400100100 mg QD N 501 N 440 W8 SOFVEL 400100 mg QD gt 18 years Chronic HCV infection Genotype 1 2 3 4 5 or 6 Treatmentnaïve or IFNexperienced Compensated cirrhosis allowed ID: 556976
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Slide1
SOF/VEL/VOX400/100/100 mg QD
N = 501
N = 440
W8
SOF/VEL 400/100 mg QD
>
18 years
Chronic HCV infectionGenotype 1, 2, 3, 4, 5 or 6Treatment-naïve or IFN-experiencedCompensated cirrhosis ** allowed (exclusion of genotype 3 with cirrhosis)
Randomisation*1 : 1Open-label
*
Randomisation
only in genotype 1, 2, 3 and 4, stratified on genotype, cirrhosis (yes or no) and prior treatment-experience (naïve or IFN-experienced) ; No randomisation (open-label SOF/VEL/VOX) for other genotypes
SVR12
** Metavir F4 or Ishak 5-6 or Fibroscan > 12.5 kPa or Fibrotest > 0.75 + APRI > 2
POLARIS-2
Design
ObjectiveSVR12 (HCV RNA < 15 IU/mL), by ITT: non-inferiority of SOF/VEL/VOX (wo-sided significance level of 5%, lower margin of the 95% CI for the difference = -5%, 95% power)
POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6
Jacobson IM. Gastroenterology 2017; 153:113-22
W12
SVR
12Slide2
SOF/VEL/VOX8 weeks
N = 501
SOF/VEL
12 weeksN = 440
Age, years, mean
53
55
Female, %49
46
White / Black,
%
78 / 10
83 / 11
Genotype, %
1a1b1 other2345 /
6 / unknown
34
13< 11318134 / 6 / < 1
39
13< 112
20
130 / 2 / 0
HCV RNA,
log
10 IU/mL, mean6.16.2IL28B CC, %3331Cirrhosis, %1819IFN-experienced, %2423Discontinuation, N Adverse event / lost to follow-up / pregnancy10 / 0 / 132 / 1 / 0
Baseline characteristics and patient disposition
POLARIS-2
POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6
Jacobson IM.
Gastroenterology
2017; 153:113-22Slide3
SVR12 overall and in genotype 1, %
0
20
40
60
80
100
95 *
Overall
98
233
93
232
169
99
63
172
Genotype 1b
97
21 relapses
4 lost to follow-up
3 relapses
1 discontinuation for AE
4 lost to follow-up
%
16 relapses
Genotype 1
Genotype 1a
92
97
59
501
440
98
2 relapses
2 lost to follow-up
14 relapses
2 relapses
1 relapse
1 lost to follow-up
1 relapse
1 lost to follow-up
SOF/VEL/VOX 8 weeks
SOF/VEL 12 weeks
* Difference (2-sided 95% CI) : -3.4 % (-6.2% to -0.6%)
non inferiority not met
POLARIS-2
POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6
N=
Jacobson IM.
Gastroenterology
2017; 153:113-22Slide4
SVR12 in genotype 2 to 6, %
0
20
40
60
80
100
97
Genotype 2
100
92
99
89
63
98
18
57
Genotype 5
100
2 relapses
1 lost to follow-up
%
Genotype 3
Genotype 4
92
94
63
53
97
1 discontinuation for AE
2 lost to follow-up
2 relapses
3 lost to follow-up
1 relapse
100
100
0
30
2
9
0
1 relapse
Genotype 6
Unknown
POLARIS-2
POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6
SOF/VEL/VOX 8 weeks
SOF/VEL 12 weeks
N=
Jacobson IM.
Gastroenterology
2017; 153:113-22Slide5
CirrhosisN = 174No CirrhosisN = 767SVR12 by cirrhosis status, %
POLARIS-2
POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6
SOF/VEL/VOX 8 weeks
SOF/VEL 12 weeks
0
20
40
60
80
100
96
98
91
%
99
N=
84
411
90
356
7 relapses
1 LTFU
1 relapse
14 relapses
3 LTFU
2 relapses
4 LTFU
1 DC due to AE
Jacobson IM. AASLD 2016, Abs. LB-12 ; Jacobson
IM. Gastroenterology 2017; 153:113-22Slide6
SVR12 by baseline RASs, %
Any
RASs
NS3
only
NS5A
only
NS3 + NS5A
No
RASs
All 64 patients with baseline NS5B nucleoside inhibitor RASs achieved SVR
12
Any
RASs
NS3
only
NS5A
only
NS3 +
NS5A
No
RASs
0
20
406080100
98
94
100
95
228
250
110
120
19
%
99
99
100
100
218
97
921
30
208
91
99
* RASs were analyzed using a 15% cut off
POLARIS-2
POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6
SOF/VEL/VOX 8 weeks
SOF/VEL 12 weeks
N=
Jacobson IM.
Gastroenterology 2017; 153:113-22Slide7
Impact of baseline NS5A RASFor patients with genotype 1a, SVR12 with SOF/VEL/VOX 8 weeks89% if baseline RASs95% if no baseline RASs88% if baseline Q80K94% if absence of baseline 80KViral resistance testing at failureOf the 21 patients who relapsed in the SOF/VEL/VOX group, 1 had treatment-emergent NS5A resistance-associated substitutions Q30R and L31M Among patients receiving SOF/VEL, 1
of the 3 patients who relapsed had the Y93N variant, which is associated with resistance to NS5A inhibitors, at relapse
POLARIS-2
POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6
Jacobson IM. Gastroenterology 2017; 153:113-22Slide8
SOF/VEL/VOX8 weeks
N = 501
SOF/VEL
12 weeksN = 440
At least one adverse
event, %
72
69Serious adverse events, N (%)related to study drug
15 (3%)0
7 (2%)
0
Grade 3-4 adverse events, N (%)
11 (2%)
6 (1%)
Discontinuation due to adverse event, N (%)
0
2 (< 1%) *
Death0
0
Adverse
events in
> 5%
of patients, %
Headache
2723Fatigue2120Diarrhea187Nausea169Asthenia6
6
Insomnia
5
5
Arthralgia
4
5
Grade 3-4 laboratory abnormalities,
%
Hemoglobin < 10 g/dl
ALT > 5 x ULN / AST >
5 x ULN
5
1
0 / < 1
4
1
< 1 / 0
Adverse events
*1 upper respiratory tract infection and 1
Clostridium difficile
infection, both not related to the study medication
POLARIS-2
POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6
Jacobson IM.
Gastroenterology 2017; 153:113-22Slide9
SummarySOF/VEL/VOX for 8 weeks resulted in a 95% SVR12 rate in DAA-naïve genotype 1-6 patients with and without cirrhosisDid not meet non-inferiority as compared to the 98% SVR12 rate with SOF/VEL for 12 weeksThe difference between the regimens was largely attributed to more relapses among patients with genotype 1a infection in the SOF/VEL/VOX groupSOF/VEL/VOX and SOF/VEL were safe and well toleratedMild gastrointestinal adverse events (nausea and diarrhea) were associated with treatment regimens that included VOXThere was no evidence of VOX-related hepatotoxicityThese findings in DAA-naïve patients with or without cirrhosis underscore the very high rates of SVR conferred by SOF/VEL across all HCV genotypesSOF/VEL/VOX for 8 weeks provides a highly efficacious and well-tolerated short-duration regimen in patients for whom adherence to a longer duration regimen may be challenging
POLARIS-2
POLARIS-2 study: SOF/VEL/VOX 8 weeks vs SOF/VEL 12 weeks in patients with genotype 1 to 6
Jacobson IM. AASLD 2016, Abs. LB-12 ; Jacobson IM.
Gastroenterology 2017; 153:113-22