C-WORTHY/B - PowerPoint Presentation

Slide1

C-WORTHY/B

Randomisation*

Open-label

>

18 years

HCV genotype 1HCV RNA ≥ 10,000 IU/mlTreatment naïve and compensated cirrhosis (Child-Pugh A)orNull responders to previous PEG-IFN + RBV, with or without cirrhosisNo HBV or HIV co-infection

Primary efficacy endpoint

SVR12 (HCV RNA < 25 IU/ml), with 2-sided 95% CI,comparison between groups (intention to treat analysis)

*

Randomisation stratified on genotype (1a or non-1a) ;cohort 2 also stratified on cirrhosis (presence or absence).Patients and investigators were masked to the duration of therapy until W12, but not to RBV allocation

Lawitz E. Lancet 2015;385:1075-86

C-WORTHY Study part B: grazoprevir + elbasvir + RBV, 12 weeks vs 18 weeks in genotype 1

Design

Cohort 1 = Treatment-naïve, cirrhosis

Cohort 2 = Null responders,

with or without cirrhosisSlide2

Naïve with cirrhosis

GZR + EBR + RBV = B4

GZR + EBR = B5

W18

GZR + EBR + RBV = B6

W12

GZR + EBR = B7

Cohort 1

Cohort 2

Null responders to PEG-IFN + RBV with or without cirrhosis

GZR + EBR + RBV = B8

GZR + EBR = B9

GZR + EBR + RBV = B10

GZR + EBR = B11

Treatment groups

N = 32

N = 31

N = 32

N = 31

N = 32

N = 33

N = 33

N = 29

Dosage of study drugs

Grazoprevir

(GZR) 100 mg

qd

Elbasvir

(EBR) : 50 mg

qd

RBV (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

C-WORTHY/B

Lawitz E. Lancet 2015;385:1075-86

C-WORTHY Study part B: grazoprevir + elbasvir

+

 RBV, 12 weeks vs 18 weeks in genotype 1Slide3

GZR + EBR

+ RBV 12W

N = 31

GZR + EBR

12W

N = 29

GZR + EBR

+ RBV 18W

N = 32

GZR + EBR 18W

N = 31

Mean

age, years

57

59

59

59

Female

39%

34%

53%

32%

HCV genotype

1a

1b

other

65%

32%

3%

69%

24%

7%

75%

25%

0

74%

26%

0

HCV RNA log

10

IU/ml, mean

6.53

6.43

6.4

6.6

Discontinued treatment , N

Virologic

failure

Adverse event

3

3

0

1

1

0101110

Baseline characteristics and patient disposition(Cohort 1 : treatment-naïve with cirrhosis)

C-WORTHY/B

Lawitz E. Lancet 2015;385:1075-86

C-WORTHY Study part B: grazoprevir + elbasvir

+

 RBV, 12 weeks vs 18 weeks in genotype 1Slide4

GZR + EBR

+ RBV 12W

N = 32

GZR + EBR 12W

N = 33

GZR + EBR

+ RBV 18W

N = 33

GZR + EBR 18W

N = 32

Mean

age, years

52

54

56

54

Female

37%

39%

52%

44%

HCV genotype

1a

1b

56%

44%

67%

33%

58%

42%

53%

47%

HCV RNA log

10

IU/ml, mean

6.64

6.67

6.81

6.80

Discontinued treatment , N

Virologic

failure

Adverse event

Death

2

0

1

1

3

3

0

0

1

0

001100Baseline characteristics and patient disposition(Cohort 2 : null responders with or without cirrhosis)C-WORTHY/B

Lawitz E. Lancet 2015;385:1075-86 C-WORTHY Study part B: grazoprevir + elbasvir + RBV, 12 weeks vs 18 weeks in genotype 1Slide5

SVR

12

(

HCV RNA < 25 IU

/ml) , % (95% CI)

GZR + EBR + RBV 12W GZR + EBR 12W

GZR + EBR + RBV 18W

GZR + EBR 18W

Early discontinuation

0

0

1

0

2

0

0

0

Virologic

breakthrough

1

0

0

0

0

0

0

1

Relapse

2

1

0

2

0

3

0

0

%

Cohort 2 with cirrhosis : SVR

12

= 92% with 12W and 100% with 18W ; 94% for GT1a and 100% for GT1b

C-WORTHY/B

Lawitz E. Lancet 2015;385:1075-86

C-WORTHY Study part B: grazoprevir + elbasvir

+

 RBV, 12 weeks vs 18 weeks in genotype 1

0

20

40

60

80

100

Treatment-naïve (Cohort 1)

Null responders (Cohort 2)

94

(79-99)100(89-100)90 (74-88)97(82-100)97(84-100)91(76-98)N2932333297(84-100)3194(79-99)323331Slide6

GZR + EBR + RBV 12W

GZR + EBR 12W

GZR + EBR + RBV 18W

GZR + EBR 18W

Serious adverse events

2 (3%)

3 (5%)

1 (2%)

2 (3%)

Discontinuation due to AE

1 (2%)

0

1 (2%)

0

Death

1 (2%)

0

0

0

Adverse events in ≥ 10%

Fatigue

24%

23%

37%

21%

Headache

17%

18%

26%

32%

Asthenia

14%

9%

16%

14%

Hemoglobin

< 10 g/dl

10%

0

8%

0

Elevation of bilirubin > 2.5 to 5.0 x baseline

11%

0

28%

6%

Elevation of bilirubin > 5 x baseline

2 (3%)

0

1 (2%)

0

Elevation of ALT or AST > 2.5 x baseline

0

0

1 (2%)

5 (8%)

Adverse events and laboratory abnormalities, N (%)

C-WORTHY/B

Lawitz E. Lancet 2015;385:1075-86

C-WORTHY Study part B: grazoprevir + elbasvir

+

 RBV, 12 weeks vs 18 weeks in genotype 1Slide7

SVR

12

according to detection of resistance-associated variants at baseline

NS3 variants at baseline

NS5A variants at baseline

NO

YES

NO

YES

N

169

79

209

34

SVR

12

(HCV RNA < 25 IU/ml)

96.4%

92.4%

97.1%*

82.4% *

Mutations detected

Most prevalent NS3 variants

at failure :

Y56H

A156T/G/V

D168A/Y

Most prevalent NS5A variants

at failure :

M28T

Q30L/R

L31M

Y93H/N

* p < 0.001

C-WORTHY/B

Lawitz E. Lancet 2015;385:1075-86

C-WORTHY Study part B: grazoprevir + elbasvir

+

 RBV, 12 weeks vs 18 weeks in genotype 1Slide8

C-WORTHY Study part B: grazoprevir + elbasvir

+ RBV, 12 weeks vs 18 weeks in genotype 1

SummaryIn this phase II study, oral treatment with grazoprevir and elbasvir

, with or without RBV, in HCV genotype 1-infected patients that are difficult to cure with HCV therapy (patients with well compensated cirrhosis and null responders with or without well compensated cirrhosis), high rates of SVR

12 were shown across all groups, irrespective of the addition of RBV or extension of treatment duration from 12 to 18 weeks12 weeks of GZR + EBR without RBV achieved SVR12 of

97% in previously untreated patients with cirrhosis, 91% in null responder patients with or without cirrhosis, 92% in null responder patients with cirrhosisThe rate of virologic failure with GZR + EBR with or without RBV was low (4%)Similar efficacy was seen in patients with genotype 1a and 1bPatients with NS5A baseline resistance-associated variants had lower SVR12Treatment-emergent, clinically significant, adverse events were infrequent

No discontinuation for AE in the groups without RBV

C-WORTHY/BLawitz E. Lancet 2015;385:1075-86