Roth D. Lancet 2015; Oct 6; 386:1537-45

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease

N = 111GZR + EBR

Placebo

GZR + EBR (Intensive PK)

N = 113

N = 11

GZR/EBR

W12 W16 W28

Objective– SVR12 (HCV RNA < 15 IU/ml) > 45% in immediate and PK groups :

reference rate, with 2-sided significance level of 0.05

≥ 18 yearsHCV infection,

Genotype 1CKD stage 4/5** ± hemodialysisTreatment naïve or pre-treated

with IFN-based regimenCompensated cirrhosis allowed

No HBV or HIV co-infectionOpen label

Resultsnotavailable

Design Randomisation*1 : 1

Double blind

* Randomisation was stratified on diabetes (yes or no) and hemodialysis status (yes or no)** based on eGFR (MDRD equation) : 15-29 ml/min = CKD 4 ; < 15 ml/min = CKD 5GZR 100 mg qd, EBR 50 mg qd, GZR/EBR 100mg/50 mg fixed dose combination 1 pill qd

C-SURFER

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease

GZR + EBR(Immediate + PK groups)

N = 122PlaceboN = 113

Mean age, years 57 55Female 25% 29%White / African-American 50% / 45% 43% / 47%Genotype, n (%)

1a1b1 other

63 (52)59 (48)

0

59 (52)53 (47)1 (<1)

IL28B CC 26.2% 26.5%HCV RNA > 800,000 IU/ml 56.6% 58.4%Prior treatment history, n (%)

NaïveExperienced

101 (83)21 (17)

88 (78)25 (22)

Cirrhosis, n (%) 7 (6) 7 (6)Diabetes, n (%) 44 (36) 36 (32)Dialysis, n (%) 92 (75) 87 (77)CKD stage, n (%)

Stage 4Stage 5

22 (18)100 (82)

22 (19)91 (81)

C-SURFER

Baseline characteristics

Roth D. Lancet 2015; Oct 6; 386:1537-45

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease

0

25

50

75

100

99.1(95.3-100)

94.3(88.5-97.7)

116 122

ModifiedFull analysis Set

Full analysis Set

SVR12 (HCV RNA < 15 IU/ml), % (95% CI), mITT

%

Primary analysis100

(94.1-100)

61

98.2(90.3-100)

55

97.6(87.1-99.9)

41

100(95.2-100)

75

1a 1b NoYes

DiabetesGenotype

* Genotype 1b, non cirrhotic, CKD stage 5, NS5A RAV at baseline : L31M, at failure : L31M + Y93H

Modified full analysis set excluded patients who died or discontinued for reasons unrelated to treatment

C-SURFER

Relapse 1* 1

Discontinuation unrelatedto treatment 0 6

Roth D. Lancet 2015; Oct 6; 386:1537-45

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease Virologic outcome

– SVR12 (99%) > to historical control (45%), p < 0.001– SVR rates similar in patients with unfavourable baseline characteristics

(African American, IL28B non-CC, cirrhosis), and in in all subgroups including haemodialysis and non-haemodialysis

Resistance associated variants at baseline– NS3 : 36/112 (32.1%) patients : SVR12 in 36/36– NS5A : 17/115 (14.8%) of patients : SVR12 in 16/17

C-SURFER Roth D. Lancet 2015; Oct 6; 386:1537-45

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease

GZR + EBRN = 111

PlaceboN = 113 p

Discontinuation due to an adverse event 0 5 (4.4%) 0.026Serious adverse event 14,4% 16,8% -Drug-related serious adverse event 0 1 -Death 1 (0.9%) 3 (2.7%) -Adverse events in ≥ 10% in either group

HeadacheNauseaFatigueInsomniaDizzinessDiarrhea

17.1%15.3%9.9%6.3%5.4%5.4%

16.8%15.9%15.0%10.6%15.9%13.3%

-----

0.0110.044

Hemoglobin < 10 g/dl* 28.8% 21.2% -ALT > 2.5 x baseline 0.8% 6.2% -ALT > 2.5 x baseline 0 4.6% 0.045Total bilirubin > 2.5 -5 x baseline 0.9% 2.7% -

Adverse events and laboratory abnormalities, N (%)

* Erythropoietin use : 23% of GZR + EBR group vs 35% of placebo

C-SURFER Roth D. Lancet 2015; Oct 6; 386:1537-45

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease

C-SURFER

GZR + EBRN = 111

PlaceboN = 113

Initiation of maintenance dialysis, n/N 2/25 0/26Increase in CKD stage, not on dialysis, n/N 4/25 2/26Worsening of proteinuria, n 4 8

Mean change from baseline in eGR (mL/min/1.73m2) in patients not on dialysis

- At W12- At follow-up W4

- 0.32 ± 4.79- 0.13 ± 4.79

- 1.08 ± 3.83- 1.13 ± 4.85

Renal function monitored events

Roth D. Lancet 2015; Oct 6; 386:1537-45

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease Summary

– Once daily GZR + EBR for 12 weeks achieved SVR12 of 99% for treatment of HCV genotype 1 infection among patients with chronic kidney disease stage 4-5

• SVR12 of 100% in naïve patients• SVR12 of 95% in experienced patients

– Efficacy was consistent across different subpopulation• Genotypes 1a and 1b• Diabetes• Hemodialysis

– Failure to achieve SVR12 was rare• One patient with genotype 1b relapsed

– Once daily GZR + EBR for 12 weeks was well-tolerated

C-SURFER Roth D. Lancet 2015; Oct 6; 386:1537-45