sofosbuvir/velpatasvir/voxilaprevirfor 12 weeks as a ... · diana m. brainard, g. mani subramanian,...
TRANSCRIPT
Sofosbuvir/Velpatasvir/Voxilaprevir for 12 Weeks as a Salvage Regimen in NS5A
Inhibitor-Experienced Patients with Genotype 1–6 Infection: The Phase 3 POLARIS-1 StudyMarc Bourlière, Stuart C. Gordon, Alnoor Ramji, Natarajan Ravendhran,
Tram T. Tran, Robert H. Hyland, Jie Zhang, Hadas Dvory-Sobol, Luisa M. Stamm, Diana M. Brainard, G. Mani Subramanian, John G. McHutchison, Ziad H. Younes,
Michael P. Curry, Eugene R. Schiff, K. Rajender Reddy, Michael P. Manns
Abstract 194
POLARIS-1: Pangenotypic Single Tablet Regimen with Inhibitors of HCV NS5B (Nucleotide) + NS5A + NS3
Sofosbuvir (SOF)/Velpatasvir (VEL)• SOF: Nucleoside polymerase inhibitor with activity
against HCV GT 1-6• VEL: Potent pangenotypic
NS5A inhibitor
Voxilaprevir (VOX)• HCV NS3/4A Pl with potent antiviral activity
against GT 1-6, including most RASs
SOF/VEL/VOX• Once daily, oral, fixed-dose combination
(400/100/100 mg) for GT 1-6
Bourlière M, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 194.
VELNS5Ainhibitor
SOFNucleotidepolymerase
inhibitor
VOXNS3/4Aproteaseinhibitor
VELNS5Ainhibitor
SOFNucleotidepolymerase
inhibitor
VOXNS3/4Aproteaseinhibitor
SOF/VEL/VOXn=263
Placebon=152
0 12Week
SVR12
SVR12
24
POLARIS-1: Study Design
• Double-blind, randomized, placebo-controlled trial in NS5A-experienced GT 1–6 patients conducted at 109 sites (USA, Canada, France, Germany, UK, Australia, New Zealand)
• Patients with GT 1 at screening randomized equally to SOF/VEL/VOX or matching placebo (all other GTs assigned to SOF/VEL/VOX)• Stratified by presence of cirrhosis
Bourlière M, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 194.
POLARIS-1: DemographicsSOF/VEL/VOX
12 weeksn=263
Placebo12 weeks
n=152Mean age, y (range) 58 (27–84) 59 (29–80)
Male, n (%) 200 (76) 121 (80)
White, n (%) 211 (80) 124 (82)
Mean BMI, kg/m2 (range) 29 (18–67) 29 (18–61)
Cirrhosis, n (%) 121 (46) 51 (34)
Genotype, n (%)
1a / 1b / Other 101 (38) / 45 (17) / 4 (2) 117 (77) / 31 (20) / 2 (1)
2 5 (2) —
3 78 (30) —
4 22 (8) —
5 / 6 / Unknown 1 (<1) / 6 (2) / 1 (<1) 0 / 2 (1) /0
IL28B CC, n (%) 47 (18) 27 (18)
Mean HCV RNA, log10 IU/mL (range) 6.3 (1.6–7.7) 6.3 (3.7–7.6)
Bourlière M, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 194.
POLARIS-1: Results: Prior NS5A Treatment
51
27
11 13
0
10
20
30
40
50
60
Patie
nts,
%
LDV DCV OMB Other
133263
70263
30263
33263
3 patients received both LDV and DCV; DCV, daclatasvir; LDV, ledipasivir; OMB, ombitasvir.
Bourlière M, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 194.
POLARIS-1: Results: SVR12
• No patients who received placebo achieved SVR• p <0.001 for superiority compared with prespecified 85% performance
goal for SOF/VEL/VOX* Exposure was consistent with non-adherence.
SVR
12, %
96
0
20
40
60
80
100
SOF/VEL/VOX12 Weeks
253/263
6 relapses1 on-treatment failure*2 withdrew consent1 LTFU
Bourlière M, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 194.
POLARIS-1: Results (SVR12) by Cirrhosis Status
Bourlière M, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 194.
9993
0
20
40
60
80
100
No Cirrhosis Cirrhosis
SVR
12, %
SOF/VEL/VOX 12 Weeks (n=263)
140/142 113/121
1 withdraw consent1 LTFU
6 relapses1 on-treatment failure1 withdraw consent
POLARIS-1: Results (SVR12) by Subtype/Genotype
Bourlière M, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 194.
SOF/VEL/VOX 12 Weeks (n=263)97 96 100 100 95 91
100 100
0
20
40
60
80
100
GT 1 GT 1a GT 1b GT 2 GT 3 GT 4 GT 5 GT 6
SVR
12, %
146150
97101
4545
55
7478
2022
66
11
POLARIS-1 : Results (SVR12)
Bourlière M, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 194.
SOF/VEL/VOX 12 Weeks (n=263)98 96 100
94 97
0
20
40
60
80
100
No RASs Any RASs NS3 Only NS5A Only NS3 + NS5A
SVR
12, %
146150
199208
99
120127
7072
Two patients had S282T at baseline, both achieved SVR12
A Randomized, Controlled, Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir/Velpatasvirfor 12 Weeks in Direct-Acting Antiviral-Experienced Patients
with Genotype 1–6 HCV Infection: The POLARIS-4 StudyStefan Zeuzem, Steven L. Flamm, Myron Tong, John M. Vierling, Stephen Pianko, Peter Buggisch,
Victor de Lédinghen7 Robert H. Hyland, Xiaoru Wu, KC Huang, Evguenia S. Svarovskaia, Luisa M. Stamm, Diana M. Brainard, G. Mani Subramanian, John G. McHutchison, Elizabeth C. Verna, Meena B. Bansal,
Charles S. Landis, Simone I. Strasser, Curtis L. Cooper, Kris Kowdley
Abstract 109
n=182 SOF/VEL/VOX
SOF/VELn=151
0 12Week 24
SVR12
POLARIS-4: Study Design
• Open-label, randomized, active-comparator trial in DAA-experienced GT 1–6 patients without prior NS5A inhibitor experience conducted at 102 sites (USA, Canada, France, Germany, UK, Australia, New Zealand)
• Patients with HCV GT 1, 2, and 3 at screening were randomized equally to SOF/VEL/VOX or SOF/VEL (all other GTs assigned to SOF/VEL/VOX)• Stratified by GT and presence of cirrhosis
Zeuzum S, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 109.
POLARIS-4: Demographics• Randomized controlled trial of persons who failed
non-NS5A containing DAA regimens (SOF 73% or SOF+RBV/IFN)• SOF/VEL/VOX for 12 weeks (n=182) versus SOF/VEL for 12 weeks (n=151)
Zeuzum S, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 109.
SOF/VEL/VOX12 Weeks
n=182
SOF/VEL12 Weeks
n=151Mean age, y (range) 57 (25-85) 57 (24-80)Male, n (%) 143 (79) 114 (75)White, n (%) 160 (88) 131 (87)Mean BMI, kg/m2 (range) 29 (18-45) 29 (18-53)Cirrhosis, n (%) 84 (46) 69 (46)
Genotype, n (%)
1a / 1b 54 (30) / 24 (13) 44 (29) / 22 (14)2 31 (71) 33 (22)3 54 (30) 52 (34)4 19 (10) -
IL28B CC, n (%) 33 (18) 29 (19)Mean HCV RNA, log10 IU/mL (range) 6.3 (5.0 – 7.5) 6.3 (3.6 - 7.3)
POLARIS-4: Prior HCV Treatment
Other NS5B included mericitabine (n=7); other NS5B+NS3 included deleobuvir+faldaprevir (n=14), mercitabine+danoprevir (n=8), and SOF+telaprevir (n=6); one patient without prior DAA exposure is excluded; SMV, simeprevir; SOF, sofosbuvir
69
4 11 142
0
20
40
60
80
231 12 37 47 5n=
SOF Other SOF+SMV Other Other
NS5B NS5B + NS3 Other
Patie
nts,
%
Zeuzum S, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 109.
POLARIS-4: Results SVR12
Error bars represent 95% confidence intervals.
• p <0.001 for superiority compared with prespecified 85% performance goal for SOF/VEL/VOX • p=0.092 for SOF/VEL
SOF/VEL/VOX12 weeks
SOF/VEL12 weeks
9790
0
20
40
60
80
100
SVR
12, %
177/182
1 relapse1 death3 LTFU
136/151
1 breakthrough14 relapses
Zeuzum S, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 109.
POLARIS-4: Results SVR12 by Cirrhosis Status
Error bars represent 95% confidence intervals.
Cirrhosisn=153
9686
0
20
40
60
80
100
SOF/VEL/VOX SOF/VEL
59/69
98 94
0
20
40
60
80
100
SOF/VEL/VOX SOF/VEL
SVR
12, %
No Cirrhosisn=180
96/98 81/8477/82
Zeuzum S, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 109.
POLARIS-4: Results SVR12 by Genotype
Error bars represent 95% confidence intervals.
SVR
12, %
98 96 100 94 10089
95 9785
00
20
40
60
80
100
GT 1a GT 1b GT 2 GT 3 GT 4
5354
1919
5154
3131
2324
3944
4452
3233
2122
GT 4GT 3GT 2GT 1bGT 1a
SOF/VEL/VOX 12 weeks (n=182)
SOF/VEL12 weeks (n=151)
Zeuzum S, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 109.
POLARIS-4: Results SVR12 by Baseline RASs
*10 patients and †6 patients were excluded due to incomplete RAS data; RASs were analyzed using a 15% cut off; error bars represent 95% confidence intervals.
• Twenty-two patients had NS5B RASs – all achieved SVR12
• No treatment-emergent RASs were observed in the patient who relapsed following SOF/VEL/VOX
• In the SOF/VEL group, 10 of the 15 patients with virologic failure developed Y93H or Y93C
94 100 100 100 10089 90 9194
50
0
20
40
60
80
100
No RAVs Any RAVs NS3 Only NS5A only NS3+NS5A
SVR
12, %
No RASs NS3 Only NS5A only NS3+NS5AAny RASs
SOF/VEL/VOX 12 weeks (n=182*)
SOF/VEL12 weeks (n=151†)
8489
8383
44
3939
4040
6775
6370
24
2932
3234
50
Zeuzum S, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. 109.
A Randomized Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir for 8 Weeks Compared
to Sofosbuvir/Velpatasvir for 12 Weeks in DAA-Naïve Genotype 1–6 HCV Infected Patients: The POLARIS-2 Study
Ira M. Jacobson, Tarik Asselah, Ronald Nahass, Bal R. Bhandari, Albert Tran, Robert H. Hyland, Luisa M. Stamm, Hadas Dvory-Sobol, Yanni Zhu, Diana M. Brainard, G. Mani Subramanian,
John G. McHutchison, Stephen Shafran, Mitchell Davis, Catherine A. Stedman, Eric Lawitz, Edward J. Gane
Abstract LB-12
POLARIS-2: Study Design
SOF/VEL/VOXn=501
SOF/VELn=440SVR12
SVR12
0 8 12Week 20 24
• Open-label, randomized, active-comparator trial at 117 sites (USA, Canada, France, Germany, UK, Australia, and New Zealand)
• Genotypes 1–6 with and without compensated cirrhosis• GT 3 patients with cirrhosis were enrolled in a separate study (POLARIS-3)
• 1:1 randomization for GT 1–4 (other GTs assigned to SOF/VEL/VOX) • Stratified by GT, cirrhosis, and prior treatment experience (naïve or IFN experienced)
Jacobson I, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. LB-12.
POLARIS-2: Demographics• Open-label• Treatment-naïve and experienced (interferon/ribavirin only)• HCV genotype 1, 2, 3, 4, 5, 6
Jacobson I, et al. 67th AASLD; Boston, MA; November 11-15, 2016; Abst. LB-12.
SOF/VEL/VOX8 Weeks
n=501
SOF/VEL12 Weeks
n=440Mean age, y (range) 53 (18–78) 52 (19–82)Male, n (%) 255 (51) 237 (54)White, n (%) 391 (78) 365 (83)Mean BMI, kg/m2 (range) 27 (17–57) 27 (18–54)Cirrhosis, n (%) 90 (18) 84 (19)
Genotype, n (%)*
1a / 1b / Other 169 (34) / 63 (13) / 1 (<1) 172 (39) / 59 (13) / 1 (<1)2 63 (13) 53 (12)3 92 (18) 89 (20)4 63 (13) 57 (13)5 / 6 / Unknown 18 (4) / 30 (6) / 2 (<1) 0 / 9 (2) / 0
IFN experienced, n (%) 118 (24) 100 (31)IL28B CC, n (%) 166 (33) 136 (31)Mean HCV RNA, log10 IU/mL (range) 6.1 (2.7–7.6) 6.2 (4.0–7.6)