UNITY-1 Study: daclatasvir/asunaprevir/beclabuvir
in genotype 1 without cirrhosis
 Design
≥ 18 years
Chronic HCV infection
Genotype 1
HCV RNA > 10,000 IU/ml
Naïve or pre-treated with IFNbased regimen
No cirrhosis*
No HBV or HIV co-infection
W12
No
randomisation
Open-label
N = 415
SVR12
DCV/ASV/BCB
Co-formulated DCV/ASV/BCB 30/100/75 mg qd : 1 pill bid
* Liver biopsy with Metavir < F4, or Fibrotest® ≤ 0.48 + APRI < 1, or Fibroscan kPa ≤ 9.6
 Objective
– Primary endpoint : SVR12 (HCV RNA < 25 IU/ml) in treatment-naïve patients, noninferiority margin of 15% = lower bound of 2-sided 95% CI > 79%, rate of historical
control (SVR achieved in this population with SOF + PEG-IFN + RBV)
– Secondary endpoint : SVR12 (HCV RNA < 25 IU/ml) in treatment-experienced
patients, with lower bound of 2-sided 95% CI > 49%, rate of historical control
(composite SVR in this population with SMV + PEG-IFN + RBV), 95% power
UNITY-1
Poordad F. JAMA 2015;313:1728-35
UNITY-1 Study: daclatasvir/asunaprevir/beclabuvir
in genotype 1 without cirrhosis
Baseline characteristics and patient disposition
Treatmentnaïve
N = 312
Treatmentexperienced
N = 103
Median age, years
53.5
57
Female
44%
38%
Race : white / black
87% / 11%
88% / 7%
Genotype : 1a / 1b
73% / 27%
73% / 27%
IL28B CC genotype
29%
16%
HCV RNA > 800,000 IU/ml
78%
90%
-
90.3%
Prior IFN-based treatment, N (%)
Relapse
37.9%
Null response
24.3%
Partial response
11.7%
Interferon intolerant
6.8%
Indeterminate
9.7%
Discontinuation, N
Lack of virologic response / adverse event / pregnancy
UNITY-1
7
4
6/0/1
1/3/0
Poordad F. JAMA 2015;313:1728-35
UNITY-1 Study: daclatasvir/asunaprevir/beclabuvir
in genotype 1 without cirrhosis
SVR12 (HCV RNA < 25 IU/ml) , % (95% CI)
All patients
Naïve
%
100
92*
(89-95)
89.3*
(83.4-95.3)
Experienced
97.6
90
100
85.3
 SVR12 comparable
across subgroups :
75
–
–
–
–
50
25
0
N 312
103
Non-response
3
2
Virologic breakthrough
6
2
Relapse
15
6
229
75
1a
83
Gender
Age
HCV RNA level
IL28B genotype
28
1b
* Superior to historical control
UNITY-1
Poordad F. JAMA 2015;313:1728-35
UNITY-1 Study: daclatasvir/asunaprevir/beclabuvir
in genotype 1 without cirrhosis
 Resistance analysis
– Genotype 1a : 32 virologic failures
• NS5A resistance-associated variants in 28/29 (most frequent : Q30)
• NS3 RAVs in 25/26 (most frequent : R155)
• NS5B RAVs in 12/28 (most frequent : P495)
– Genotype 1b : 2 virologic failures
– Baseline NS5A polymorphims (28, 30, 31, 93) associated with
resistance to DCV
• Genotype 1a : 34/102 (11%) : SVR12 in 25/34 (74%)
• Genotype 1b : 17/106 (16%) : SVR12 in 17/17 (100%)
– Baseline NS3 and NS5B variants did not affect SVR12
UNITY-1
Poordad F. JAMA 2015;313:1728-35
UNITY-1 Study: daclatasvir/asunaprevir/beclabuvir
in genotype 1 without cirrhosis
Adverse events and laboratory abnormalities, N
N = 415
Discontinuation for adverse event
3 (0.7%)
Serious adverse event
7 (1.7%)
Adverse event in > 10% of patients
Headache
25.8%
Fatigue
16.6%
Diarrhea
14.0%
Nausea
13.5%
Grade 3-4 laboratory abnormalities
Hemoglobin < 9 g/dl
UNITY-1
0
Lymphocytes < 0.5 x 109/l
1 (0.2%)
Neutrophils < 0.75 x 109/l
2 (0.5%)
ALT > 5 x ULN
19 (4.6%)
AST > 5 x ULN
9 (2.2%)
Lipase > 3 x ULN
16 (3.9%)
Poordad F. JAMA 2015;313:1728-35
UNITY-1 Study: daclatasvir/asunaprevir/beclabuvir
in genotype 1 without cirrhosis
 Summary
– In this open-label, uncontrolled study, 12 weeks of treatment with a fixeddose combination of daclatasvir, asunaprevir and beclabuvir in HCV
genotype 1-infected patients without cirrhosis was associated with high
SVR12
• 92% in treatment-naive patients
• 89% in patients previously treated for HCV infection
• SVR12 rates were higher with genotype 1b than with genotype 1a in both the
treatment-naive (98% vs 90%, respectively) and -experienced (100% vs 85%,
respectively) cohorts
– There were low rates of serious AEs and treatment discontinuations
– All genotype 1b-infected patients with baseline NS5A polymorphisms
achieved SVR12 while only 74% with genotype 1a had SVR12
– Resistance-associated variants at amino acids positions NS5A-Q30,
NS3-R155K and NS5B-P495 were observed most frequently at viral
breakthrough; NS5B variants were generally not observed in patients
experiencing relapse
UNITY-1
Poordad F. JAMA 2015;313:1728-35