SPRINT-2/RESPOND-2Boceprevir 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
► 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
► To compare the rate of sustained virologic response (SVR) of Boceprevir (BOC) dosed in combination with Peg-interferon 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.
► 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► 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
► RESPOND-2– 403 prior treatment failures to P/R (patients failing to attain sustained
virologic response after an adequate course of therapy)
► 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
– 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• 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
SPRINT-2/RESPOND-2 Phase 3 Trials
Methods► 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.
TrugeneGenotype Assay
Genotype 1a Genotype 1 orGenotype 1b
NS3/4a Sequence Assay
Confirm Subtypeby NS5B Sequence
G1aSequence
Failed
Method 1
Method 2
Phylogenetic Analysis Method 3
HCV Genotype 1 Subtype Analysis
● 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 Genotypein SPRINT-2 and RESPOND-2
● 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.
SPRINT-2(Treatment Naive)
PR only BOC-RGT BOC-PR480
20
40
60
80 G1aG1b
Treatment Arm
35%41%
62/177 51/126 106/179 89/134 147/237 85/117
59%66% 62%
73%
% o
f Pat
ient
s Ac
hiev
ing
SVR
RESPOND-2(Previous PR non-responders)
PR only BOC-RGT BOC-PR48
0
20
40
60
80 G1aG1b
Treatment Arm
24%18%
53%
67% 64%71%
11/46 6/34 50/94 44/66 61/96 43/61%
of P
atie
nts
Achi
evin
g SV
R
Detection of Resistance Associated Variants (RAVs) in Boceprevir Treated patients(SPRINT-2 and RESPOND-2)
●There was a consistently higher % of patients with RAVs detected in patientsinfected with HCV G1a compared to G1b in both BOC arms of each trial.
RAVs (% of all BOC treated patients)
SPRINT 2 RESPOND 20
20
40
60
80G1aG1b
87/468 24/232 31/188 14/127
19%10%
16%11%
% P
atie
nts
with
RAV
s D
etec
ted
RAVs (% of all non-SVR Subjects treated with BOC)
SPRINT 2 RESPOND 20
20
40
60
80 G1aG1b
58%
48% 48%41%
87/151 24/50 31/65 13/41
% o
f Pat
ient
s w
ith R
AVs
Det
ecte
d
Frequency of RAVs in Non-SVR Patients by Genotype 1 subtype
9743
32
15
117
38
0
50
100
150
200
250
300
Genotype 1a Genotype 1b
Pat
ient
s, n
Patients with No Sequence DataPatients with RAVs DetectedPatients with no RAVs Detected
n=246
n=96
47%†
55%†
(SPRINT-2 and RESPOND-2)
9743
32
15
117
38
0
50
100
150
200
250
300
Genotype 1a Genotype 1b
Pat
ient
s, n
Patients with No Sequence DataPatients with RAVs DetectedPatients with no RAVs Detected
n=246
n=96
47%†
55%†
(SPRINT-2 and RESPOND-2)
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
3
61
60 0
19
3 1
68
8 5 40
70 1 1 0 03 3
42
3 3
37
24
0 3 0
26
3 5 5
32
0 0 3 5
0
10
20
30
40
50
60
70
80
90
100
Varia
nts,
%
G1aG1b
Frequency Distribution of Boceprevir RAVs Detected Post Baseline Among Boceprevir Treated patients
(SPRINT-2 and RESPOND-2)
● V36M and R155K were the predominant (>25%) RAVs in HCV G1a● T54A/S, A156S and V170A were the predominant RAVs (>25%) in HCV G1b
RAV Genotype WT Codon RAV Codon # changes
V36M G1aG1b
GTG GTT/C
ATGATG
12
R155K G1aG1b
AGGCGG
AAGAAG
12
T54A G1aG1b
ACTACT
GCTGCT
11
T54S G1aG1b
ACTACT
TCTTCT
11
A156S G1aG1b
GCCGCC/T
TCCTCC or TCT
11
V/I170A G1aG1b
ATCG/ATA/G
GCCGCA/G
21
Genetic Variation Between Genotype 1a and 1b Partially Explains Different RAV Frequencies
►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
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.
8752
39 115
020406080
100120140160180
Interferon Responsive Poorly Interferon Responsive
Pat
ient
s, n
Patients With No RAVs Detected Patients With RAVs Detected
31% 69%
126
167
≥1 log ↓ in viral load at TW4 <1 log ↓ in viral load at TW4
8752
39 115
020406080
100120140160180
Interferon Responsive Poorly Interferon Responsive
Pat
ient
s, n
Patients With No RAVs Detected Patients With RAVs Detected
31% 69%
126
167
≥1 log ↓ in viral load at TW4 <1 log ↓ in viral load at TW4
Frequency and Distribution of RAVs Detected at Baseline vs. Post-Baseline RAVs Associated With Virologic Failure
(Boceprevir Arm of SPRINT-2 and RESPOND-2)
All data based on population sequencing.RAVs=resistance associated amino acid variants.
Baseline RAVs Post-Baseline RAVs
8072
3623
1613
1210
96
422
1111110000
0 20 40 60 80
R155KV36MT54ST54A
A156SV55A
V170AV158I
R155TA156TV36A
A156VM175LT54CT54GI170FI170T
V170TV55I
V170MV36I
V36LQ41H
Patients, n
12
1810
22000000100000
1522
144
0 20 40 60 80
R155KV36MT54ST54A
A156SV55A
V170AV158I
R155TA156TV36A
A156VM175LT54CT54GI170FI170T
V170TV55I
V170MV36I
V36LQ41H
Patients, n
Not associated with Viral Failure
Associated with Viral Failure
0%778%3643V36M, R155K, T54S/A and V55A50%680%1521Other Baseline RAVs23%1376%5164Patients with Baseline RAVs34%25479%648902Patients without Baseline RAVs
SVR(%)
Patientsn
SVR(%)
PatientnTotal†
Poor Interferon Responders§
Interferon Responders‡
0%778%3643V36M, R155K, T54S/A and V55A50%680%1521Other Baseline RAVs23%1376%5164Patients with Baseline RAVs34%25479%648902Patients without Baseline RAVs
SVR(%)
Patientsn
SVR(%)
PatientnTotal†
Poor Interferon Responders§
Interferon Responders‡
(SPRINT-2 and RESPOND-2)
SVR Rates By Treatment Week 4 Response in Patients With or Without Baseline RAVs
†Total 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 log10 decrease in viral load at treatment week 4.§ Patients with <1 log10 decrease in viral load at treatment week 4.SVR=sustained virologic response; RAVs=resistance associated amino acid variants.
SummaryBoceprevir, 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
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