1. LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
Design
Randomisation*
1 : 1
Open label
W12
W24
Randomisation
1 : 1
DCV 30 mg qd + SMV 150 mg qd
N = 76
> 18 years
Chronic HCV infection
Genotype 1
Treatment naïve or prior null response to PEG-IFN + RBV
HCV RNA ≥ 100,000 IU/ml
Compensated cirrhosis ** allowed
No HBV or HIV coinfection
Stop
GT 1b
DCV 30 mg + SMV 150 mg qd
+ RBV
N = 71
Continue
GT 1a
N = 21
DCV 30 mg qd + SMV 150 mg qd + RBV
* Randomisation was stratified on cirrhosis (yes or no) and prior treatment (naïve or null response)
** Biopsy or Fibroscan ≥ 14.6 kPa
RBV (bid dosing): 1000 mg/d (< 75 kg) or 1200 mg/d (≥ 75 kg)
Objective
SVR12 (HCV RNA < 25 IU/ml), by mITT, with 80% CI, by cohort based on HCV genotype 1 subtype and prior treatment experience
SVR12 was also reported by treatment regimen (with or without RBV) and treatment duration (12 or 24 weeks) for the genotype 1b cohort
LEAGUE-1
Zeuzem S, J Hepatol 2016; 64:

2. LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
ARV-trial.com
LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
Baseline characteristics and patient disposition
Genotype 1b
Genotype 1a
Treatment-naïve
Null responder
DCV + SMV
N = 53
DCV + SMV + RBV
N = 51
N = 23
N = 20
+ RBV
N = 21 *
Median age, years 54 53 56 59 52
Female
59%
51%
48%
55%
33%
Race : white
91%
92%
100%
85%
95%
HCV RNA log10 IU/ml, mean
6.2
6.4
6.3
Metavir : F0-F2 / F3 / F4, %
70 / 19 / 11
77 / 10 / 14
39 / 22 / 39
60 / 20 / 20
43 / 29 / 29
IL28B CC
30%
26% 4% 5%
14%
Resistance-associated polymorphisms
NS5A
NS3
14% 17%
22%
18%
33% 33%
20%
25%
Discontinuation, N
Lack of efficacy
Adverse event
Other 6 4 2 1
0 0 13 11
* Treatment-naïve, N = 12 ; null responder to prior PEG-IFN + RBV, N = 9
LEAGUE-1
Zeuzem S, J Hepatol 2016; 64: 2

3. LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
ARV-trial.com
LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
SVR12 (HCV RNA < 25 IU/ml) in genotype 1b 25 50
100 75
84.9 %
74.5
Treatment-naïve
80.8
88.7
85.3 N 53 51 47 4 6 14 16
73.9
78.6
85.1
93.8 44 7
All
Cirrhosis
83.3
DCV + SMV + RBV
DCV + SMV
Null-responder
12W of
therapy
24W of No
cirrhosis 95
88.9
82.6
55.6 9
57.8
69.6 23 20
Of the 29 failures, there were 15 virologic breakthrough and 5 relapses
LEAGUE-1
Zeuzem S, J Hepatol 2016; 64: 3

4. LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
Outcome in genotype 1a
SVR12 in treatment-naïve patients: 66.7%
All prior null responders with genotype 1a were offered the addition of PEG-IFN for 24 weeks after the initial 5 patients experienced virologic breakthrough. They were considered SVR12 non responders
Resistance analysis in genotype 1b
At baseline, NS5A polymorphisms at L28, R30, L31, or Y93 were detected in 29/136 (21.3%) available sequences;
SVR12 in 16/29 (55.2%) compared with 97/107 (90.7%) patients without these polymorphisms
Baseline NS3 polymorphisms at V36, T54, Q80, or S122 were detected in 30/138 genotype 1b–infected patients with available sequences ;
SVR12 in 24/30 (80.0%) versus 89/108 (81.5%) patients without these polymorphisms
LEAGUE-1
Zeuzem S, J Hepatol 2016; 64:

5. LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
ARV-trial.com
LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
Adverse events and grade 3-4 laboratory abnormalities, N (%)
DCV + SMV
N = 76
DCV + SMV + RBV
N = 92
Serious adverse event
9.2%
4.3%
Adverse event leading to discontinuation
2 (2.6%)
2 (2.2%)
Death
1 (1.3%)
Adverse event in ≥ 10% of patients
Asthenia
55%
54%
Headache
43%
Nausea
35%
40%
Pruritus
31%
34%
Fatigue
25%
Nasopharyngitis
Dyspnea
28%
27%
Hemoglobin < 9 g/dl
Neutrophils < 750/mm3 1
Lymphocytes < 500/mm3
ALT > 5 x ULN / AST > 5 x ULN
0 / 0
1 / 1
Total bilirubin > 2.5 x ULN 3 14
Lipase > 3 x ULN
LEAGUE-1
Zeuzem S, J Hepatol 2016; 64: 5

6. LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
ARV-trial.com
LEAGUE-1 study: daclatasvir + SMV + RBV for genotype 1
Summary
With all-oral, IFN-free treatment of DCV + SMV, with or without RBV
In genotype 1b, treatment for 12 or 24 weeks achieved combined SVR12 rates of 84.9% (DCV + SMV) and 74.5% (DCV + SMV + RBV) in treatment naïve patients and 69.6% (DCV + SMV) and 95.0% (DCV + SMV + RBV) in prior null responders
SVR12 rates were higher in patients without NS5A polymorphisms at baseline
In genotype 1a, DCV + SMV + RBV for 24 weeks achieved SVR12 of 66.7% in treatment-naïve patients. Null responders required intensification with PEG-IFN
The DCV dose of 30 mg in combination with SMV provided lower than expected DCV exposure, however no relation with SVR12
DCV + SMV was well tolerated with or without RBV
The standard 60mg dose of DCV will be utilized in all future studies involving DCV and SMV
DCV + SMV + RBV is not recommended for the treatment of genotype 1a
Other available options for HCV genotype 1b infection have surpassed this regimen in terms of efficacy
LEAGUE-1
Zeuzem S, J Hepatol 2016; 64: 6