C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3 C-WORTHY/D Gane E. EASL 2015, Abs. P0776 GZR + EBR + RBV N = 21 N = 20 Design W12W18

C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3

C-WORTHY/D Gane E. EASL 2015, Abs. P0776

GZR + EBR + RBV

GZR + EBR + RBVN = 21

N = 20

DesignW12 W18

SVR12

> 18 yearsHCV genotype 3

HCV RNA ≥ 10,000 IU/mlTreatment naïve

No cirrhosisNo HBV or HIV co-infection

Randomisation1 : 1

Open-label

Primary efficacy endpoint– SVR12 (HCV RNA < 25 IU/ml), with 2-sided 95% CI, comparison between

groups (intention to treat analysis)

Grazoprevir (GZR) : 100 mg qdElbasvir (EBR) : 50 mg qdRBV (bid dosing) : 800mg/day if 51-65 kg, 1000 mg/day if 66-80 kg, 1200 mg/day if 81-105 kg, 1400 mg/day if > 105 kg

GZR + EBR + RBV12 weeks (N = 20)


Female 60% 62%

Age, years (mean) 49 42

IL28B CC 40% 38%

HCV RNA ≤ 10M IU/ml75% 76.2%

Metavir F0-F2 / F3 95% / 5% 95.2% / 4.8 %

DiscontinuationOn-treatment failureAdverse eventLost to follow-up, Withdrew consent

2101

2011

Baseline characteristics and patient disposition



100

75

50

25

0

45.0(23.1-68.5)

57.1(34.0-78.2)

12 weeks 18 weeks

20 21

Rebound 3 2

Breakthrough 6 5

Futility 1 (quantifiable virus at TW8) 0

Relapse 0 0

SVR12 (HCV RNA < 25 IU/ml), % (95% CI), ITT %



NS3 RAVs NS5A RAVs

12W arm At baseline At failure At baseline At failureBreakthrough V170I V170I WT A30S, Y93Y/H, L31L/I

Breakthrough V170I Q80K WT A30S, Y93H

Rebound V170I na WT na

Breakthrough V170I V170I, A156G WT Y93H

Breakthrough V170I Q80K, V170I WT Y93H

Rebound V170I V170I, A156G, Q80K WT Y93H

Breakthrough V170I, L132I Q80R, V170I, L132I WT Y93H

Futility V170I Q80K, V170I A30A/E/K/T, Y93H Y93H

Rebound V170I Y56Y/H, Q168Q/K, V170I Y93H Y93H

Breakthrough V170I V170I, A156G WT Y93H

18W arm

Breakthrough V170I, Q168R V170I, Q168R WT L31F

Breakthrough V170I Q80K, V170I WT L31F

Breakthrough V170I V170I WT Y93H

Rebound V170I V170I, A156G WT Y93H

Rebound V170I A156G A30K A30K, P58S

Breakthrough V170I Q80K, V170I WT Y93H

Breakthrough V170I Q80K WT Y93H

Resistance associated variants in subjects with virologic failure



SVR12 according to baseline RAVs

OverallPopulation

GZR + EBR + RBV12 weeks

GZR + EBR + RBV18 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%)





Adverse events

Headache

Upper respiratory tract infection

Accidental overdose

Insomnia

Rash

Nausea

Asthenia

17 (85.0)

5 (25.0)

3 (15.0)

3 (15.0)

3 (15.0)

3 (15.0)

3 (15.0)

2 (10.0)

19 (90.5)

5 (23.8)

5 (23.8)

2 (9.5)

3 (14.3)

2 (9.5)

5 (23.8)

3 (14.3)

Serious adverse event 0 0

Serious drug-related adverse event 0 0

Discontinuation due to adverse event 0 1* (4.8)

Adverse events, N (%)

* dyspnea, fatigue and asthenia 2-3 days after starting treatment



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)



Documents

C-WORTHY Study Part D : grazoprevir + elbasvir + RBV in genotype 3 C-WORTHY/D Gane E. EASL 2015, Abs. P0776 GZR + EBR + RBV N = 21 N = 20 Design W12W18