1. No HBV or HIV co-infection
C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3
Design
Randomisation
1 : 1
Open-label
W12
W18
> 18 years
HCV genotype 3
HCV RNA ≥ 10,000 IU/ml
Treatment naïve
No cirrhosis
No HBV or HIV co-infection
N = 21
GZR + EBR + RBV
SVR12
GZR + EBR + RBV
N = 20
Grazoprevir (GZR) : 100 mg qd
Elbasvir (EBR) : 50 mg qd
RBV (bid dosing) : 800mg/day if kg, 1000 mg/day if kg, 1200 mg/day if kg, 1400 mg/day if > 105 kg
Primary efficacy endpoint
SVR12 (HCV RNA < 25 IU/ml), with 2-sided 95% CI, comparison between groups (intention to treat analysis)
C-WORTHY/D
Gane E. EASL 2015, Abs. P0776

2. C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3
Baseline characteristics and patient disposition
GZR + EBR + RBV 12 weeks (N = 20)
GZR + EBR + RBV 18 weeks (N = 21)
Female
60%
62%
Age, years (mean) 49 42
IL28B CC
40%
38%
HCV RNA ≤ 10M IU/ml
75%
76.2%
Metavir F0-F2 / F3
95% / 5%
95.2% / 4.8 %
Discontinuation
On-treatment failure
Adverse event
Lost to follow-up, Withdrew consent 2 1
C-WORTHY/D
Gane E. EASL 2015, Abs. P0776

3. C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3
SVR12 (HCV RNA < 25 IU/ml), % (95% CI), ITT %
100
57.1 ( ) 75
45.0 ( ) 50 25 20 21
12 weeks
18 weeks
Rebound 3 2
Breakthrough 6 5
Futility
1 (quantifiable virus at TW8)
Relapse
C-WORTHY/D
Gane E. EASL 2015, Abs. P0776

4. Resistance associated variants in subjects with virologic failure
C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3
Resistance associated variants in subjects with virologic failure
NS3 RAVs
NS5A RAVs
12W arm
At baseline
At failure
Breakthrough
V170I WT
A30S, Y93Y/H, L31L/I
Q80K
A30S, Y93H
Rebound na
V170I, A156G
Y93H
Q80K, V170I
V170I, A156G, Q80K
V170I, L132I
Q80R, V170I, L132I
Futility
A30A/E/K/T, Y93H
Y56Y/H, Q168Q/K, V170I
18W arm
V170I, Q168R
L31F
A156G
A30K
A30K, P58S
C-WORTHY/D
Gane E. EASL 2015, Abs. P0776

5. SVR12 according to baseline RAVs
C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3
SVR12 according to baseline RAVs
Overall Population
GZR + EBR + RBV 12 weeks
GZR + EBR + RBV 18 weeks
Overall efficacy, n/N (%)
21/38 (55%)
9/19 (47%)
12/19 (63%)
NS3 RAVs not detected, n/N (%)
3/3 (100%)
2/2 (100%)
1/1 (100%)
NS3 RAVs at baseline, n /N (%)
18/35 (51%)
7/17 (41%)
11/18 (61%)
NS5A RAVs not detected, n/N (%)
18/31 (58%)
7/14 (50%)
11/17 (65%)
NS5A RAVs at baseline, n/N (%)
3/7 (43%)
2/5 (40%)
1/2 (50%)
C-WORTHY/D
Gane E. EASL 2015, Abs. P0776

6. GZR + EBR + RBV 12 weeks (N = 20) GZR + EBR + RBV 18 weeks (N = 21)
C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3
Adverse events, N (%)
GZR + EBR + RBV 12 weeks (N = 20)
GZR + EBR + RBV 18 weeks (N = 21)
Adverse events
Headache
Upper respiratory tract infection
Accidental overdose
Insomnia
Rash
Nausea
Asthenia
17 (85.0)
5 (25.0)
3 (15.0)
2 (10.0)
19 (90.5)
5 (23.8)
2 (9.5)
3 (14.3)
Serious adverse event
Serious drug-related adverse event
Discontinuation due to adverse event
1* (4.8)
* dyspnea, fatigue and asthenia 2-3 days after starting treatment
C-WORTHY/D
Gane E. EASL 2015, Abs. P0776

7. C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3
Summary
Efficacy of 12 or 18 weeks of GZR + EBR + RBV in HCV genotype 3 infected patients
Was suboptimal due to on-treatment virologic failure in 17 of 41 patients
No subject relapsed after the end of therapy
NS5A RAVs found in 16 of 17 failures, Y93H the most common NS5A RAV identified
GZR + EBR + RBV was generally safe and well tolerated
Adverse events were slightly more common in the 18 week arm compared with the 12 week arm
No differences in serious adverse events or laboratory abnormalities
Adverse event considered to be severe in intensity reported in only 1 patient (non-drug related depression during follow-up)
C-WORTHY/D
Gane E. EASL 2015, Abs. P0776