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The ASTRAL ProgramAbstracts LB-2, LB-12, 205, 209
The ASTRAL Program
1. Jacobson IM, et al. N Engl J Med 2013;368:1867-772. Lawitz E, et al. N Engl J Med 2013;368:1878-873. Cheng G, et al. EASL 2013, poster 11914. German P, et al. EASL 2013, poster 11955. Lawitz E, et al. EASL 2013, poster 1082.
ASTRAL1
GT1, 2, 4‒6
ASTRAL2
GT2
ASTRAL3
GT3
ASTRAL4
GT1‒6
CPT-B Cirrhosis
SOF Nucleotide polymerase inhibitor
VELNS5A inhibitor
SOF/VEL FDC– Once daily, oral, FDC (400/100 mg)– 12 weeks of Treatment
ASTRAL-1: Study Design
Double blind, placebo controlledBroad inclusion criteria5:1 randomization to SOF/VEL or placebo
Stratified by HCV genotype and cirrhosis (presence/absence)GT 5 patients not randomized
Conducted at 81 sites in US, Canada, UK, Germany, France, Italy, Belgium, and Hong Kong
Week 0 Week 12 Week 24
Placebo
SVR12
SVR12
SOF/VELn=500
n=100
Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2.
Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2.
ASTRAL-1: Total SVR12SOF/VEL
Error bars represent 95% confidence intervals.
99 98 99 100 100 97 100
0
20
40
60
80
100
Total 1a 1b 2 4 5 6
SVR
12 (%
)
Genotype
1 relapse 1 death
618624
206210
117118
104104
116116
3435
4141
ASTRAL-1: SVR12 by HCV Genotype
99 98 99 100 100 97 100
0
20
40
60
80
100
Total 1a 1b 2 4 5 6
SVR
12 (%
)
Genotype
1 relapse2 lost to follow-up1 withdrew consent
1 relapse 1 death
618624
206210
117118
104104
116116
3435
4141
Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2.
Error bars represent 95% confidence intervals.
ASTRAL-1: SVR12 by Cirrhosis Status and Treatment History (SOF/VEL)
99 99 99 99 99
0
20
40
60
80
100
SVR
12 (%
)
618624
496501
120121
418423
200201
Cirrhosis Status Treatment History
No Yes Naïve ExperiencedTotal
Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2.
Error bars represent 95% confidence intervals.
ASTRAL-1: Resistance Analysis (1% Cut-off)
58% No BL
NS5A RAVsn=359
42% BL NS5A RAVs
n=257
100% SVR12
359/359
99% SVR12
255/257
Total, n=616
Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2.
SOF/VEL
ASTRAL-1: Safety
Adverse Event, n (%) Placebo n=116
SOF/VEL n=624
Headache 33 (28) 182 (29)
Fatigue 23 (20) 126 (20)
Nasopharyngitis 12 (10) 79 (13)
Nausea 13 (11) 75 (12)
Feld J, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-2.
ASTRAL-2: Study Design
Open-label, active-comparator trial Broad inclusion criteria1:1 randomization to SOF/VEL or SOF + RBV
Stratified by prior treatment (TN/TE) and cirrhosis (presence/absence)
Conducted at 51 sites in US
Sulkowski M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 205.
Week 0 Week 12 Week 24
SVR12
SVR12
SOF/VEL
SOF + RBV
n=250
n=250
9994
0
20
40
60
80
100
SVR
12 (%
)
1 LTFU
ASTRAL-2: SVR12 by Treatment Arm
133/134 124/132
SOF/VEL SOF + RBV
6 Relapse2 LTFU
p=0.018
Sulkowski M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 205.
Error bars represent 95% confidence intervals.
ASTRAL-3: Study Design
Open-label, active-comparator trial Broad inclusion criteria1:1 randomization to SOF/VEL or SOF + RBV
Stratified by prior treatment (TN/TE) and cirrhosis (presence/absence)
Conducted at 76 sites in US, Canada, UK, Germany, France, Italy, Australia, and New Zealand
Mangia A, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 249.
Week 0 Week 12 Week 24
SVR12
SVR12
SOF/VEL
SOF + RBV
Week 36
n=250
n=250
ASTRAL-3: SVR12 By Treatment Arm
9580
0
20
40
60
80
100
SVR
12 (%
)
264/277 221/275
P=0.001
Mangia A, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 249.
SOF/VEL SOF + RBV
Pooled ASTRAL, SOF/VEL 12 Weeks: SVR12
TotalGT 1 GT 2 GT 3 GT 4 GT 5 GT 6
99 100 95 100 97 100 98
0
20
40
60
80
100
SVR
12 (%
)
Of the 20 patients who did not achieve SVR1212 had relapse1 had re-infection7 did not have a SVR12 assessment
10151035
323328
264277
116116
3435
4141
237238
Mangia A, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 249.
ASTRAL-4: SOF/VEL in Patients with Decompensated Liver Disease
Open-label, randomized (1:1:1) US study (NCT02201901) HCV GT 1‒6 treatment-naïve or -experienced patients with Child-Pugh-Turcotte (CPT) B cirrhosis Key eligibility criteria: creatinine clearance (CLcr) >50 mL/min, platelets >30,000/mm3; no hepatocellular carcinoma or liver transplant
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
SVR12, sustained virologic response 12 weeks after treatment end.
Week 0 Week 12 Week 24
SVR12
SVR12
SOF/VEL
SOF + RBV
Week 36
n=75
n=75
SVR12SOF/VELn=75
ASTRAL-4: Results - Overall SVR12P-value < 0.001 for comparison of SVR12 rate to 1% for each treatment group
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
8394
86
0
20
40
60
80
100
SVR
12 (%
)
SOF/VEL + RBV 12 week
SOF/VEL24 week
82/87 77/90
SOF/VEL12 week
75/90
ASTRAL-4: Results - SVR12 in GT 1 Patients
88 96 92
0
20
40
60
80
100
SVR
12 (%
)
SOF/VEL + RBV 12 week
SOF/VEL24 week
65/68 65/71
SOF/VEL12 week
60/68
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
ASRAL-4: Results - SVR12 in GT 3 Patients
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
50
85
50
0
20
40
60
80
100
SVR
12 (%
)
SOF/VEL + RBV 12 week
SOF/VEL24 week
11/13 6/12
SOF/VEL12 week
7/14
ASTRAL-4: Results - SVR12 in GT 2, 4, 6 Patients
0
20
40
60
80
100
SVR
12 (%
)
SOF/VEL + RBV 12 week
SOF/VEL24 week
SOF/VEL12 week
GT 2 (4/4)GT 4 (4/4)
GT 2 (4/4)GT 4 (2/2)
GT 2 (3/4)GT 4 (2/2)GT 6 (1/1)
100 100
86
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
ASTRAL-4: Results - CPT Score Change From Baseline
<1 <1 2
13
31
43
72 <1 <1
0
10
20
30
40
50
60
-5 -4 -3 -2 -1 0 1 2 4 5
Patie
nts
(%)
47% Improved 10% Worsened
Change in CPT Score ‒4‒5 ‒3 ‒2 ‒1 0 1 2 4 5
n= 72 992951 1 416 1 1
Total n=234; 5 patients had no follow-up Week 12 assessment.
ASTRAL-4: Results - Overall Safety Summary
SAEs assessed as related included dyspnea (SOF/VEL +RBV 12 Weeks) and hepatorenal syndrome peritonitis, sepsis, hypotension (SOF/VEL 24 weeks)Deaths: sepsis/septic shock/MOF (n=4); liver failure (n=2); cardiopulmonary arrest (n=1); respiratory failure (n=1); myocardial infarction (n=1)
None considered treatment related
Patients, n (%)SOF/VEL12 Weeks
n=90
SOF/VEL + RBV12 Weeks
n=87
SOF/VEL24 Weeks
n=90Any AE 73 (81) 79 (91) 73 (81)Grade 3 or 4 AE 16 (18) 11 (13) 17 (19)SAE 17 (19) 14 (16) 16 (18)
Treatment-related SAE 0 1 (1) 1 (1)
AE leading to D/C 1 (1) 4 (5) 4 (4)Transplant 0 0 1 (1)Death 3 (3) 3 (3) 3 (3)
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
ASTRAL-4: Results - RBV Tolerance
Charlton M, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-13.
Patients, n (%)SOF/VEL + RBV
12 Weeksn=87
Hemoglobin <10 g/dL, n (%) 20 (23)Hemoglobin <8.5 g/dL, n (%) 6 (7)
Max median hemoglobin decline, mg/dL (range) -1.5 (-5.1, 1.6)
RBV dosingMedian average daily dose, mg (range) 1124 ( 486-1200)Median days on RBV, n (range) 84 (4-89)Discontinued, n (%) 15 (17)Dose interruption ≥3 days, n (%) 4 (5)Dose reduction, n (%) 32 (37)
Concomitant blood products or epoetin, n (%)Anti anemia therapy 1 (1)Blood substitutes 2 (2)