C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 Zeuzem S. Ann Intern Med 2015; 163:1-13 GZR/EBR 100/50 mg qd N = 316 N = 105  Design W12W24.

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Presentation transcript:

C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 Zeuzem S. Ann Intern Med 2015; 163:1-13 GZR/EBR 100/50 mg qd N = 316 N = 105  Design W12W24 W16 Placebo GZR/EBR W28 C-EDGE TN > 18 years HCV infection Genotype 1, 4, 6 Treatment-naïve HCV RNA > 10,000 IU/ml Compensated cirrhosis** allowed No HBV or HIV co-infection Randomisation* 3 : 1 Double blind * Randomisation was stratified on genotype (1 or 4 or 6) and cirrhosis (yes or no) ** Metavir F4 or fibroscan > 12.5 kPa or FibroTest > APRI > 2 Objective SVR 12 (HCV RNA < 15 IU/ml) by intention to treat analysis : superiority to historical SVR 12 of simeprevir + PEG-IFN + RBV (73%), at an overall 1-sided alpha value of 0.025, 99% power

GZR/EBR N = 316 Placebo N = 105 Age, years, mean Female46%47% Black / White / Asian 19% / 60% / 17%17% / 70% / 12% Genotype 1a 1b % 42% 6% 3% 51% 38% 8% 3% HCV RNA log 10 IU/ml6.4 IL28B CC34%35% Metavir F422%21% ALT, IU/L, mean (SD)77 (62)75 (64) Platelets < 10 9 /L, mean Discontinuation, n For adverse event / lost to follow-up / death 5 3 / 1 / / 0 / 0 C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 C-EDGE TN Baseline characteristics and patient disposition Zeuzem S. Ann Intern Med 2015; 163:1-13

C-EDGE TN C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 Non-virologic failure43100 Breakthrough11000 Relapse ( ) 92 (86-96) 99 (95-100) 100 (82-100) 80 (44-98) All patientsGenotype 1aGT 1bGT 4GT % SVR 12 (HCV RNA < 15 IU/ml), % (95% CI) Zeuzem S. Ann Intern Med 2015; 163:1-13

C-EDGE TN C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 0 MaleCCNon-CCNoYes SVR 12 (HCV RNA < 15 IU/ml) by subgroup, % (95% CI) Female NoYes (88-96) 93 (87-97) 96 (92-98) 94 (90-97) 97 (90-100) % (92-99) 100 (96-100) 92 (88-96) 222 Sex IL28B genotypeCirrhosis HCV RNA > IU/ml Zeuzem S. Ann Intern Med 2015; 163:1-13

C-EDGE TN C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 RAV at baseline % (n/N) SVR 12 all patients % (N/n) SVR 12 RAVs with ≤ 5-fold  susceptibility SVR 12 RAVs with > 5-fold  susceptibility NS3 RAVs Genotype 1a Present Absent 57% (86/151) 43% (65/151) 97% (83/86) 89% (58/65) 97% (83/86) - 0% (0/0) - Genotype 1b Present Absent 19% (25/129) 81% (104/129) 96% (24/25) 100% (104/104) 96% (21/22) - 100% (3/3) - NS5A RAVs Genotype 1a Present Absent 12% (19/154) 88% (135/154) 58% (11/19) 99% (133/135) 90% (9/10) - 22% (2/9) - Genotype 1b Present Absent 14% (18/130) 86% (112/130) 94% (17/18) 100% (112/112) 100% (1/1) - 94% (16/17) - All 11 patients with virologic failure had baseline HCV RNA > 800,000 IU/ml (selection of NS5A RAV in 10/11) SVR 12 in genotype 1 according to baseline NS3 and NS5A RAVs Zeuzem S. Ann Intern Med 2015; 163:1-13

C-EDGE TN C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 NS3 RAVsNS5A RAVs GT Baseline HCV RNA (IU/ml) Day of virologic failure Baseline Emerging at failure (in addition) Baseline Emerging at failure (in addition) Breakthrough 1a1,238,923Rx D71Q80K, S122GV36ML31L/MQ30R Relapse 1a5,127,102F/U D28WTNoneL31MQ30R Relapse 1a2,134,448F/U D71WTD168AQ30H/QY93H Relapse 1a948,279F/U D70Q80KD168A M28V, Q30L, Y93H L31V Relapse 1a3,908,965F/U D84WTD168A M28M/V, H58H/D Q30R Relapse 1a5,282,871FU D62WTNoneL31MQ30R Relapse 1a1,846,427F/U D54WTNoneWTQ30R, L31M Relapse 1a1,939,436F/U D61WTY56H, D168AWTY93N Relapse 1b4,475,338F/U D89T54SV170IY93HL31F Relapse 1a3,913,374F/U D29V55AD168AQ30R, L31L/MNone Relapse 615,689,194F/U D25 V36I, L80Q, S122T, I132L, I170V D168YWTNone Relapse 1a1,574,151F/U D56WTNoneM28VM28G Relapse 615,056,901F/U D25L80K, I170VY56Y/H, D168EF28LL31M Baseline and emergent resistance variants in virologic failure cases Zeuzem S. Ann Intern Med 2015; 163:1-13

C-EDGE TN C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 Common AEs (> 5% in GZR/EBR) GZR/EBR N = 316 Placebo N = 105 Headache52 (17%)19 (18%) Fatigue49 (16%)18 (17%) Nausea28 (9%)8 (8%) Arthralgia20 (6%)6 (6%) Non-cirrhoticCirrhotic GZR/EBR N = 246 Placebo N = 83 GZR/EBR N = 70 Placebo N = 22 At least one adverse event175 (71%)57 (69%)38 (54%)15 (68%) Drug-related adverse event96 (39%)32 (39%)18 (26%)9 (41%) Serious adverse events7 (3%)3 (4%)2 (3%)0 (0%) Serious drug-related adverse event0 (0%) Discontinuation due to adverse event2 (1%)0 (0%)1 (1%)1 (5%) Death1 (<1%)0 (0%)1 (1%)0 (0%) Adverse events, n (%) Zeuzem S. Ann Intern Med 2015; 163:1-13

C-EDGE TN C-EDGE TN Study : grazoprevir/elbasvir in genotype 1, 4 or 6 GZR/EBR N = 316 Placebo N = 105 Late elevation of ALT or AST > x ULN > 5.0 x ULN 3 (1.0%) 4 (1.3%) 4 (3.8%) 0 (0%) Elevation of total bilirubin > x ULN > 5.0 x ULN 3 (0.9%) 1 (0.3%) 0 (0%) Decreased hemoglobin Grade 1-2 Grade (2.9%) 0 (0%) 4 (3.8%) 0 (0%) Increased creatinine Grade 1 Grade 2 2 (0.6%) 0 (0%) 1 (1.0%) 0 (0%) Increased lipase Grade 1-2 Grade (32.0%) 19 (6.0%) 25 (23.8%) 5 (4.8%) Laboratory abnormalities, n (%) Zeuzem S. Ann Intern Med 2015; 163:1-13

C-EDGE TN  Summary –A 12-week regimen of the oral fixed dose combination of once-daily, single-tablet of grazoprevir/elbasvir, achieved an overall SVR 12 of 95% High efficacy in genotypes 1 and 4 SVR 12 lower in genotype 6 High efficacy in cirrhotics (SVR 12 = 97.1%) Lower efficacy observed among patients with high viral load (HCV RNA > 800,000 IU/ml) –Overall virologic failure rate was 4% Baseline NS3 RAVS did not affect efficacy Association between virologic failure and the presence of baseline NS5A RAVs, which was most apparent in genotype 1a with baseline RAVs demonstrating > 5-fold potency reduction to elbasvir Emergence of (additional) NS3 and/or NS5A RAVs at failure was common –Grazoprevir/elbasvir was generally well-tolerated, with a similar safety profile in cirrhotic and non-cirrhotic patients –Limitations No active-control group C-EDGE TN Study: grazoprevir/elbasvir in genotype 1, 4 or 6 Zeuzem S. Ann Intern Med 2015; 163:1-13