1. LEPTON Study: SOF/VEL + GS-9857 genotype 1 or 3 Phase II
Design
Open-label W4 W6 W8
SOF/VEL + GS-9857
> 18 years Genotype 1 or 3
Treatment- naïve
or-experienced
No cirrhosis or compensated cirrhosis
No HBV or HIV
co-infection G
E N O T Y P E 1
Naïve, no cirrhosis
N = 30
SOF/VEL + GS-9857
Naïve, cirrhosis
N = 15
SOF/VEL + GS-9857
PEG-IFN + RBV experienced, cirrhosis
SOF/VEL + GS-9857
N = 17
PI-experienced, ± cirrhosis
N = 28
SOF/VEL + GS-9857
DAA-experienced , ± cirrhosis
N = 30
SOF/VEL + GS-9857
SOF/VEL: 400/100 mg
FDC qd;
GS-9857: 100 mg qd
GT3
Naïve, cirrhosis
N = 18
SOF/VEL + GS-9857
PR- experienced, cirrhosis
N = 19
SOF/VEL + GS-9857
DAA- experienced, ± cirrhosis
N = 4
SOF/VEL + GS-9857
Objective
SVR12 (HCV RNA < 15 IU/ml), by ITT
LEPTON
Gane EJ, Gastroenterology 2016; 151:

2. LEPTON Study: SOF/VEL + GS-9857 genotype 1 or 3 Phase II
Baseline characteristics and outcome in genotype 1
with 4 or 6 weeks of therapy
4 weeks
6 weeks
Naïve
No cirrhosis
N = 15
Cirrhosis
Prior DAA failure *
± cirrhosis
N = 30
Age, years, mean 54 50 59 55
Female
40%
53%
27%
20%
White
80%
93%
90%
HCV RNA, log10 IU/ml, mean
6.3
6.0
IL28B CC
33%
100%
17%
Genotype 1a
73%
77%
SVR12
87%
67%
Cirrhosis: 60%
No cirrhosis: 68%
All failures were relapses
* Danoprevir + mericitabine, N = 14 ; danoprevir + mericitabine + ritonavir + RBV, N = 6 ; DCV + VX135, N = 3,
SOF/LDV + RBV, N = 1 ; faldaprevir + deleobuvir + RBV, N = 4 ; TVR + lomibuvir ± RBV, N = 2
LEPTON
Gane EJ, Gastroenterology 2016; 151:

3. LEPTON Study: SOF/VEL + GS-9857 genotype 1 or 3 Phase II
Baseline characteristics, disposition and outcome in genotype 1
with 8 weeks of therapy or in genotype 3
8 weeks
6 weeks
Genotype 1 PEG-IFN + RBV experienced
Cirrhosis
N = 17
Genotype 1
PI-experienced
± cirrhosis
N = 28
Genotype 3
Naïve
N = 18
PEG-IFN + RBV experienced
N = 19
DAA experienced
± cirrhosis N = 4
Age, years, mean 58 57 52 55 56
Female
18%
32%
44%
21%
White
94%
86%
67%
95%
75%
HCV RNA, log10 IU/ml, mean
6.3
6.1
6.9
IL28B CC
35%
14%
56%
42%
100%
39%
50%
Discontinued therapy
SVR12
Cause of failure
Relapse
Lost to follow-up
89% 3
83% 2 1
LEPTON
Gane EJ, Gastroenterology 2016; 151:

4. LEPTON Study: SOF/VEL + GS-9857 genotype 1 or 3 Phase II
SVR12 according to baseline NS5A RASs in genotype 1 with 6 weeks of therapy
Treatment naïve (N = 30)
Baseline RASs = 16  SVR12 in 100%
No RASs = 14  SVR12 in 79%
Prior DAA failure (N = 29)
Baseline RASs = 13  SVR12 in 77%
No RASs = 16  SVR12 in 63%
SVR12 according to baseline RASs in genotype 1 with 8 weeks of therapy or in genotype 3
No RASs = 46  SVR12 in 97.8%
NS5A RASs = 23  SVR12 in 87%
NS3 RASs = 26  SVR12 in 85%
LEPTON
Gane EJ, Gastroenterology 2016; 151:

5. LEPTON Study: SOF/VEL + GS-9857 genotype 1 or 3 Phase II
SVR12 according to prior failure
Failure to PI-based therapy, N = 28
Baseline NS3 RASs in 15/28 (54%)  SVR12 in 13/15 (87%)
Failure to NS5A inhibitor (N = 7)
Baseline NS3 RASs in 6/7 (86%)  SVR12 in 5/6 (83%)
Relapse, N = 28
No emergence of RAS, N = 26
No RAS at baseline and failure, N = 15
Same RASs at baseline and failure, N = 6
Baseline RASs but no RAS at failure, N = 5
Emergence of RASs, N = 2
Treatment-naïve, 6 weeks of treatment: NS3 RAS V55A emerged at 2% of the viral population at the time of relapse
PI-experienced, 8 weeks of treatment: NS5A RAS Y93H emerged at 2% of the viral population at the time of relapse in addition to the preexisting NS3 RAS R155K
LEPTON
Gane EJ, Gastroenterology 2016; 151:

6. LEPTON Study: SOF/VEL + GS-9857 genotype 1 or 3 Phase II
Adverse events and laboratory abnormalities, %
4 or 6 weeks
8 weeks
6 weeks
Genotype 1
Naïve or DAA-experienced
N = 75
Genotype 1 PEG-IFN + RBV experienced
Cirrhosis
N = 17
PI-experienced
± cirrhosis
N = 28
Genotype 3
Naïve
N = 18
PEG-IFN + RBV experienced
N = 19
DAA experienced
± cirrhosis
N = 4
Any adverse event
77%
88%
79%
83%
75%
Grade 3 AE
Serious AE
4% (n = 1) *
11% (n = 2) *
Discontinuation for AE
AE in ≥ 10% of patients
Nausea
24% 6%
11%
17%
37%
25%
Headache
18%
33%
21%
Fatigue
16%
Diarrhea 9%
22%
50%
Grade 3-4 laboratory abnormalities
12% 7%
* Atrial fibrillation, hepatocellular carcinoma and bladder cancer, all unrelated to study drug
LEPTON
Gane EJ, Gastroenterology 2016; 151:

7. LEPTON Study: SOF/VEL + GS-9857 genotype 1 or 3 Phase II
Summary
SOF/VEL + GS-9857 for 6 weeks was highly effective in treatment- naïve genotype 1 patients without cirrhosis
Shortening treatment to 4 weeks was associated with very low SVR12
SOF/VEL + GS-9857 for 8 weeks resulted in high SVR12 rates in difficult-to-cure, treatment-experienced patients
100% in cirrhotic PEG-IFN + RBV-experienced genotype 1 and genotype 3
89% in PI-experienced genotype 1
Baseline NS3 RASs had limited impact on SVR rates among PI- experienced patients treated with SOF/VEL + GS-9857 for 8 weeks
SVR12 of 87% if RASs at baseline vs 92% if no RAS
The combination was safe and well tolerated
LEPTON
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