Transcript Slide 1

Predictors of treatment response,
baseline and on-treatment
A case study of telaprevir therapy
Alex Thompson
Key learning objectives
• Identify the key predictors of treatment
response for HCV genotype 1:
– peg-IFN + RBV
• IL28B genotype, fibrosis stage, baseline viral load
• On-treatment response (RGT)
– DAA – telaprevir
• IL28B genotype, fibrosis stage, HCV 1a vs 1b
• Past treatment response
• Importance of on-treatment response
– eRVR (RGT)
– Stopping rules
Mrs CW
• 55-year-old professional woman
• Experimental IDU in early 20s
• Moderate-heavy alcohol intake 25-50 years
– 40-60 g alcohol/day
– Abstinent since diagnosis of HCV 3 years prior
• No symptoms of HCV or CLD
Mrs CW
•
•
•
•
Obese (BMI 37)
Hyperlipidaemia
Glucose intolerance
Medication
– Atorvastatin
– Fish oil tablets
Mrs CW
What results do you want to know?
Mrs CW
• Investigation results:
– FBE – platelets 130
– LFTs – albumin 36, ALT 150, BR 6
– HCV – 1a
– HCV viral load 900,000 IU/mL
– IL28B genotype TT
– Fasting glucose 6.2, fasting lipids TC 5.6, LDL 3.0
– US – echogenic liver c/w fatty infiltration, spleen
at upper limit normal
Mrs CW
• Fibroscan – not possible (body habitus)
• Liver biopsy – cirrhotic
Mrs CW
• What is the likelihood that she will be cured:
– peg-IFN + RBV?
– DAA therapy?
Peg-IFN + RBV
peg-IFN + RBV: SVR rates
100
peg-IFN /
RBV
(6-12 mths)[6,7]
SVR (%)
80
IFN /
RBV
(6-12 mths)[3,4]
60
40
20
Standard
IFN
(6 mths)[1]
Standard
IFN
(12-18 mths)[2,3]
38-43%
50-60%
peg-IFN
monotherapy
(6-12 mths)[5,6]
25-30%
15-20%
8-12%
0
1991
1995
1998
2001
1. Carithers RL Jr., et al. Hepatology. 1997;26:83S-88S. 2. Zeuzem S, et al. N Engl J Med. 2000;343:1666-1672. 3. Poynard T, et al. Lancet.
1998;352:1426-1432. 4. McHutchison JG, et al. N Engl J Med. 1998;339:1485-1492. 5. Lindsay KL, et al. Hepatology. 2001;34:395-403. 6. Fried
MW, et al. N Engl J Med. 2002;347:975-982. 7. Manns MP, et al. Lancet. 2001;358:958-965.
IDEAL Study: peg-IFN alfa-2a vs alfa-2b in
treatment-naive HCV genotype 1 patients
100
ITT analysis
(n=3070)
SVR (%)
80
60
40
40%
38%
peg-IFN alfa-2b
1.5 µg/kg/wk +
RBV 800-1400 mg/day
peg-IFN alfa-2b
1.0 µg/kg/wk +
RBV 800-1400 mg/day
41%
20
0
peg-IFN alfa-2a
180 µg/wk +
RBV 1000-1200 mg/day
McHutchison JG, et al. N Engl J Med. 2009;361:580-593.
peg-IFN and RBV: IL28B-type and fibrosis stage
predict for SVR in HCV genotype 1
Response rate (%)
100
HCV-1
80
69
60
100
100
F0-2
80
72
60
F3-4
80
60
41
40
27
33
20
0
40
30
34
20
TT CT CC
0
40
20
TT CT CC
0
22
11
TT CT CC
SVR
SVR
SVR
n=1171
n=988
n=133
Thompson, Gastro, 2010
peg-IFN + RBV: On-treatment virological response
predicts SVR in HCV genotype 1
SVR 88%
SVR <5%
106
20 %
HCV RNA (IU/mL)
105
16 %
NR
SVR 29%
22 %
42 %
104
SVR 68%
pEVR
103
2 log10 IU/mL
decline
102
RVR
cEVR
Undetectable
< 50 IU/mL
10
//
0
4
8
12
20
Likelihood of SVR
24
48 wks
Marcellin, AASLD, 2007
Fried, EASL, 2008
Telaprevir therapy
ADVANCE: Telaprevir + peg-IFN/RBV in
HCV-1 treatment-naive patients
Wk 8
TVR + PR*
(n=364)
Treatment-naive
patients with
genotype 1 HCV
TVR + PR*
(n=363)
Wk 24
Wk 12
eRVR†: PR*
Follow-up
PR*
Follow-up
Follow-up
eRVR†: PR*
PR*
(n=1088)
Wk 72
Wk 48
PR*
(n=361)
Follow-up
Follow-up
*TVR 750 mg q8h, peg-IFN alfa-2a 180 µg/wk, weight-based RBV 1000-1200 mg/day.
†eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12.
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
Telaprevir triple therapy: SVR rates in
treatment-naïve genotype 1 patients
Pooled analysis from ADVANCE and
ILLUMINATE[2]
ADVANCE[1]
p<0.001
100
75
Delta = 33%
60
80
SVR (%)
SVR (%)
80
Nonblack
Black
100
44
40
75
61
60
45
40
25
20
0
n/
N=
158/
361
271/
363
PR
T12 PR
20
0
n/
N=
151/ 7/
333 28
PR
599/ 60/
804 99
T12 PR
1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Dusheiko GM, et al. EASL 2011. Abstract 1788.
Telaprevir triple therapy: SVR rates in
treatment-naïve genotype 1 patients*
74–79*
n/N =
PR 48
T12/PR
166/361
683/903
*p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCE. SVR, considered virologic cure, was defined
as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the
last HCV RNA data point from Week 12 of follow-up onwards was used
Telaprevir EU SmPC
Telaprevir
Predicting response in treatment-naïve patients:
1. Baseline:
– Fibrosis stage
– IL28B genotype
– Other - Genotype 1a vs 1b, HCV viral load, etc.
2. On-treatment:
– Extended RVR (eRVR) and response-guided therapy
(RGT)
– Stopping rules
*
SVR by advanced fibrosis or cirrhosis in
patients receiving TVR + peg-IFN/RBV
F3
Cirrhosis
SVR (%)
F0 – F2
n/N=
PR 48
T12 PR
PR 48
T12 PR
PR 48
T12 PR
140/288
237/290
18/52
33/52
8/21
15/21
SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window.
In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used
Telaprevir EU SmPC
Direct antiviral therapy & IL28B
ADVANCE (telaprevir, treatment-naïve)
n=454/1088 (42%)
100
90
80
70
60
SVR (%) 50
40
30
20
10
0
90
87
64
73 71
59 58
TT
CT
CC
23 25
26 80 55
PR
32 76 45
T8PR
22 68 50
T12PR
Jacobson, EASL, 2011
Extended RVR (eRVR) = undetectable HCV RNA at
Weeks 4 and 12
Week 4 (RVR)
Weeks 4 and 12 (eRVR)
Patients with undetectable
HCV RNA (%)
Patients eligible to receive 24 weeks of
treatment in total
66-72%
58 -65%
n/N=
PR 48
T12 PR
PR 48
T12 PR
34/361
635/903
29/361
565/903
Adapted from Sherman KE, et al. CROI 2011. Abstract 957
Telaprevir: SVR rates by eRVR status
eRVR+
eRVR–
24-week regimen
SVR (%)
48-week
regimen
n/N=
PR 48
T12 PR
PR 48
T12 PR
27/29
195/212
139/332
90/151
SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window.
In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used
Telaprevir EU SmPC
IL28B CC genotype predicts for
short duration therapy
ADVANCE – Telaprevir arms, n=293
90
78
80
HCV RNA
undetectable
(%)
72
70
60
61
54
54
48
50
TT
CT
CC
40
30
20
10
0
RVR
eRVR
Jacobson, EASL, 2011
Telaprevir: Duration of therapy for
treatment-naive patients
•
After 12 wks, telaprevir should be discontinued and peg-IFN/RBV continued
– Cirrhotic patients with undetectable HCV RNA at Wks 4 and 12 may nevertheless benefit
from additional 36 wks of peg-IFN/RBV (48 wks total) rather than response-guided therapy
Response-Guided Therapy
HCV RNA
Triple Therapy:
TVR + peg-IFN/RBV
Dual Therapy:
peg-IFN/RBV
Total Treatment
Duration
Undetectable at Wks 4 and 12
First 12 wks
Additional 12 wks
24 wks
Detectable (but ≤1000 IU/mL) at
Wks 4 and/or 12
First 12 wks
Additional 36 wks
48 wks
Stopping Rules
Time Point
Criteria
Action
Wk 4 or 12
HCV RNA >1000 IU/mL
Discontinue all therapy
HCV RNA detectable
Discontinue peg-IFN/RBV
Discontinuation of peg-IFN/RBV for any reason
Discontinue TVR
Wk 24
Any
Telaprevir [package insert]. 2011.
Mrs CW
• Key issues:
– Treatment naïve
– Cirrhotic
– Poor response IL28B genotype
– HCV-1a
– High VL
– Obese/metabolic syndrome
Mrs CW
• OPTIMIZE study: Telaprevir BD
• Well tolerated
• Week 4 HCV RNA = detected <1000
Retrospective analysis of TVR Ph III trials
underscores validity of TVR futility rules
•
•
No pt with HCV RNA >1000 IU/mL at Wk
4 (n=25) or Wk 12 (n=12) had SVR
Viral kinetics analysis of pts with HCV
RNA >1000 IU/mL at Wk 4
– 23 of 25 reached HCV RNA nadir
before Wk 4
– In most pts, HCV RNA already
increasing from nadir by Wk 4
Emergence of highly TVR-resistant
variants in majority of pts with HCV RNA
>1000 IU/mL at Wk 4
HCV NS3/4A
variant
Tx Naive (n = 14)
HCV RNA, IU/mL
•
Tx Experienced (n = 11)
108
108
107
107
106
106
105
105
104
104
103
103
102
102
10
10
0
2 4 6 8 10 12
Wks on treatment
0
2 4 6 8 10 12
Wks on treatment
Level of TVR
resistance
Tx-naive pts with HCV RNA
>1000 IU/mL at Wk 4, n (n=14)
Tx-exp’d pts with HCV RNA
>1000 IU/mL at Wk 4, n (n=11)
V36M + R155K
High
12*
8
A156S/T/V
High
1
0
R155K
Low
0
2
Wild type
None
1
1
Jacobson I, et al. EASL 2012. Abstract 55.
*1 patient had R155K present at baseline.
Mrs CW
• OPTIMIZE study: Telaprevir BD
• Week 12 HCV RNA = 33
– Stopping rule for the study
• Continued on peg-IFN / RBV off-study
• Week 16 HCV RNA = 62,000
• Treatment stopped
Key issues:
Telaprevir – Predicting response in treatment-naïve
HCV-1 patients:
1. Baseline predictors of SVR:
– Fibrosis stage
– IL28B genotype
– HCV-1a vs 1b
2. On-treatment response:
– eRVR
– Week 4, week 12 stopping rules
REALIZE: Telaprevir + peg-IFN/RBV in HCV-1
treatment-experienced patients
Wk 4
TVR + PR*
(n=264)
Treatmentexperienced
patients with
genotype 1 HCV
Wk 72
Wk 48
Wk 12 Wk 16
Follow-up
PR*
Follow-up
Follow-up
TVR + PR*
(n=266)
PR*
Follow-up
(n=663)
PR*
(n=132)
Follow-up
*TVR 750 mg q8h, peg-IFN alfa-2a 180 µg/wk, weight-based RBV 1000-1200 mg/day.
†eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12.
Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428
Telaprevir triple therapy: SVR in prior relapsers,
partial responders, null responders
Prior relapsers
*
Prior partial
responders
*
Prior null
responders
*
SVR (%)
*
*
n/N=
PR 48
LI T12/
PR 48
T12/
PR 48
15/68
124/141 122/145
*
PR 48
LI T12/
PR 48
T12/
PR 48
PR 48
LI T12/
PR 48
T12/
PR 48
4/27
27/48
30/49
2/37
25/75
22/72
*p<0.001 vs PR 48. SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the
Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used
Telaprevir EU SmPC
IL28B genotyping is less useful if IFN-experienced
Relapsers
Partial responders
Null responders