Roth D. Lancet 2015; Oct 6; 386:1537-45 C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease N = 111 GZR + EBR Placebo GZR.

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Roth D. Lancet 2015; Oct 6; 386: C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease N = 111 GZR + EBR Placebo GZR + EBR (Intensive PK) N = 113 N = 11 GZR/EBR W12W16W28  Objective –SVR 12 (HCV RNA 45% in immediate and PK groups : reference rate, with 2-sided significance level of 0.05 ≥ 18 years HCV infection, Genotype 1 CKD stage 4/5** ± hemodialysis Treatment naïve or pre-treated with IFN-based regimen Compensated cirrhosis allowed No HBV or HIV co-infection Open label Results not available  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) : ml/min = CKD 4 ; < 15 ml/min = CKD 5 GZR 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 = 122 Placebo N = 113 Mean age, years5755 Female25%29% White / African-American50% / 45%43% / 47% Genotype, n (%) 1a 1b 1 other 63 (52) 59 (48) 0 59 (52) 53 (47) 1 (<1) IL28B CC26.2%26.5% HCV RNA > 800,000 IU/ml56.6%58.4% Prior treatment history, n (%) Naïve Experienced 101 (83) 21 (17) 88 (78) 25 (22) Cirrhosis, n (%)7 (6) Diabetes, n (%)44 (36)36 (32) Dialysis, n (%)92 (75)87 (77) CKD stage, n (%) Stage 4 Stage 5 22 (18) 100 (82) 22 (19) 91 (81) C-SURFER Baseline characteristics Roth D. Lancet 2015; Oct 6; 386:

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease ( ) 94.3 ( ) Modified Full analysis Set Full analysis Set SVR 12 (HCV RNA < 15 IU/ml), % (95% CI), mITT % Primary analysis 100 ( ) ( ) ( ) ( ) 75 1a1bNoYes Diabetes Genotype * 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 Relapse1*1 Discontinuation unrelated to treatment 06 Roth D. Lancet 2015; Oct 6; 386:

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease  Virologic outcome –SVR 12 (99%) > to historical control (45%), p < – 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 : SVR 12 in 36/36 –NS5A : 17/115 (14.8%) of patients : SVR 12 in 16/17 C-SURFER Roth D. Lancet 2015; Oct 6; 386:

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease GZR + EBR N = 111 Placebo N = 113 p Discontinuation due to an adverse event05 (4.4%)0.026 Serious adverse event14,4%16,8%- Drug-related serious adverse event01- Death1 (0.9%)3 (2.7%)- Adverse events in ≥ 10% in either group Headache Nausea Fatigue Insomnia Dizziness Diarrhea 17.1% 15.3% 9.9% 6.3% 5.4% 16.8% 15.9% 15.0% 10.6% 15.9% 13.3% Hemoglobin < 10 g/dl*28.8%21.2%- ALT > 2.5 x baseline0.8%6.2%- ALT > 2.5 x baseline04.6%0.045 Total bilirubin > x baseline0.9%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:

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease C-SURFER GZR + EBR N = 111 Placebo N = 113 Initiation of maintenance dialysis, n/N2/250/26 Increase in CKD stage, not on dialysis, n/N4/252/26 Worsening of proteinuria, n48 Mean change from baseline in eGR (mL/min/1.73m 2 ) in patients not on dialysis -At W12 -At follow-up W ± ± ± ± 4.85 Renal function monitored events Roth D. Lancet 2015; Oct 6; 386:

C-SURFER Study: grazoprevir + elbasvir in genotype 1 with chronic kidney disease  Summary –Once daily GZR + EBR for 12 weeks achieved SVR 12 of 99% for treatment of HCV genotype 1 infection among patients with chronic kidney disease stage 4-5 SVR 12 of 100% in naïve patients SVR 12 of 95% in experienced patients –Efficacy was consistent across different subpopulation Genotypes 1a and 1b Diabetes Hemodialysis –Failure to achieve SVR 12 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: