1. CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
ARV-trial.com
CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
Design
Open-label
20-70 years, Japanese
Chronic HCV infection
Genotype 1
HCV RNA ≥ IU/ml
Treatment-naive, or IFN-based pre-treated with non-response or relapse
No prior DAA therapy
No cirrhosis
No HBV or HIV co-infection
N = 79
SMV 12W + PEG-IFN + RBV 24-48W *
* Response-guided therapy in naive and relapsers ;
W48 in non-responders
SMV: 100 mg 1 capsule qd
PEG-IFNa-2b: 1.5 mg/kg SC once weekly
RBV: 600 or 1000 mg/day according to body weight
Dosage adjustment of PEG-IFN and RBV permitted
Objective
Primary efficacy endpoint: SVR12 (undetectable HCV RNA), with 95% CI
Safety: 70 patients sufficient to detect a 97% probability of detecting an adverse event of special interest with ≥ 5% incidence
CONCERTO-4
Kumada H. Hepatol Research 2015;45:501-13 1

2. CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
ARV-trial.com
CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
Baseline characteristics, and disposition
Naive
N = 24
Relapsers
N = 29
Non-responders
N = 26
Median age, years 60 53
Female 67 45 50
Genotype 1b, %
100
96.2
IL28B CC genotype, % 90 8
HCV RNA log10 IU/ml, median
6.6
6.5
Metavir stage in patients with biopsy: F1 / F2 / F3, %
83 /17 / 0
67 / 17 /17
71 / 29 /0
Prior therapy, %
IFN only
PEG-IFN only
IFN + RBV
PEG-IFN + RBV NA
3.4
96.6
11.5
88.5
Discontinuation, N 3 1 11
CONCERTO-4
Kumada H. Hepatol Research 2015;45:501-13 2

3. CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
SVR12 (undetectable HCV RNA IU/ml), % (95% CI), ITT
91.7
(73-99)
100
( )
38.5
( ) 20 40 60 80
91.7%
90.9% 2
100% 1 NA 6 4
Met RGT criteria (stop W24)
SVR12 in those patients
Virologic breakthrough, N
Relapse, N 24 29 26 %
Naive
Relapsers
Non-responders
CONCERTO-4
Kumada H. Hepatol Research 2015;45:501-13

4. CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
ARV-trial.com
CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
Emerging mutations in treatment failure
Sequencing analysis of NS3: 17/18 failures (naive = 2, relapser = 1, non-responders = 14)
Emerging mutations: 16/17
Most frequent emerging mutations
D168V, N = 8
Q80R + D168E, N = 3
D168E, N = 2
R155K, N = 1
D168T, N = 1
Q80K + D168E, N = 1
CONCERTO-4
Kumada H. Hepatol Research 2015;45:501-13 4

5. CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
Adverse events (entire treatment period)
Naive
N = 24
Relapsers
N = 26
Non-responders
Treatment discontinuation of any study medication due to adverse event
SMV only, N 1
Dosage adjustment of PEG-IFN due to AE
Temporary interruption / Dose reduction
3 / 11
4 / 4
3 / 9
Dosage adjustment of RBV due to AE
4 / 10
6 / 11
4 / 9
Grade 3-4 adverse events, N 6 5 7
Serious adverse event, N
Common adverse events, %
Pyrexia
Decreased white blood cell count
Anemia
Malaise
Headache
Decreased appetite
Injection-site reactions
Rash
Alopecia
Arthralgia
Decreased neutrophil count
Decreased platelet count 75 50
45.8
93.1
55.2
30.8
CONCERTO-4
Kumada H. Hepatol Research 2015;45:501-13

6. CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
ARV-trial.com
CONCERTO-4 Study: SMV + PEG-IFNa-2b + RBV for genotype 1
Summary
Treatment with SMV 100 mg qd for 12 weeks in combination with PEG IFN-α-2b + RBV (for 24 or 48 weeks) demonstrated potent antiviral activity and high rates of SVR12 in patients who were treatment-naive or had previously relapsed after IFN-based therapy, with most patients having a shorter treatment duration (24 weeks)
Antiviral activity was also demonstrated in some patients who had failed to respond to prior IFN-based therapy
SMV was well tolerated in all patients
No discontinuation of SMV for adverse event
Only 1 case of serious adverse event considered related to SMV (hyperbilirubinemia)
Limitation: small sample size for the 3 populations (79 patients in total)
CONCERTO-4
Kumada H. Hepatol Research 2015;45:501-13 6