C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis

Jacobson IM. EASL 2015, Abs. O008

Design

Child-Pugh B

GZR 100 mg + EBR 50 mg

GZR 50 mg + EBR 50 mg

Non-cirrhotic

W12Open-label

SVR12

N = 30

N = 10

≥ 18 yearsChronic HCV infection

Genotype 1Naïve or pre-treated with

IFN-based regimen Child-Pugh B cirrhosis

No HBV or HIV co-infection

No-cirrhosis(PK intensive study)

Objective– Primary endpoint : SVR12 (HCV RNA < 15 IU/ml), by ITT analysis

C-SALT

Child Pugh-BN = 30

Non-cirrhotic (PK arm)N = 10

Mean age, years 58.3 60.4Female 43.3% 50%White 96.7% 90%Genotype

1a1b

90%10%

60%40%

Prior treatment status Naive Null responsePartial response Relapse

63.3%20%0%

16.7%

60%20%10%10%

Child-Pugh score789

70%23.3%6.7%

000

MELD score, (mean ± SD) 9.9 ± 2.5 6.4 ± 1.0

C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Baseline characteristics

Jacobson IM. EASL 2015, Abs. O008C-SALT

Virologic failure 2 (6.7%) 0Breakthrough 0 0Rebound 0 0Relapse 2 0

100

75

50

25

0

90(73.5-97.9)

30 10

Child-Pugh B Non-cirrhotic

100(69.2-100)

C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosisSVR12 (HCV RNA < 15 IU/ml) , % (95% CI)

%

Child-Pugh B sub-groups

Genotype1a

Genotype1b

Baseline HCV RNA (IU/ml)

≤ 1 M > 1 M

15 15 27 3

8793 89

100

Jacobson IM. EASL 2015, Abs. O008C-SALT

2

1

0

-1

-2

-3

*Relapse patients (N = 2)

*

*

C-SALT Study: grazoprevir + elbasvirin genotype 1 with Child-Pugh B cirrhosisChild-Pugh score change from baseline to follow-up W12§

N = 18

N = 4N = 7

§ 1 died at follow-up W4

Jacobson IM. EASL 2015, Abs. O008C-SALT

GMR (90% CI)Child-Pugh B / Non-cirrhotic

GrazoprevirC2hr

C24hr

AUC0-24

1.06 (0.53, 2.11)1.71 (0.87, 3.33)1.25 (0.70, 2.24)

ElbasvirC2hr

C24hr

AUC0-24

0.93 (0.64, 1.33)1.04 (0.67, 1.60)0.90 (0.63, 1.60)

GZR exposure was slightly higher (not significant) in patients with Child-Pugh B cirrhosis receiving 50 mg dose compared to non-cirrhotic patients receiving 100 mg dose

EBR (50 mg) PK was similar in both patient populations

C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Pharmacokinetics

Plasma samples collected over 24 hours at treatment W4 • PK group (non-cirrhotic, N = 9) with GZR 100 mg• Child-Pugh B (N = 9) with GZR 50 mg

Jacobson IM. EASL 2015, Abs. O008C-SALT

Child-Pugh BN = 30

Non cirrhotic (PK)N = 10

Discontinuation due to an AE, N (%) 0 0

Serious adverse event, N (%) 4 (13.3%)* 0

Adverse events, N (%)FatigueArthralgiaNauseaPyrexiaHeadache

30%16.7%10%10%10%

30%20%20%

050%

Grade 3-4 ALT/AST elevation, N (%) 0 0

Grade 3-4 bilirubin elevation, N (%) 4 (13.3) 0

Death**, N (%) 1 (3.3) 0

C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Adverse events, N (%)

* All unrelated to study treatment : hepatocellular carcinoma, N = 1; ascites and encephalopathy, N = 1 ; bacterial peritonitis, cerebral infarction and hepatic failure (**death at follow-up W4) N = 1 ; hematemesis, N = 1

Jacobson IM. EASL 2015, Abs. O008C-SALT

C-SALT Study: grazoprevir + elbasvir in genotype 1 with Child-Pugh B cirrhosis Summary

– High rates of virologic response were observed in Child-Pugh B patients receiving a combination of once-daily GZR 50 mg + EBR 50 mg

– The regimen was well tolerated with no evidence of hepatotoxicity– Plasma GZR exposure was slightly higher in Child-Pugh B

patients receiving 50 mg compared to non-cirrhotic patients receiving 100 mg

– EBR exposure was similar in both Child-Pugh B and non-cirrhotic groups

– This regimen was highly effective and well-tolerated in a traditionally hard-to-treat patient group with no currently approved treatment options

Jacobson IM. EASL 2015, Abs. O008C-SALT