Forns X. J Hepatology 2015; 63: 564-72

C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen

– NS3 and NS5A RAVs identified by population sequencing at baseline and VF

Design

N = 79

GZR 100 mg + EBR 50 mg+ weight-based RBV (BID

dosing (800-1400 mg/day)

Open-label

C-SALVAGE

W12 W24> 18 years

Chronic HCV infectionGenotype 1

HCV RNA ≥ 10,000 IU/mlFailure to ≥ 4 weeks of

treatment with PEG-IFN + RBV + (BOC, TVR, or SMV)

Compensated cirrhosis*allowed

No HBV or HIV co-infection

* Metavir F4 or Fibroscan > 12.5 kPa or FibroTest > 0.75 + APRI > 2

Objective– SVR12 (HCV RNA < 15 IU/ml) with 95% CI, no formal statistical hypothesis :

Primary endpoint : per-protocol ; secondary : efficacy and safety on full set

All patientsN = 79

Evaluable patients (with baseline sequencing data)

Baseline NS3 RAVsN = 34*

No baseline NS3 RAVsN = 44

Mean age, years 54.4 53.9 54.6Female 42% 32% 45%Genotype 1a / 1b 38% / 62% 68% / 32% 16% / 84%HCV RNA, log10 IU/ml, mean 6.1 6.1 6.0Metavir F4 43% 44% 43%Prior DAA experience, n (%)

Boceprevir Telaprevir Simeprevir

28 (35.4) 43 (54.4) 8 (10.1)

10 (29.4) 19 (55.9) 5 (14.7)

17 (38.6)24 (54.5)

3 (6.8) Past history of virologic failure 83.5% 94.1% 75%Baseline NS5A polymorphisms 8** (10.1%) 6 (17.6%) 1 (4.5%)Discontinued therapy 1 (for AE)

C-SALVAGE

* Variants with > 5 fold decrease susceptibility to grazoprevir : 4 (11.8%)** NS5A variants with > 5 fold decrease susceptibility to elbasvir : 5/8 (62.5%)

Baseline characteristics and disposition

C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen

Forns X. J Hepatology 2015; 63: 564-72

C-SALVAGE

SVR12 (HCV RNA < 15 IU/ml), % (95% CI), full analysis set

Per protocol : 97.1% (90.1-99.7) * 3 virologic failures

+ 3 relapses

C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen

96.2(89.3-99.2)

66

Allpatients

Prior virologicfailure

95.5 *(87.3-99.1)

13

100(75.3-100)

Prior non-virologic

failure

93.3(78-99)

Genotype

94.1(80-99)

Cirrhosis

3079

98(89-100)

49

1a 1b Yes No

97.8(88-100)

25

50

100

75

%

045N 34

Forns X. J Hepatology 2015; 63: 564-72

93.1(77-99)

BaselineHCV RNA (IU/ml)

< 800,000 > 800,000

98.0(89-100)

5029

RAV at baseline

% (n/N)

SVR12 all patients

% (N/n)

SVR12RAVs with ≤ 5-fold

susceptibility

SVR12

RAVs with > 5-fold susceptibility

NS3 RAVsAll patients

PresentGT 1a Q80K+GT1b

Absent

44% (34/78)76.7% (23/30)36.7% (11/30)22.9% (11/48)56% (44/78)

91.2% (31/34)91.3% (21/23)90.9% (10/11)90.9% (10/11)100% (44/44)

93.3% (28/30)

----

75% (3/4)

----

NS5A RAVs

All patientsPresentAbsent

10% (8/81)90% (73/81)

75% (6/8)98.6% (72/73)

100% (3/3)-

60% (3/5)-

In the 3 virologic failures : emergence of resistance variants to grazoprevir (NS3 A156T in 3 cases + other variants in 2 cases) and to elbasvir (NS5A Y93H in 2 cases, Q30R in 1 case)

SVR12 according to baseline NS3 and NS5A RAVs

C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen

C-SALVAGE Forns X. J Hepatology 2015; 63: 564-72

GZR + EBR + RBV, N = 79Any drug-related adverse event 45 ( 57.0) Serious adverse event 4 (5.1)*Discontinuations due to an adverse event 1 (1.3)Specific adverse event in >10% of patients

Fatigue Headache Asthenia Nausea

22 (27.8)15 (19.0)12 (15.2)9 (11.4)

Grade 3-4 laboratory abnormalitiesTotal bilirubin > 2.5 x ULNLipase > 3 x ULNINR > 1 ULNHemoglobin < 9 g/dl

5 (6.3)4 (5.1)1 (1.3)2 (2.5)

C-SALVAGE

Adverse events and laboratory abnormalities, N (%)

* None related to study medication

RBV dose was reduced in 11 (14%) patients ; all achieved SVR12

C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen

Forns X. J Hepatology 2015; 63: 564-72

Summary

– GZR + EBR + RBV for 12 weeks resulted in SVR12 in 76/79 patients (96.2%) who had failed previous PEG-IFN + RBV plus an earlier-generation PI

• SVR12 was attained in 63/66 (95.5%) patients with a history of VF

• SVR12 was attained in 31/34 (91.2%) patients harboring baselineNS3 RAVs conferring decreased susceptibility to 1st-generation PIs

– GZR + EBR + RBV was generally well tolerated• Only 1 patient stopped study treatment (adverse event unrelated to

study treatment)• No serious drug-related adverse event

C-SALVAGE

C-SALVAGE Study: grazoprevir + elbasvir + RBV in genotype 1 with failure to PI-based regimen

Forns X. J Hepatology 2015; 63: 564-72