Transcript Slide 1

AASLD 2010
HCV Feedback
October 29 - November 2, 2010
Boston, Massachusetts
Dr Allister J Grant
Consultant Hepatologist
Leicester Liver Unit
Boceprevir and Telaprevir
1. Boceprevir, a potent inhibitor
of HCV NS3 protease
2. Telaprevir, a potent inhibitor of
HCV NS3/4A protease
3. Both being tested in
combination with standard-ofcare peginterferon alfa-2/
ribavirin in phase III studies in
chronic HCV infection
Trials reported at AASLD 2010
1. Boceprevir
•
SPRINT-2: naive GT1 patients
•
RESPOND-2: nonresponder
GT1 patients
2. Telaprevir
•
ADVANCE: naive GT1 patients
•
ILLUMINATE: responseguided therapy in naive GT1
patients
SPRINT-2:
Boceprevir + PegIFN/RBV in G1 Tx-Naive Patients
Phase III, Randomized, placebo-controlled trial
PR*
(n = 316,
52)
Treatment-naive
patients with
genotype 1 HCV
(2 cohorts:
N = 938
nonblack and 159
black)
BOC + PR*
(n = 316 nonblack,
52 black)
RVR†
Wk 28
Wk 4
Wk 72
Wk 48
Follow-up
No RVR

PR*
Follow-up
PR*
(n = 311,
55)
BOC + PR*
(n = 311 nonblack, 55 black)
Follow-up
PR*
(n = 311,
52 )
PR*
(n = 311 nonblack, 52 black)
Follow-up
*BOC 800 mg q8h; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day.
†Undetectable HCV RNA at Wk 4 of BOC treatment (ie, at Wk 8) and at all subsequent assays.
Poordad F, et al. AASLD 2010. Abstract LB-4.
SPRINT-2: Response Rates According to Race
4-wk PR + response-guided BOC + PR
Nonblack Patients
100
4-wk PR + 44 weeks BOC + PR
48-wk PR
Black Patients
100
P < .0001
80
67
60
40
40
23
20
9
0
P = .044
68
Patients (%)
Patients (%)
80
n = 211 213 125
SVR
P = .004
60
53
42
40
23
20
12
8
21 18 37
Relapse
Poordad F, et al. AASLD 2010. Abstract LB-4.
0
22
29
SVR
12
3
17
14
6
2
Relapse
SPRINT-2: Response Rates
• >1 log drop in VL at wk 4:
– 82% SVR for both B/PR arms
• <1log drop in VL at wk 4:
– 28% SVR in RGT (response guided therapy)
– 38% SVR in 44BOC/PR
• PCR neg at week 4 and 8
– 97% SVR in RGT (47% of patients)
– 98% SVR in 44BOC/PR
RESPOND-2:
Boceprevir in G1 Prior Non-responders to PegIFN/RBV
Phase III, Randomised
Wk 4
If detectable
at Wk 8
Treatmentexperienced
patients with
GT1 HCV
(N = 403)
PR*
(n = 162)
PR*
(n = 161)
Wk 36
Wk 8
BOC + PR*
BOC + PR*
PR*
Follow-up†
Follow-up†
BOC + PR*
PR*
(n = 80)
*BOC 800 mg TID; pegIFN alfa-2b 1.5 µg/kg/wk; weight-based RBV 600-1400 mg/day.
†Follow-up for 24 wks after completion of therapy.
Bacon BR, et al. AASLD 2010. Abstract ♯216.
Wk 48
Follow-up†
Follow-up†
RESPOND-2: SVR Rates According to Treatment
Arm and Prior Response
100
P < .0001 vs
control
(both arms)
80
75
69
SVR (%)
66
60
4-wk PR + response-guided
BOC + PR (n = 162)
4-wk PR + 44-wk
BOC + PR (n = 161)
48-wk PR (n = 80)
59*
52
40
40
29
20
0
21
95/ 107/ 17/
162 161 80
23/ 30/ 7
57 58 2/29
72/ 77/ 15/
105 103 51
Overall
Previous
Nonresponders
Previous
Relapsers
Bacon BR, et al. AASLD 2010. Abstract 216.
PROVE 1:
Combination of Telaprevir with PegIFN/Ribavirin significantly
increases SVR in treatment-naïve patients with HCV Genotype 1
Wk 12
12-Wk Arm
TVR* + PegIFN/RBV†
(n = 17)
Treatmentnaive patients
infected with
genotype 1
HCV
24-Wk Arm
TVR* + PegIFN/RBV†
(n = 79)
(N = 250)
48-Wk Arm
TVR* + PegIFN/RBV†
(n = 79)
48-Wk Control Arm
PegIFN/RBV† + Placebo
(n = 75)
Wk 24
Wk 48
24-wk
follow-up
24-wk
follow-up
PegIFN/RBV*
24-wk
follow-up
PegIFN/RBV*
24-wk
follow-up
PegIFN/RBV*
*1250 mg loading dose of TVR administered on Day 1, then 750 mg 3 times daily.
†PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day.
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
PROVE 1: Results
12-wk TVR + pegIFN/RBV (n = 17)
12-wk TVR + 24-wk pegIFN/RBV (n = 79)
12-wk TVR + 48-wk pegIFN/RBV (n = 79)
Control (n = 75)
100
Patients (%)
80
60
40
67‡
61†
41
35
33
23
20
0
2 6
SVR
Relapse
N/A, not applicable. *P < .001 vs control. †P = .02 vs control. ‡P = .002 vs control.
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
Frequency of undetectable HCV RNA levels
during and after treatment
Week
T12/PR24
N=79
T12/PR48
N=79
T12/PR12
N=17
PR48
N=75
4
64(81%)
64(81%)
10(59%)
8(11%)
12
54(68%) 12%
45(57%) 14%
63(80%)
12(71%)
34(45%)
56(71%)
NA
43(57%)
24
48
NA
51(65%)
NA
35(47%)
SVR
48(61%)
53(67%)
6(35%)
31(41%)
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
T12/PR24 vs T12/PR48
RVR
T12/PR24
81%
T12/PR48
81%
SVR
61%
67%
Relapse
2%
25.3%
47%
6%
13.9%
32%
DC 2° to A/E
Dropouts
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
PROVE 1: Conclusions
1. Coadministration of a 12-week course of TVR with 24 or 48
weeks of pegIFN/RBV significantly increased SVR rates in
treatment-naive patients infected with genotype 1 HCV vs 48
weeks of pegIFN/RBV alone
2. Coadministration of TVR also resulted in higher rate of RVR and
lower relapse rate compared with pegIFN/RBV
3. TVR coadministration increased rate of treatment
discontinuation due to adverse effects, predominantly rash
McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838.
Prove 3
24 vs 48wks of T/PR in patients with G1 previously treated with PEG IFN/ RBVWeek 4 non-response - <1log decline in control arm or detectable HCV in TPR arms
Outcome
Control
Arm
(n = 114)
12-Wk TVR +
24-Wk
PegIFN/RBV
(n = 115)
24-Wk TVR +
48-Wk
PegIFN/RBV
(n = 113)
24-Wk TVR +
PegIFN
(n = 111)
14
51*
53*
24†
 Previous
nonresponders, % (n/N)
9 (6/68)
39* (26/66)
38* (24/64)
11‡ (7/62)
 Previous relapsers, %
(n/N)
20 (8/41)
69* (29/42)
76* (31/41)
42§ (16/38)
8
53
45
18
SVR, %
 Cirrhotics %
*P < .001 vs control. †P = .024 vs control. ‡P = .297 vs control.
McHutchison JG, et al. AASLD 2009. Abstract 66, NEJM 2010.
§P
= .029 vs control.
ADVANCE:
Telaprevir + PegIFN/RBV in G1 Tx-Naive Patients

Phase III, Randomized, placebo-controlled trial
Wk 8
TVR + PR*
(n = 364)
Treatment-naive
patients with
genotype1 HCV
(N = 1088)
Wk 24
Wk 12
TVR + PR*
(n = 363)
eRVR†: PR*
Follow-up
PR*
Follow-up
Follow-up
eRVR†: PR*
PR*
PR*
(n = 361)
*TVR 750 mg q8h; pegIFN 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. AASLD 2010. Abstract 211.
Wk 72
Wk 48
Follow-up
Follow-up
ADVANCE:
1088 Treatment naïve G1 patients randomised:
TPV/PEG/RBV x8 weeks then PEG /RBV x16 weeks (T8/PR24)
TPV/PEG/RBV x12 weeks then PEG /RBV x12 weeks (T12/PR24)
PEG/RBV x48 weeks (PR48)
RESULTS:
T8/PR24
N=364
T12/PR24
N=363
PR48
N=361
RVR (%)
67
68
9
eRVR (%)
57
58
8
SVR (%)
69
75
44
eRVR-SVR
83
89
97
Completion %
71.4
73.8
56
PR Viral
breakthrough
10.2
5
NA
Jacobson I AASLD ♯211
Kiefer T AASLD LB-11
ILLUMINATE:
Response-Guided Telaprevir + PegIFN/RBV in G1 Naive Pts

Phase III Open-label, randomized trial, ITT analysis
Wk 12 Wk 20
Treatmentnaive patients
with GT1 HCV
(N = 540)
Wk 24
eRVR†
TVR + PR*
PR*
(n = 162)
Wk 48
Follow-up
PR*
(n = 160)
Follow-up
PR*
(n = 218)
Follow-up
PR*
No
eRVR†
*TVR 750 mg q8h; pegIFN 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.
Sherman KE, et al. AASLD 2010. Abstract LB-2.
Wk 72
ILLUMINATE: Overall SVR Rates
100
SVR (%)
80
92
88
72
60
40
20
0
n/N = 388/540
Overall
149/162
140/160
24-wk
therapy
48-wk
therapy
Patients With eRVR
Sherman KE, et al. AASLD 2010. Abstract LB-2.
ILLUMINATE:
• Adverse Events
– Anaemia <8.5
• 9% in TPV
• 2% in PR
• 0.6% DC
– Fatigue (1.1% DC)
– Rash
• Eczematous rash in 37%
• 7% severe rash
– Pruritis
– Nausea
• Overall discontinuation
rate 17%
• In first 12 weeks there
was:
– 7% DC of all drugs
– 12% DC of Telaprevir
Interferon Free Therapy?
BMS-790052 + BMS-650032 Alone or With PegIFN/RBV in
G1 Null Responders

Open-label, randomized, placebo-controlled phase IIa trial

BMS-790052: NS5A polymerase inhibitor

BMS-650032: NS3 protease inhibitor
Prior null
responders
with GT1 HCV
(N = 21)
Wk 72
Wk 24
BMS-790052 60 mg QD +
BMS-650032 600 mg BID
(n = 11)
Follow-up
BMS-790052 60 mg QD +
BMS-650032 600 mg BID
+ PR*
(n = 10)
Follow-up
*PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day.
Lok A, et al. AASLD 2010. Abstract LB-8.
Wk 12 Interim Analysis
100
BMS-790052 + BMS-650032
BMS-790052 + BMS-650032 + PR
90
Patients (%)
80
64
60
60
60
46
36
40
20
0
7/11 6/10
RVR
4/11 6/10
eRVR
5/11 9/10
cEVR
 All viral breakthroughs occurred in patients with GT1a
Lok A, et al. AASLD 2010. Abstract LB-8.
Other Protease/Polymerase Inhibitors
• TMC435- NS3/4a Protease inhibitor (PILLAR Trial)
–
–
–
–
Phase IIa , G1 Naive
Once Daily
12-24 weeks Rx +PR48
SVR 91%-98% (4 vs12 wks )
Fried M, et al. AASLD 2010. Abstract LB-5.
• Daneprovir
– RG7227 phase II, in G1 naive patients (ATLAS trial)
– 88% to 92% of patients achieved cEVR when combined with pegIFN/RBV vs
43% with SOC
Terrault N, et al. AASLD 2010. Abstract 32.
• Vaniprevir- NS3/4a Protease Inhibitor
– MK-7009 phase IIa study G1 naive patients without cirrhosis
– Significantly higher when combined with pegIFN/RBV vs SOC
• RVR: 67% to 84% vs 5%
Manns MP, et al. AASLD 2010. Abstract 82
HCV Pharmacogenetics
• GWAS used patients from IDEAL and Muir Studies
• 1137 samples on patients with SVR
• SNP’s
rs12979860 on Chr 19 strongly associated with SVR & localised to IL28β
90
80
80
70
SVR %
60
50
50
40
41
CT
32
30
15
20
17
10
0
Caucasian
Thomas DL, et al. Nature. 2009;461:798-801.
TT
African American
CC
Regional Distribution of IL28B
rs12979860 CC Genotype
Thomas DL, et al. Nature. 2009;461:798-801.
IL28β Associations in Patients With
Hepatitis C
 IL28β polymorphisms associated with
– Higher SVR rates[1]
– Higher RVR rates[2]
– Higher HCV RNA[3]
– Higher LDL levels[4]
– Higher baseline ALT levels[5]
– Higher rate of spontaneous viral clearance[6]
1. Ge D, et al. Nature. 2009;461:399-401. 2. Mangia A, et al. AASLD 2010. Abstract 897. 3. Liu L, et al.
AASLD 2010. Abstract 231. 4. Saito H, et al. AASLD 2010. Abstract 732. 5. Thompson AJ, et al. AASLD
2010. Abstract 1893. 6. Thomas DL, et al. Nature. 2009;461:798-801.
And if time
♯214:Maintenance PEG IFN to prevent HCC
•
•
•
•
Extended FU from HALT-C trial
1084 patients 6.1-8.7yr FU
88 HCC (20 clinical HCC)
No difference between Rx and Control at 3/5/7yr
• Subgroup analysis
– Cirrhotics who had PEG for >2 yearsmarginal benefit
A Lok et al AASLD 2010, Abstract 214
EXTEND Trial:
Long Term FU of PROVE 1-3 patients
• 3 yr FU of T/PR treated patients
• 123 patients who had SVR’s from previous
studies
• 122/123 had durable SVR (99%)
• 79 patients without SVR analysed for
resistance and after 22 mo 89% reverted to
wild type
S Zeuzem et al AASLD 2010 , Abstract 227
♯213: Effect of SVR on all cause mortality
• Dept of Veterans Affairs Data Registry
• 23000 patients
• 16800 with post Rx RNA , SVR rate 44%
– 52% smokers, 20% DM, 15% COPD, 12% CAD, 26% alcohol, 36% depression
– 1535 died (median 3.7yrs)
G3 No SVR
G1,2 No SVR
Mortality
G1,2,3 with SVR
Time