1. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
Randomised*
Double-blind
W12
W24
W48
Design
18-70 years
Chronic HCV infection
Genotype 1
HCV RNA > 10,000 IU/ml
Failure (but not intolerant)
to ≥ 12 weeks
prior PEG-IFN + RBV
Compensated cirrhosis
allowed
No HBV or HIV-co-infection
N = 66
SMV 100 mg +
PEG-IFN + RBV
Placebo + PEG-IFN + RBV
N = 66
SMV 150 mg + PEG-IFN + RBV
Placebo + PEG-IFN + RBV
N = 65
SMV 100 mg +
PEG-IFN + RBV
Placebo + PEG-IFN + RBV
N = 68
SMV 150 mg +
PEG-IFN + RBV
Placebo + PEG-IFN + RBV
N = 66
SMV 100 mg + PEG-IFN + RBV
SMV : 100 (1 capsule) or 150 mg (2 x 75 mg capsules) QD
PEG-IFN a-2a : 180 mg/week
RBV (in 2 divided doses) : mg/day if < 75 kg or mg/day if ≥ 75 kg
N = 65
SMV 150 mg + PEG-IFN + RBV
N = 66
Placebo + PEG-IFN + RBV
* Randomisation was stratified on genotype (1a or 1b or other) and prior response to PEG-IFN + RBV (null response or partial response or relapse)
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41

2. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
W12
W24
W48
Design
Randomised*
Double-blind
18-70 years
Chronic HCV infection
Genotype 1
HCV RNA > 10,000 IU/ml
Failure (but not intolerant)
to ≥ 12 weeks
prior PEG-IFN + RBV
Compensated cirrhosis
allowed
No HBV or HIV-co-infection
N = 66
SMV 100 mg +
PEG-IFN + RBV
Placebo + PEG-IFN + RBV
N = 66
SMV 150 mg + PEG-IFN + RBV
Placebo + PEG-IFN + RBV
N = 65
SMV 100 mg +
PEG-IFN + RBV
Placebo + PEG-IFN + RBV
N = 68
SMV 150 mg +
PEG-IFN + RBV
Placebo + PEG-IFN + RBV
N = 66
SMV 100 mg + PEG-IFN + RBV
N = 65
SMV 150 mg + PEG-IFN + RBV
N = 66
Placebo + PEG-IFN + RBV
Objective : SVR24 (HCV RNA < 25 IU/ml) by intention to treat. Significant difference in the overall population at 5% overall significance level, power 89%.
Comparison SMV100 vs placebo, SMV150 vs placebo, then each SMV group vs placebo
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41

3. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
ARV-trial.com
ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
Baseline characteristics
SMV 100 mg
SMV 150 mg
12W
N = 66
24W
N = 65
48W
N = 68
Placebo
Median age, years 52 50 48 51
Female
33%
32%
37%
26%
36%
White
89%
92%
94%
90%
97%
HCV RNA log10 IU/ml, median
6.5
6.7
6.6
HCV RNA > 800,000 IU/ml
88%
91%
86%
85%
83%
Genotype 1a
Genotype 1b
39% 59%
44% 54%
39%
60%
45% 55%
45%
52%
64%
41%
59%
Metavir F3 / F4 (%)
22 / 11
25 / 21
21 / 21
17 / 20
16 / 19
11 / 20
20 / 16
IL28B CC
16%
17%
12%
18%
20%
22%
Response to prior PEG-IFN + RBV
Null response
Partial response
Relapse
24% 35%
25% 35% 40%
27%
33% 39%
35%
25%
40%
34% 40%
24%
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41 3

4. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
Protocol-defined virologic stopping rules
Patients with an insufficient response to treatment, ie, not achieving 1 log10 reduction from baseline in HCV RNA at W4, 2 log10 reduction from baseline in HCV RNA at W12, or HCV RNA ≥ 25 IU/ml detectable at W24 or W36, discontinued all study medication (SMV/placebo and PEG- IFN/RBV)
Study medication was also discontinued if viral breakthrough (confirmed, on treatment increase in HCV RNA of > 1 log10 IU/ml from the lowest level reached, or confirmed HCV RNA > 100 IU/ml in patients with HCV RNA previously < lower limit of quantification of 25 IU/ml or undetectable) at any time point during treatment
Premature discontinuation
N = 39 (8,4%) : withdrawal of consent, N = 21, lost to follow-up, N = 12, adverse event, N = 1, other, N = 5
Discontinuation of study medication
SMV/placebo + PEG-IFN + RBV, N = 134 (29%)
SMV/placebo only, N = 7 (1,5%)
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41

5. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
ARV-trial.com
ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
SVR24 (HCV RNA < 25 IU/ml) 25 50
100 75
69.7 %
72.1 N 66
66.2
12W 80
22.7
66.7 65 68
60.6
24W
48W
SMV 100 mg
SMV 150 mg
Placebo
SVR24 : 60.6% to 80% for SMV arms versus 22.7% for placebo (p < 0.001) ;
65.5% for SMV 100mg and 72.9% for SMV 150 mg (p < for both groups versus placebo);
68.2% for SMV 12W versus 69.2% for SMV 24W versus 70.2% for SMV 48W
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41 5

6. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
ARV-trial.com
ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
SVR24 (HCV RNA < 25 IU/ml) according to prior
response to PEG-IFN + RBV 25 50 75 37 % 57 N 27 85 19 9 68 16 23 67 78
Placebo
SMV 100 mg
SMV 150 mg 46 51 49
100
Relapse
Partial response
Null response
SVR24 : 60.6% to 80% for SMV arms versus 22.7% for placebo (p < 0.001) ;
65.5% for SMV 100mg and 72.9% for SMV 150 mg (p < for both groups versus placebo);
68.2% for SMV 12W versus 69.2% for SMV 24W versus 70.2% for SMV 48W
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41 6

7. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
ARV-trial.com
ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
SVR24 (HCV RNA < 25 IU/ml) by genotype,
according to prior response to PEG-IFN + RBV 25 50
100 75 33 39 N 12 82 56 13 7 8 23 34 85 42 24 26 1a 1b 15 44 45 43 9 40 68 89 88 84 58
Placebo
SMV 100 mg
SMV 150 mg %
Relapse
Partial response
Null response
SVR24 for SMV 150 mg : 63.1% for genotype 1a (60.9% if Q80K+ and 66.1% if Q80K-) versus 80.4% for genotype 1b
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41 7

8. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
SVR24 in SMV 150 mg group according to other characteristics and prior response to PEG-IFN + RBV
Metavir F4
Relapse : 73%
Prior partial response : 82%
Prior null response : 31%
IL28B genotype
CC : 88%
CT : 74%
TT : 61%
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41

9. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
Treatment failure
SMV 100 mg
SMV 150 mg
Placebo
Viral breakthrough*
24 (12.2%)
18 (9%)
1 (1.5%)
Relapse
21 (10.7%)
17 (8.5%)
12 (44.4%)
Meeting virologic stopping rule
18 (4.5%)
34 (52%)
* Generally before or at W12
NS3 emerging mutations
Viral breakthrough : 41/42
Relapse : 34/35
Mostly R155K or D168V alone or a combination of Q80K or Q80R, R155K, and/or D168E mutations
Genotype 1a : mainly R155K ; genotype 1b : mainly D168V
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41

10. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
ARV-trial.com
ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
Adverse events, N (%)
SMV 100 mg
SMV 150 mg
12W
N = 66
24W
N = 65
48W
N = 68
Placebo
Adverse event leading to discontinuation
SMV/placebo
SMV/placebo + PR
10.6% 9.1%
9.1%
6.2%
4.6%
7.6%
6.1%
3.0%
4.5%
10.3%
2.9%
10.8%
9.2%
7.2%
Grade 3-4 adverse event
32%
20%
36%
35%
39%
26%
Serious adverse event
7.7%
10.6%
7.4%
12.3%
Most frequent adverse event
Fatigue
Headache
Pruritus
Influenza-like illness
Neutropenia
46%
27%
29%
24%
43%
40%
37%
23%
52%
44%
30%
24% 27%
41%
38%
27% 27%
22%
31%
17%
Other AE of clinical interest
Hepatobiliary
Rash (any type)
Anemia
8% 20% 23% 3%
22% 17% 5%
18%
5% 26%
15%
9% 39%
5% 18% 20%
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41 10

11. ASPIRE Study: SMV + PEG-IFN + RBV for genotype 1 experienced patients
Summary
Simeprevir once daily in combination with PEG-IFN + RBV achieved significantly improved SVR rates compared with placebo plus PEG-IFN + RBV in patients infected with HCV genotype 1 who failed to respond to previous PEG- IFN + RBV therapy
Higher SVR24 rates were seen in patients with a prior partial or null response treated with SMV150 mg compared with SMV 100 mg. This trend was also observed across most subgroups
No consistent beneficial trend for treatment duration > 12W with SMV
SVR24 with SMV 150 mg was higher in genotype 1b than 1a among patients with a prior null or partial response
SVR24 in patients with cirrhosis in the SMV150 mg group were substantially higher than in the placebo group (62% versus 0%, respectively)
Viral breakthrough and relapse tended to be less common with SMV 150 mg versus 100 mg. Almost all failures had emerging NS3 resistance mutations
No difference in incidence or severity of adverse events with SMV vs placebo
No increase in anemia. Rash and neutropenia were more common with SMV
Transient mild hyperbilirubinemia with SMV (inhibition of OATP1B1)
ASPIRE
Zeuzem S. Gastroenterology 2014;146:430-41