400100100 mg QD N 263 N 152 W12 Placebo gt 18 years Chronic HCV infection Genotype 1 2 3 4 5 or 6 NS5A inhibitorexperienced for 4 weeks exclusion if discontinued due to an adverse ID: 623567
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Slide1
SOF/VEL/VOX400/100/100 mg QD
N = 263
N = 152
W12
Placebo
>
18 years
Chronic HCV infectionGenotype 1, 2, 3, 4, 5 or 6NS5A inhibitor-experienced for ≥ 4 weeks (exclusion if discontinued due to an adverseevent or unsuccessful due to non-compliance)Compensated cirrhosis ** allowed
Randomisation*1 : 1Double blind
*
Randomisation
only in genotype 1, stratified on cirrhosis (yes or no) ;
No randomisation (open-label SOF/VEL/VOX) for all other genotypes
SVR12
** Metavir F4 or Ishak 5-6 or Fibroscan > 12.5 kPa or Fibrotest > 0.75 + APRI > 2
POLARIS-1
Design
ObjectiveSVR12 (HCV RNA < 15 IU/mL), with 95% CI, by ITT: superiority > 10% to a prespecified rate of 85% (2-sided significance level of 5%), for each regimen, 90% power
POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6
Bourlière
M. NEJM 2017; 376:2134-46Slide2
SOF/VEL/VOXN = 263
Placebo
N = 152
Age, years, mean
58
59
Female, %
24
20
White, %
80
82
Genotype, %
1a
1b1 other234
5 / 6 / unknown
38
1722308< 1 / 2 / < 1
77
20
10000 / 1 / 0HCV RNA, log10 IU/mL, mean6.36.3Cirrhosis, %4634Previous HCV treatment, %NS5A + NS3 +± NS5BNS5A + NS5BNS5ANS5B ± NS3≥ 2 regimens32617< 13941536133Discontinuation, N (adverse event / lost to follow-up)2 (1 / 1)3 (3 / 0)
Baseline characteristics and patient disposition
POLARIS-1
POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6
Bourlière
M. NEJM 2017; 376:2134-46Slide3
* Superiority to 85% (p < 0.001)SOF/VEL/VOX 12 weeks: SVR12 overall and by subgroups, % (95% CI)
0
20
40
60
80
100
96.2 *
(93-98)
Total
99
(95-100)
No
121
93
(87-97)
Cirrhosis
150
101
100
(92-100)
4
5
100
6
Genotype
45
5
95
(87-99)
6 relapses
1 on-treatment failure
2 withdrew consent
1 lost to follow-up
1 withdrew consent
1 lost to follow-up
%
6 relapses
1 on-treatment failure
1 withdrew consent
1
3
1b
1a
2
96
(90-99)
100
(48-100)
78
22
6
1
100
(54-100)
263
142
97
91
(71-99)
Yes
POLARIS-1
POLARIS-1 study: SOF/VEL/VOX in NS5A
inhibitor-experienced patients with genotype 1 to 6
N=
Bourlière
M. NEJM 2017; 376:2134-46Slide4
SVR12 by baseline RASs (15% cutoff), %
0
20
40
60
80
100
97.7
97.1
97.2
100
96.8
Any RASs
NS3 only
NS5A only
NS3 + NS5A
No RASs
43
205
9
124
72
%
Two patients had S282T at baseline, both achieved SVR
12
None of the patients who relapsed had treatment-emergent RASs
POLARIS-1
POLARIS-1 study: SOF/VEL/VOX in NS5A
inhibitor-experienced patients with genotype 1 to 6
N=
Bourlière
M. NEJM 2017; 376:2134-46Slide5
Sex, age, raceGenotype
Cirrhosis
HCV
RNA, log10 IU/mL
Prior HCV regimen
Resistance-associated
substitutions
NS3
NS5A
Baseline
Relapse
Baseline
Relapse
M, 61, white
1a
Yes
6.7
LDV/SOF
24W
Q80K
Q80KY93NY93NM, 60, white3aYes7.6SOF/VEL 12WNoneNoneY93Y/HY93HF, 62, White3aYes6.3DCV + SOF 12WNoneNoneA30KA30KM, 65, white3aYes4.9DCV + SOF 25WNoneNone
None
None
M, 60, white
3a
Yes
5.3
SOF/VEL
12W
None
None
Y93Y/H
Y93H
M, 61, white
4d
Yes
5.7
LDV/SOF 12W
None
None
L30R
L30R + Y93H
M, 60, black *
1a
Yes
6.3
LDV/SOF
Q80K
Q80K
Q30T
Q30T + L31L/M + Y93Y/H
*
Only
patient
with
virologic
breakthrough
:
low plasma concentrations of GS-331007 (the chief SOF metabolite), VEL, and VOX at weeks 8 and 12, suggestive of nonadherenceCharacteristics of patients with virologic
failure (n = 7)POLARIS-1POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6 Bourlière M. NEJM 2017; 376:2134-46Slide6
SOF/VEL/VOXN = 263
Placebo
N = 152
At least one adverse
event, %
78
70
Serious adverse events, N (%)related to study drug
5 (2%)0
7 (5%)
0
Grade 3-4 adverse events, N (%)
5 (2%)
4
(3%)
Discontinuation due to adverse event, N (%)
1 (< 1%)
Angioedema attributed to ramipril3 (2%)
Death
0
0Adverse events in > 10% of patients, %Headache2517Fatigue2120Diarrhea1812Nausea148Grade 3 / Grade 4 laboratory abnormalities, %5 / 2
12
/ 2
Adverse events
POLARIS-1
POLARIS-1 study: SOF/VEL/VOX in NS5A
inhibitor-experienced patients with genotype 1 to 6
Bourlière
M. NEJM 2017; 376:2134-46Slide7
SummaryIn NS5A-inhibitor experienced patients, treatment with SOF/VEL/VOX for 12 weeks resulted in a 96.2% SVR12 rate in difficult-to-cure patients with multiple unfavorable characteristics Treatment-emergent NS5A RAS was observed in 1/6 patients with relapseSOF/VEL/VOX was well tolerated with an adverse event profile similar to that observed in placebo recipientsSOF/VEL/VOX for 12 weeks provides a single tablet, once daily, highly effective, RBV-free treatment for NS5A inhibitor-experienced patients
POLARIS-1
POLARIS-1 study: SOF/VEL/VOX in NS5A inhibitor-experienced patients with genotype 1 to 6
Bourlière M. NEJM 2017; 376:2134-46