C-EDGE TN Study: grazoprevir/elbasvir
in genotype 1, 4 or 6
 Design
Randomisation*
3:1
Double blind
> 18 years
HCV infection
Genotype 1, 4, 6
Treatment-naïve
HCV RNA > 10,000 IU/ml
Compensated cirrhosis** allowed
No HBV or HIV co-infection
** Metavir F4 or fibroscan > 12.5 kPa or
FibroTest > 0.75 + APRI > 2
W12
W24 W28
N = 316 GZR/EBR
100/50 mg qd
W16
N = 105
Placebo
GZR/EBR
* Randomisation was stratified on genotype (1 or 4 or 6) and
cirrhosis (yes or no)
• Objective
•
C-EDGE TN
SVR12 (HCV RNA < 15 IU/ml) by intention to treat analysis : superiority to historical SVR12 of
simeprevir + PEG-IFN + RBV (73%), at an overall 1-sided alpha value of 0.025, 99% power
Zeuzem S. Ann Intern Med 2015; 163:1-13
C-EDGE TN Study: grazoprevir/elbasvir
in genotype 1, 4 or 6
Baseline characteristics and patient disposition
Age, years, mean
Female
Black / White / Asian
GZR/EBR
N = 316
Placebo
N = 105
52.2
46%
53.8
47%
19% / 60% / 17%
17% / 70% / 12%
50%
42%
6%
3%
6.4
34%
22%
77 (62)
190
5
51%
38%
8%
3%
6.4
35%
21%
75 (64)
194
1
3/1/1
1/0/0
Genotype
1a
1b
4
6
HCV RNA log10 IU/ml
IL28B CC
Metavir F4
ALT, IU/L, mean (SD)
Platelets < 109/L, mean
Discontinuation, n
For adverse event / lost to follow-up / death
C-EDGE TN
Zeuzem S. Ann Intern Med 2015; 163:1-13
C-EDGE TN Study: grazoprevir/elbasvir
in genotype 1, 4 or 6
SVR12 (HCV RNA < 15 IU/ml), % (95% CI)
%
100
99
(95-100)
100
(82-100)
157
131
18
10
Genotype 1a
GT 1b
GT 4
GT 6
94.6
(91.5-96.8)
92
(86-96)
316
All patients
80
(44-98)
75
50
25
0
Non-virologic failure
4
3
1
0
0
Breakthrough
1
1
0
0
0
Relapse
12
9
1
0
2
C-EDGE TN
Zeuzem S. Ann Intern Med 2015; 163:1-13
C-EDGE TN Study: grazoprevir/elbasvir
in genotype 1, 4 or 6
SVR12 (HCV RNA < 15 IU/ml) by subgroup, % (95% CI)
100
97
(92-99)
93
(87-97)
96
(92-98)
171
145
106
208
246
70
Male
Female
Non-CC
No
Yes
93
%
(88-96)
97
94
(90-97) (90-100)
100
(96-100)
92
(88-96)
75
50
25
0
Sex
C-EDGE TN
CC
IL28B genotype
Cirrhosis
94
No
222
Yes
HCV RNA
> 800 000 IU/ml
Zeuzem S. Ann Intern Med 2015; 163:1-13
C-EDGE TN Study: grazoprevir/elbasvir
in genotype 1, 4 or 6
SVR12 in genotype 1 according to baseline NS3 and NS5A RAVs
RAV
at baseline
% (n/N)
SVR12
all patients
% (N/n)
SVR12
RAVs with ≤ 5-fold
 susceptibility
SVR12
RAVs with > 5-fold
 susceptibility
57% (86/151)
43% (65/151)
97% (83/86)
89% (58/65)
97% (83/86)
-
0% (0/0)
-
19% (25/129)
81% (104/129)
96% (24/25)
100% (104/104)
96% (21/22)
-
100% (3/3)
-
12% (19/154)
88% (135/154)
58% (11/19)
99% (133/135)
90% (9/10)
-
22% (2/9)
-
14% (18/130)
86% (112/130)
94% (17/18)
100% (112/112)
100% (1/1)
-
94% (16/17)
-
NS3 RAVs
Genotype 1a
Present
Absent
Genotype 1b
Present
Absent
NS5A RAVs
Genotype 1a
Present
Absent
Genotype 1b
Present
Absent
All 11 patients with virologic failure had baseline HCV RNA > 800,000 IU/ml
(selection of NS5A RAV in 10/11)
C-EDGE TN
Zeuzem S. Ann Intern Med 2015; 163:1-13
C-EDGE TN Study: grazoprevir/elbasvir
in genotype 1, 4 or 6
Baseline and emergent resistance variants in virologic failure cases
NS3 RAVs
Emerging
Baseline
at failure
(in addition)
GT
Baseline
HCV RNA
(IU/ml)
Day of
virologic
failure
Breakthrough
Relapse
Relapse
1a
1a
1a
1,238,923
5,127,102
2,134,448
Rx D71
F/U D28
F/U D71
Q80K, S122G
WT
WT
V36M
None
D168A
Relapse
1a
948,279
F/U D70
Q80K
D168A
Relapse
1a
3,908,965
F/U D84
WT
D168A
Relapse
Relapse
Relapse
Relapse
Relapse
1a
1a
1a
1b
1a
5,282,871
1,846,427
1,939,436
4,475,338
3,913,374
FU D62
F/U D54
F/U D61
F/U D89
F/U D29
Relapse
6
15,689,194
F/U D25
Relapse
Relapse
1a
6
1,574,151
15,056,901
F/U D56
F/U D25
WT
WT
WT
T54S
V55A
V36I, L80Q,
S122T, I132L,
I170V
WT
L80K, I170V
C-EDGE TN
NS5A RAVs
Emerging at
Baseline
failure
(in addition)
None
None
Y56H, D168A
V170I
D168A
L31L/M
L31M
Q30H/Q
M28V, Q30L,
Y93H
M28M/V,
H58H/D
L31M
WT
WT
Y93H
Q30R, L31L/M
Q30R
Q30R
Y93H
Q30R
Q30R, L31M
Y93N
L31F
None
D168Y
WT
None
None
Y56Y/H, D168E
M28V
F28L
M28G
L31M
L31V
Q30R
Zeuzem S. Ann Intern Med 2015; 163:1-13
C-EDGE TN Study: grazoprevir/elbasvir
in genotype 1, 4 or 6
Adverse events, n (%)
GZR/EBR
N = 316
Placebo
N = 105
Headache
52 (17%)
19 (18%)
Fatigue
49 (16%)
18 (17%)
Nausea
28 (9%)
8 (8%)
Arthralgia
20 (6%)
6 (6%)
Non-cirrhotic
Cirrhotic
Common AEs (> 5% in GZR/EBR)
GZR/EBR
N = 246
Placebo
N = 83
GZR/EBR
N = 70
Placebo
N = 22
At least one adverse event
175 (71%)
57 (69%)
38 (54%)
15 (68%)
Drug-related adverse event
96 (39%)
32 (39%)
18 (26%)
9 (41%)
Serious adverse events
7 (3%)
3 (4%)
2 (3%)
0 (0%)
Serious drug-related adverse event
0 (0%)
0 (0%)
0 (0%)
0 (0%)
Discontinuation due to adverse event
2 (1%)
0 (0%)
1 (1%)
1 (5%)
Death
1 (<1%)
0 (0%)
1 (1%)
0 (0%)
C-EDGE TN
Zeuzem S. Ann Intern Med 2015; 163:1-13
C-EDGE TN Study : grazoprevir/elbasvir in
genotype 1, 4 or 6
Laboratory abnormalities, n (%)
GZR/EBR
N = 316
Placebo
N = 105
3 (1.0%)
4 (3.8%)
4 (1.3%)
0 (0%)
3 (0.9%)
0 (0%)
1 (0.3%)
0 (0%)
9 (2.9%)
4 (3.8%)
0 (0%)
0 (0%)
2 (0.6%)
1 (1.0%)
Grade 2
Increased lipase
0 (0%)
0 (0%)
Grade 1-2
101 (32.0%)
25 (23.8%)
Grade 3-4
19 (6.0%)
5 (4.8%)
Late elevation of ALT or AST
> 2.0-5.0 x ULN
> 5.0 x ULN
Elevation of total bilirubin
> 2.5-5.0 x ULN
> 5.0 x ULN
Decreased hemoglobin
Grade 1-2
Grade 3-4
Increased creatinine
Grade 1
C-EDGE TN
Zeuzem S. Ann Intern Med 2015; 163:1-13
C-EDGE TN Study: grazoprevir/elbasvir
in genotype 1, 4 or 6
 Summary
– A 12-week regimen of the oral fixed dose combination of once-daily,
single-tablet of grazoprevir/elbasvir, achieved an overall SVR12 of 95%
•
•
•
•
High efficacy in genotypes 1 and 4
SVR12 lower in genotype 6
High efficacy in cirrhotics (SVR12 = 97.1%)
Lower efficacy observed among patients with high viral load (HCV RNA >
800,000 IU/ml)
– Overall virologic failure rate was 4%
• Baseline NS3 RAVS did not affect efficacy
• Association between virologic failure and the presence of baseline NS5A
RAVs, which was most apparent in genotype 1a with baseline RAVs
demonstrating > 5-fold potency reduction to elbasvir
• Emergence of (additional) NS3 and/or NS5A RAVs at failure was common
– Grazoprevir/elbasvir was generally well-tolerated, with a similar safety
profile in cirrhotic and non-cirrhotic patients
– Limitations
• No active-control group
C-EDGE TN
Zeuzem S. Ann Intern Med 2015; 163:1-13