UNITY-2 Study: daclatasvir/asunaprevir/beclabuvir
+ RBV in genotype 1 with compensated cirrhosis
 Design
≥ 18 years
Chronic HCV infection,
Genotype 1
HCV RNA ≥ 10,000 IU/ml
Naïve or pre-treated with IFNbased regimen
Compensated cirrhosis**
No HBV or HIV co-infection
W24
Randomisation*
1:1
Double-blind
N = 55
DCV/ASV/BCB + RBV
Naïve
N = 57
DCV/ASV/BCB + placebo
N = 45
DCV/ASV/BCB + RBV
Experienced
N = 45
SVR12
DCV/ASV/BCB + placebo
* Randomisation was stratified on genotype (1a or 1b)
** Liver biopsy with Metavir F4, or Fibrotest® > 0.75 + APRI > 2, or Fibroscan kPa > 14.6
– Co-formulated DCV/ASV/BCB 30/200/75 mg qd : 1 pill bid
– 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 97.5% CI, significantly
> 69%, rate of historical control (composite of SVR achieved in this population
with approved direct-acting antivirals + PEG-IFN + RBV), 90% power
UNITY-2
Muir AJ. JAMA 2015;313:1736-44
UNITY-2 Study: daclatasvir/asunaprevir/beclabuvir
+ RBV in genotype 1 with compensated cirrhosis
Baseline characteristics and patient disposition
Treatment-naïve
DCV/ASV/BCB DCV/ASV/B
+ RBV
CB +
placebo
N = 57
N = 55
Median age, years
Treatment-experienced
DCV/ASV/B DCV/ASV/
CB + RBV
BCB +
placebo
N = 45
N = 45
59
58
60
59
36%
32%
40%
29%
Race : white / black
83% / 11%
86% / 10%
82% / 13%
91% / 4%
Genotype : 1a / 1b
71% / 27%
70% 30%
78% / 22%
78% / 22%
IL28B CC genotype
33%
23%
20%
33%
HCV RNA log10 IU/ml, mean
6.4
6.5
6.7
6.8
-
-
41 (91%)
44 (98%)
Virologic breakthrough
0
2
IFN intolerant
10
6
16 /2/ 8
19 / 6 / 8
Female
Prior IFN-based treatment, n (%)
Null response/ Partial response / Relapse
Discontinuation
Virologic breakthrough / Adverse event
UNITY-2
0
0
2
1
-
-
1/1
1/0
Muir AJ. JAMA 2015;313:1736-44
UNITY-2 Study: daclatasvir/asunaprevir/beclabuvir
+ RBV in genotype 1 with compensated cirrhosis
SVR12 (HCV RNA < 25 IU/ml) , % (95% CI)
Experienced, DCV/ASV/BCB + RBV
Experienced, DCV/ASV/BCB + placebo
Naïve, DCV/ASV/BCB + RBV
Naïve, DCV/ASV/BCB + placebo
%
100
98.2
(89-100)
93.3
93
(85-100) (85-100)
86.7
(75-98)
100
97.4
90
91.4
40
35
100
100
90
85.7
75
50
25
N 55
57
45
45
Early discontinuation
1
0
0
0
Virologic breakthrough
0
0
1
1
Relapse
0
4
1
5
0
UNITY-2
39
Genotype 1a
35
15
17
10
10
Genotype 1b
Muir AJ. JAMA 2015;313:1736-44
UNITY-2 Study: daclatasvir/asunaprevir/beclabuvir
+ RBV in genotype 1 with compensated cirrhosis
 SVR12 by sub-group
– Comparable according to age, sex, baseline HCV RNA level, and IL28B genotype
– Among the 35 prior null responders in the experienced cohort, 34 (97%) achieved
SVR12
 Resistance analysis
– NS5A polymorphisms at positions 28, 30, 31, or 93 were detected at baseline in
15 of 149 patients (10%) with genotype 1a infection and 13 of 52 patients (25%)
with genotype 1b infection
– 13/15 (87%) with genotype 1a and 13/13 with genotype 1b achieved SVR12
– 2 patients, in the treatment-experienced group, relapsed : one had M28V at
baseline and the other had Q30H and Y93H at baseline
– In genotype 1a, emergence of NS5A resistance variants in patients with virologic
failure in 11/12 patients; of NS3 resistance variants in 10/12 patients (R155K) ; of
NS5B resistance variants in 2 patients (P495)
– For the single relapse in genotype 1b, only NS5A-Y93H was detected at virologic
failure, with no signature NS3 or NS5B resistance variants detected
UNITY-2
Muir AJ. JAMA 2015;313:1736-44
UNITY-2 Study: daclatasvir/asunaprevir/beclabuvir
+ RBV in genotype 1 with compensated cirrhosis
Adverse events and laboratory abnormalities, n
DCV/ASV/BCB + RBV
N = 100
DCV/ASV/BCB + placebo
N = 102
Discontinuation for adverse event
4
0
Serious adverse event
7
2
Headache
23
17
Nausea
17
14
Diarrhea
9
13
Fatigue
28
12
Insomnia
15
6
Pruritus
15
6
Hemoglobin < 9 g/dl
5
0
ALT > 5 x ULN
1
3
AST > 5 x ULN
1
2
Lipase > 3 x ULN
1
5
Adverse event in > 10% in either group
Grade 3-4 laboratory abnormalities
UNITY-2
Muir AJ. JAMA 2015;313:1736-44
UNITY-2 Study: daclatasvir/asunaprevir/beclabuvir
+ RBV in genotype 1 with compensated cirrhosis
 Summary
– In this open-label, uncontrolled study, 12 weeks of the fixed-dose
combination of daclatasvir, asunaprevir, and beclabuvir, with or
without RBV, achieved an overall SVR12 rate of 93% in patients
with genotype 1 infection and compensated cirrhosis
• Among patients with genotype 1a infection
– SVR12 was achieved by 88% of those receiving the fixed-dose
combination alone
– and by 95% of those with RBV added to the regimen
• However, the contribution of RBV to SVR12 remains uncertain
because of the small sample size
• A 98% SVR12 rate was achieved after 12 weeks of treatment in
patients with genotype 1b infection and cirrhosis
– Overall, resistance variants at baseline were infrequent and did
not appear to have an adverse effect on SVR12 rates
UNITY-2
Muir AJ. JAMA 2015;313:1736-44