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Simeprevir + PEG + RBV in Treatment-Naïve Genotype 1
QUEST-1 Trial
Phase 3
Treatment Naïve
Jacobson IM, et al. Lancet. 2014;384:403-13.
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
Simeprevir + PEG + Ribavirin for Treatment-Naïve HCV GT1
QUEST-1 Trial
QUEST-1 Trial: Features
Design: Randomized, double-blind, placebo-controlled, phase 3 trial with
simeprevir + PEG + RBV versus PEG + RBV in treatment-naïve GT 1
Setting: Multicenter at 71 sites in 13 countries
Entry Criteria
- Treatment-naïve, chronic HCV monoinfection
- HCV Genotype 1 (1a or 1b)
Patient Characteristics
- N = 394
- HCV Genotype: 1a (56%); 1b (44%)
- IL28B Genotype: 71% non-CC
- Age: median age 48
- Sex: 56% male
- Race: 89% white, 8% black
- Liver disease: F3 = 18%; F4 = 12%
Primary end-points: Efficacy (SVR12) and safety
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
N =130 Placebo
+ PEG + RBV
Simeprevir
+ PEG + RBVN = 264
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Design
PEG + RBVPEG + RBV
PEG + RBV
Response-Guided Therapy
Patients with HCV RNA <25 IU/ml
at week 4 and <15 IU/ml at week
12 completed treatment after 24
weeks.
Randomized 2:1;
stratified on IL28B
and HCV1 subtype
Drug Dosing
Simeprevir: 150 mg once daily
Peginterferon alfa-2a (PEG): 180 mcg/week
Ribavirin (RBV) weight-based (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75kg
Week 0 12 4824 36
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Results
QUEST-1: Proportion of Patients with SVR12
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
80
50
0
20
40
60
80
100
Simeprevir + PEG + RBV PEG + RBV
Pa
tie
nts
(%
) w
ith
SV
R 1
2
Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin
P < 0.0001
65/130210/264
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
71
90
49 52
0
20
40
60
80
100
1a 1b
Pati
en
ts (
%)
wit
h S
VR
12
HCV Genotype
Simeprevir + PEG + RBV PEG + RBV
SVR12 by HCV Genotype 1 Subtype
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Results
Abbreviations: PEG = Peginterferon; RBV = Ribavirin
105/147 36/74 105/117 29/56
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
52
85
53
44
0
20
40
60
80
100
1a (with baseline Q80K) 1a (without baseline Q80K)
Pati
en
ts (
%)
wit
h S
VR
12
HCV Genotype
Simeprevir + PEG + RBV PEG + RBV
QUEST 2: SVR12 for HCV 1a by Baseline Q80K Status
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Results
Abbreviations: PEG = Peginterferon; RBV = Ribavirin
31/60 16/30 73/86 19/43
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Results
SVR12 Response in Simeprevir Arm Based on Achievement of RGT Criteria
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
91
21
0
20
40
60
80
100
Met RGT Did Not Meet RGT
Pa
tie
nts
(%
) w
ith
SR
V 1
2
RGT= response-guided therapy: in simeprevir study arm, patients with HCV RNA<25 IU/ml at week 4 (undetectable or
detectable) and <25 IU/ml at week 12 (undetectable) stopped treatment after 24 weeks
85%11%
4%
Met RGT Criteria
Did Not Meet RGT Criteria
Unclassified
SVR12 Based on Meeting RGTPatients (%) who Met RGT Criteria
203/224 6/28N = 264
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
94
76
65
78
42
24
0
20
40
60
80
100
CC CT TT
Pati
en
ts (
%)
wit
h S
VR
12
Simeprevir + PEG + RBV PEG + RBV
Abbreviations: PEG = Peginterferon; RBV = Ribavirin
QUEST 1: SVR12 by Host IL28B Genotype
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Results
72/77 29/37 114/50 32/76 24/37 4/17
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
8378
5860
26 29
0
20
40
60
80
100
F0-F2 F3 F4 (Cirrhosis)
Pati
en
ts (
%)
wit
h S
VR
12
Metavir Fibrosis Score
Simeprevir + PEG + RBV PEG + RBV
QUEST 1: SVR12 by Liver Fibrosis (Metavir Score)
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Results
Abbreviations: PEG = Peginterferon ; RBV = Ribavirin
152/183 54/90 36/46 6/23 18/31 5/17
9 9
34
21
0
10
20
30
40
50
60
On-Treatment Failure Relapse
Pati
en
ts (
%)
Simeprevir + PEG + RBV PEG + RBV
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
Stopping rules: (1) Stop simeprevir or placebo if HCV RNA>1000 at week 4; (2) Stop all therapy if HCV RNA < 2 log10 IU/mL
reduction at week 12; (3) Stop all therapy if HCV RNA ≥25 IU/mL at week 24 or 36.
On-treatment failure: Detectable HCV RNA at end of treatment.
On-Treatment Failure or Relapse
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Results
24/264 44/130 21/234 18/84
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Results
Emergent Protease Resistance in Patients who Failed to Achieve SVR12
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
Among simeprevir-treated patients who failed to achieve SVR12,
emergent mutations in NS3 protease domain detected in 35 (92%) of 38
Genotype 1A: Most common mutation = R155K alone or in combination
with mutations at codons 80 and/or 168
Genotype 1B: Most common mutation = D168V
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Adverse Effects
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
QUEST 1: Event Simeprevir + PEG + RBV(n=264)
Placebo + PEG + RBV(n=130)
Discontinuation (due to adverse event) 3% 2%
Grade 3 adverse event 25% 33%
Grade 4 adverse event 3% 5%
Fatigue 42% 41%
Headache 33% 39%
Pruritus 30% 20%
Rash (any type) 34% 32%
Anemia 20% 21%
Photosensitivity condition 3% <1%
Neutropenia 24% 18%
Bilirubin increase 9% 5%
Source: Jacobson IM, et al. Lancet. 2014;384:403-13.
Interpretation: “Simeprevir once daily with peginterferon
alfa 2a and ribavirin shortens therapy in treatment-naive
patients with HCV genotype 1 infection without worsening
the adverse event profiles associated with peginterferon alfa
2a plus ribavirin.”
Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1
QUEST-1 Trial: Conclusions
This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects.
Hepatitis C Online
www.hepatitisc.uw.edu
Hepatitis Web Study
http://depts.washington.edu/hepstudy/
Funded by a grant from the Centers for Disease Control and Prevention.