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)