1. No cirrhosis or compensated cirrhosis** No HBV or HIV co-infection
HCV-trial.com
COMMAND-3 Study: DCV vs TVR, in combination with PEG-IFN + RBV, for genotype 1a or 1b
Design
Randomisation*
2 : 1
Open-label
≥ 18 years
Chronic HCV infection,
Genotype 1a or 1b
HCV RNA ≥ IU/ml
Treatment-naive
No cirrhosis or compensated cirrhosis**
No HBV or HIV co-infection
N = 402
DCV + PEG-IFN + RBV (1)
TVR + PEG-IFN + RBV (2)
N = 200
* Randomisation was stratified on genotype (1a or 1b),
IL28B (CC or non-CC), cirrhosis (yes or no)
** Liver biopsy or Fibroscan > 14.6 kPa
(1): 24 weeks if undetectable HCV-RNA at W4 and W12 (eRVR) ;
additional 24 weeks of PEG-IFN + RBV otherwise
(2): 12 weeks + 12 weeks (if eRVR) or 36 weeks of PEG-IFN + RBV
DCV: 60 mg qd ; TVR 750 mg tid ; PEG-IFNa-2a: 180 mg SC once weekly
RBV: 1000 or 1200 mg/day (bid dosing) according to body weight (< or ≥ 75 kg)
Objective
Primary endpoint: SVR12 (HCV RNA < 25 IU/ml), with 2-sided 95% CI, noninferiority of DCV vs TVR in genotype 1b, lower margin of -12%, 91% power
COMMAND-3
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2. Baseline characteristics and patient disposition
COMMAND-3 Study: DCV vs TVR, in combination with PEG-IFN + RBV, for genotype 1a or 1b
Baseline characteristics and patient disposition
Genotype 1b
Genotype 1a
DCV
N = 268
TVR
N = 134
N = 66
Median age, years 46 48 49
51.5
Female
41%
46%
27%
29%
Race : white / black
91% / 6%
96% / 2%
90% / 8%
96% / 3%
IL28B CC genotype
20%
31%
30%
HCV RNA log10 IU/ml, mean
6.23
6.30
6.31
Cirrhosis
9.7%
11.2%
11.9%
13.6%
Discontinuation
Virologic breakthrough
Futility
Lack of efficacy
Adverse event
Patient request
Lost to follow-up
Withdrew consent / other 39 11 3 1 14 6 20 17 2 44 4 8
COMMAND-3
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3. SVR12 (HCV RNA < 25 IU/ml) , mITT
COMMAND-3 Study: DCV vs TVR, in combination with PEG-IFN + RBV, for genotype 1a or 1b
SVR12 (HCV RNA < 25 IU/ml) , mITT 25 50
100 75
81.3 * %
85.1 *
N =
134 66
268
69.7
64.9
DCV, genotype 1a
TVR genotype 1a
DCV, genotype 1b
TVR, genotype 1b
* Difference between
treatment arms : 4.3%
(95% CI: -3.3% to 11.9%) noninferiority
Virologic breakthrough 11 NA
Futility 3 4
HCV-RNA mssing/detectable at EOT 7 14
Relapse 12 20 9
Missing post treatment W12 data 2
COMMAND-3
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4. SVR12 in genotype 1b, by subgroups, mITT
COMMAND-3 Study: DCV vs TVR, in combination with PEG-IFN + RBV, for genotype 1a or 1b
SVR12 in genotype 1b, by subgroups, mITT
IL28B 53
Cirrhosis
214 27
107 15 10 17
96.2
85.2
86.0
83.2
82.2
80.4
76.9
66.7
91.7
89.2
82.7
78.4 CC
Non-CC No
Yes
Baseline HCV RNA
< IU/ml 25 50
100 75 % n
DCV, genotype 1b
TVR, genotype 1b
COMMAND-3
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5. Resistance analysis in genotype 1b
COMMAND-3 Study: DCV vs TVR, in combination with PEG-IFN + RBV, for genotype 1a or 1b
Resistance analysis in genotype 1b
NS5A population-based sequencing data
At baseline, N = 249/268
43 (17.5%): ≥ 1 of NS5A polymorphisms L28M/V, R30H/Q, L31M or Y93H
SVR12: 72.1% if NS5A polymorphisms vs 87% if no NS5A polymorphisms
At virologic failure, N = 32/40
Same NS5A RAVs at baseline and failure, N = 2
Treatment-emergent NS5A RAVS, N = 30
L31F/I/M/V, N = 22
Y93H, N = 21
L31 and Y93 together, N = 18
COMMAND-3
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6. COMMAND-3 Study: DCV vs TVR, in combination with PEG-IFN + RBV, for genotype 1a or 1b
Adverse events, N or %
DCV + PEG-IFN + RBV
N = 402
TVR + PEG-IFN + RBV
N = 200
Serious adverse event, N (%)
Drug-related SAE, N (%)
26 (6.5)
14 (3.5) *
20 (10)
16 (8) *, **
Death, N (%) (both unrelated)
1 (0.2)
1 (0.5)
AE leading to discontinuation of any drug, N (%)
28 (7)
37 (18.5)
AE leading to discontinuation of all 3 study drugs, N (%)
25 (6.2)
25 (12.5)
Adverse event in ≥ 20% in either group, %
Fatigue
Headache
Asthenia
Pruritus
Anemia
Rash
Nausea
Neutropenia
Alopecia
Influenza-like illness
Dry skin
Pyrexia
34.8
34.1
27.2
26.6
23.9
23.1
21.9
21.6
21.4
21.1
20.9
19.9
40.5
28.5
26.5
37.5
49.5
34.5
37.0
13.5
16.0
19.0
17.0
21.0
* 1 case of DRESS in each group, ** 5 cases of anemia
COMMAND-3
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7. Grade 3 or 4 emergent laboratory abnormalities, N (%)
COMMAND-3 Study: DCV vs TVR, in combination with PEG-IFN + RBV, for genotype 1a or 1b
Grade 3 or 4 emergent laboratory abnormalities, N (%)
DCV + PEG-IFN + RBV
N = 402
TVR + PEG-IFN + RBV
N = 200
Hemoglobin
26 (6.5)
41 (20.5)
Absolute neutrophil count
104 (25.9)
Lymphocytes
67 (16.7)
44 (22)
Platelet count
15 (3.7)
8 (4)
ALT
3 (0.7)
4 (2)
AST
7 (1.7)
1 (0.5)
Total bilirubin
4 (1)
6 (3)
Serum creatinine increased
1 (0.2)
Safety secondary endpoints
Hemoglobin < 10 g/dl in genotype 1b significantly lower in DCV vs TVR group (18.3% vs 47.4% ; 95% CI for difference: % to – 19.4%)
Grade 1-4 rash in genotype 1 not significantly different: 23.1% for DCV vs 34.5% for TVR (grade 3-4: 1.0% vs 3.5%)
COMMAND-3
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8. COMMAND-3 Study: DCV vs TVR, in combination with PEG-IFN + RBV, for genotype 1a or 1b
Summary
This head-to-head comparison of two classes of DAAs in treatment naive genotype 1b infected patients demonstrates that DCV + PEG-IFN + RBV is noninferior to TVR + PEG-IFN + RBV for SVR12
High SVR12 was achieved in genotype 1b infected patients across all subgroups of baseline factors known to affect response rates to PEG-IFN + RBV (cirrhosis, IL28B genotype, age, sex, baseline viral load)
In difficult-to-cure patients with cirrhosis, SVR12 was higher with DCV + PEG-IFN + RBV than with TVR+ PEG-IFN + RBV (76.9% vs 66.7%)
Post treatment relapse was more frequent with TVR than with DCV (15% vs 5%), for genotype 1b
SVR12 with DCV + PEG-IFN + RBV was lower and virologic failure was more frequent in patients infected with genotype 1a
Lower resistance barrier of DCV in genotype 1a ?
DCV + PEG-IFN + RBV was generally well tolerated, with a significantly lower rate of anemia, and an observed lower rate of rash-related events compared with TVR+ PEG-IFN + RBV
COMMAND-3
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