (all
patients received a 4 week lead-in of
P/R prior to having BOC or placebo added to their
regimen)
• Arm 1: PR48 (Control)
– 4 weeks P/R then 44 weeks P/R + BOC placebo
• Arm 2: BOC RGT
– 4 weeks P/R then P/R + BOC using response guided therapy (RGT)
• Arm 3: BOC/PR48
– 4 weeks P/R then 44 weeks P/R + BOC
– Primary endpoint: SVR in each experimental arm compared
to control arm
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•
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COBAS TaqMan 2.0 (Roche) HCV Test
Limit of Detection (LOD): 9.3 IU/ml
Limit of Quantitation: 25 IU/ml
All decisions based on LOD
Methods
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Plasma samples were collected for resistance testing from
patients at baseline and at or near the time of virologic
failure in patients that did not achieve SVR.
Viral genotype was determined at screening using the
TruGene assay. Subsequently, genotyping was
determined by a combination of NS5b sequencing and/or
inferred from positive amplification using subtype-specific
primers (Virco BVM, Belgium)
Population sequencing of the NS3 region was performed
by Virco.
Sequences from G1a and G1b viruses were aligned to the
H77S and Con 1 reference strains, respectively. Major
RAVs identified based on changes at specified loci
compared with reference strain sequences.
HCV Genotype 1 Subtype Analysis
Trugene
Method 1
Genotype Assay
Genotype 1a
Genotype 1 or
Genotype 1b
G1a
Sequence
Failed
Confirm Subtype
by NS5B Sequence
Method 2
NS3/4a
Sequence Assay
Phylogenetic Analysis
Method 3
● Many patients genotyped as 1a using the Trugene assay were inconsistent with
methods 2 and 3 (low concordance)
● High concordance was observed between method 2 (used for final data analysis)
and phylogenetic analysis of NS3/4a sequences
Patients Achieving SVR by HCV Genotype
in SPRINT-2 and RESPOND-2
80
G1a
G1b
60
40
RESPOND-2
(Previous PR non-responders)
73%
66%
59%
62%
41%
35%
20
0
62/177 51/126
PR only
106/179 89/134
BOC-RGT
147/237 85/117
BOC-PR48
Treatment Arm
% of Patients Achieving SVR
% of Patients Achieving SVR
SPRINT-2
(Treatment Naive)
80
G1a
G1b
60
67%
71%
64%
53%
40
24%
20
0
11/46
18%
6/34
PR only
50/94
44/66
BOC-RGT
61/96
43/61
BOC-PR48
Treatment Arm
● There was a consistent but small numerical advantage for patients
Infected with G1b compared to G1a to achieve SVR in both Boceprevir
arms of each study.
Detection of Resistance Associated Variants (RAVs) in
Boceprevir Treated patients
(SPRINT-2 and RESPOND-2)
80
G1a
G1b
60
40
20
19%
16%
10%
0
87/468
24/232
SPRINT 2
31/188
11%
14/127
RESPOND 2
RAVs (% of all non-SVR Subjects treated with BOC)
% of Patients with RAVs Detected
% Patients with RAVs Detected
RAVs (% of all BOC treated patients)
80
60
G1a
G1b
58%
48%
48%
41%
40
20
0
87/151
24/50
SPRINT 2
31/65
13/41
RESPOND 2
●There was a consistently higher % of patients with RAVs detected in patients
infected with HCV G1a compared to G1b in both BOC arms of each trial.
Frequency of RAVs in Non-SVR Patients by
Genotype 1 subtype
(SPRINT-2 and RESPOND-2)
Patients with No Sequence Data
300
250
n=246
Patients, n
32
Patients with RAVs Detected
Patients with no RAVs Detected
200
150
117
55%†
100
50
97
n=96
15
38
47%†
43
0
Genotype 1a
Genotype 1b
Patients infected with HCV Genotype 1b had lower % RAVs
detected compared to Genotype 1a Infected patients
† Expressed
as a percentage of patients with sequence data available.
RAVs=Resistance Associated Amino Acid Variants
Frequency Distribution of Boceprevir RAVs Detected
Post Baseline Among Boceprevir Treated patients
(SPRINT-2 and RESPOND-2)
100
G1a
G1b
90
80
68
Variants, %
70
61
60
50
42
37
40
30
24
19
20
10
32
33
3
6
0
3
0
3
26
3
10
3
8
0
5
43
0
5 75
0
5
10 10 03 0
V5
5
R1 I
55
K
R1
55
T
A1
56
S
A1
56
T
A1
56
V
V1
58
V1 I
70
A
I1
70
F
I1
70
T
V1
70
T
M
17
5L
V3
6A
V3
6M
T5
4A
T5
4C
T5
4G
T5
4S
V5
5A
0
● V36M and R155K were the predominant (>25%) RAVs in HCV G1a
● T54A/S, A156S and V170A were the predominant RAVs (>25%) in HCV G1b
Genetic Variation Between Genotype 1a and 1b
Partially Explains Different RAV Frequencies
RAV
Genotype
WT Codon
RAV Codon
#
changes
V36M
G1a
GTG
ATG
1
R155K
G1b
G1a
GTT/C
AGG
ATG
AAG
2
1
T54A
G1b
G1a
CGG
ACT
AAG
GCT
2
1
T54S
G1b
G1a
ACT
ACT
GCT
TCT
1
1
A156S
G1b
G1a
ACT
GCC
TCT
TCC
1
1
V/I170A
G1b
G1a
GCC/T
ATC
TCC or TCT
GCC
1
2
G1b
G/ATA/G
GCA/G
1
►V36M, R155K in G1b and V170A in G1a require 2 nucleotide changes and likely accounts for the different
frequency observed between HCV G1a and G1b
RAVs Detected in a higher % of Non-SVR Patients
with a poor Interferon Response at TW4
167
180
Patients, n
160
140
126
120
100
80
39
115
31%
69%
60
40
20
87
52
0
Interferon Responsive
≥1 log ↓ in viral load at TW4
Patients With No RAVs Detected
Poorly Interferon Responsive
<1 log ↓ in viral load at TW4
Patients With RAVs Detected
8 Patients missing TW4 viral load data and 42 with no sequence data are not included.
RAV=resistance associated amino acid variant; SVR=sustained virologic response; TW=treatment week.
Frequency and Distribution of RAVs Detected at Baseline
vs. Post-Baseline RAVs Associated With Virologic Failure
(Boceprevir Arm of SPRINT-2 and RESPOND-2)
Baseline RAVs
Q41H
V36L
V36I
V170M
V55I
V170T
I170T
I170F
T54G
T54C
M175L
A156V
V36A
A156T
R155T
V158I
V170A
V55A
A156S
T54A
T54S
V36M
R155K
Post-Baseline RAVs
4
14
Not associated with Viral Failure
2
2
15
0
0
0
0
0
1
0
0
0
0
0
0
22
0
1
Associated with Viral Failure
18
2
1
0
20
40
60
Patients, n
All data based on population sequencing.
RAVs=resistance associated amino acid variants.
80
Q41H
V36L
V36I
V170M
V55I
V170T
I170T
I170F
T54G
T54C
M175L
A156V
V36A
A156T
R155T
V158I
V170A
V55A
A156S
T54A
T54S
V36M
R155K
0
0
0
0
1
1
1
1
1
1
2
2
4
6
9
10
12
13
16
23
36
72
80
0
20
40
Patients, n
60
80
SVR Rates By Treatment Week 4 Response in Patients
With or Without Baseline RAVs
(SPRINT-2 and RESPOND-2)
Patients without Baseline RAVs
Patients with Baseline RAVs
Other Baseline RAVs
V36M, R155K, T54S/A and V55A
Total†
902
64
21
43
†Total
Interferon
Responders‡
Patient
SVR
n
(%)
648
79%
51
76%
15
80%
36
78%
Poor Interferon
Responders§
Patients SVR
n
(%)
254
34%
13
23%
6
50%
7
0%
with Week 4 vial load available (treatment week 4 data not available for 12 patients without baseline
RAVs and 2 with baseline RAVs).
‡Patients with ≥1 log
10 decrease in viral load at treatment week 4.
§ Patients with <1 log
10 decrease in viral load at treatment week 4.
SVR=sustained virologic response; RAVs=resistance associated amino acid variants.
Summary
Boceprevir, in combination with P/R significantly improved
SVR rates compared with P/R alone in both treatment
naïve and previously treated patients
SVR rates among patients with G1b virus were consistently
higher compared with G1a patients in both SPRINT-2 and
RESPOND-2 phase 3 trials
Detection of resistance variants was more common among
G1a vs G1b viruses in both pivotal trials when analyzed
by all boceprevir treated and subset not achieving SVR
►predominant RAVs for G1a : V36M and R155K
►predominant RAVs for G1b : T54A/S, A156S, V170A
Conclusions
► Genetic
variation between G1a and G1b viruses
likely contributes to the higher rate of SVR and
lower rate of major RAV detection (in non-SVR
patients) in HCV G1b patients treated with
Boceprevir combination therapy
► non-SVR
patients with a good Interferon response
had fewer RAVs detected
► Majority of poorly interferon responsive non-SVR
patients had RAVs detected at failure primarily due
to the fact most patients failed during the BOC
dosing period