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SAFETY AND ANTIVIRAL ACTIVITY OF
SCH 900518 ADMINISTERED AS
MONOTHERAPY AND IN COMBINATION
WITH PEGINTERFERON ALFA-2B TO
NAIVE AND TREATMENT-EXPERIENCED
HCV-1 INFECTED PATIENTS
H. W. Reesink, J. F. Bergmann, J. de Bruijne,
C. J. Weegink, J. van Lier, A. van Vliet, A. Keung, J. Li,
E. O’Mara, M. A. Treitel, E. A. Hughes,
H. L. A. Janssen, R. J. de Knegt
44th European Association for the Study of the Liver (EASL) Meeting
Copenhagen, Denmark, April 24, 2009
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Background: SCH 900518
 Mechanism-based inhibitor of the HCV NS3
serine protease
 Replicon assay activity (HCV genotype 1b)
 EC50 = 20 nM, EC90 = 40 nM
 IFN-alfa–enhanced antiviral activity
 Resistance profile of SCH 900518
 Similar to other protease inhibitors
 Decreased resistance in combination with IFNalfa in vitro
 Primarily CYP3A4-mediated metabolism
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Study Design
 Treatment-naive and treatment-experienced
patients with HCV genotype 1 infection
 Two treatment periods in a fixed-sequence
 Period 1 → Monotherapy for 7 days
 Period 2 → Combination therapy with
PEG-IFN alfa-2b for 14 days
 Two doses explored (placebo-controlled)
 800 mg TID SCH 900518
 400 mg BID SCH 900518 with
ritonavir 200 mg BID (metabolic inhibition)
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Study Design and
Treatment Regimens
Period 1
800 mg SCH 900518 TID
Tx-Naive [n = 10]
Tx-Experienced [n = 10]
Period 2
>28-Day
Washout
800 mg SCH 900518 TID
+ PEG-IFN alfa-2b (1.5 mg/kg)
SOC
400 mg SCH 900518 BID
+ 200 mg RTV BID
Tx-Naive [n = 10]
Tx-Experienced [n = 11]
>28-Day
Washout
7 days
•Randomized 4:1 (Active: Placebo)
•SCH 900518 dosed as amorphous
suspension with food
400 mg SCH 900518 BID
+ 200 mg RTV BID
+ PEG-IFN alfa-2b (1.5 mg/kg)
14 days
•SOC = Standard of care, began after period 2
•Serum HCV-RNA was determined using Roche COBAS
TaqMan (v.2.0; LLQ = 25 IU/mL, LLD = 9.3 IU/mL)
•RTV = ritonavir
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Baseline Characteristics
Tx-Naive
800 mg TID
(n = 10)
Tx-Experienced
800 mg TID
(n = 10)
Tx-Naive
400 mg BID
+ RTV
(n = 10)
Tx-Experienced
400 mg BID
+ RTV
(n = 11)
6 (60)
7 (70)
8 (80)
10 (91)
Caucasian
9 (90)
8 (80)
8 (80)
7 (64)
Black
1 (10)
1 (10)
1 (10)
0
Other
0
1 (10)
1 (10)
4 (36)
Age, mean (SD), y
51.1 (3.9)
47.9 (7.4)
43.6 (9.2)
51.1 (7.2)
Weight, mean (SD), kg
73.5 (11.5)
82.2 (12.5)
79.4 (14.8)
84.4 (13.2)
BMI, mean (SD), kg/m2
24.1 (2.1)
27.8 (4.4)
25.3 (4.1)
26.3 (5.2)
1 (10)
0
1 (10)
1 (9)
Patients with hemophilia, n (%)
0
0
1 (10)
1 (9)
Baseline HCV RNA, mean (SD)
4.8 x 106
(3.2 x 106)
6.3 x 106
(4.4 x 106)
3.8 x 106
(2.9 x 106)
4.3 x 106
(4.6 x 106)
Male, n (%)
Race, n (%)
Patients receiving
methadone, n (%)
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Safety
AEs ≥10% During 7 Days of Monotherapy
with SCH 900518 (± Ritonavir)
Tx-Naive
Tx-Exper
800 mg TID 800 mg TID
(n = 8)
(n = 8)
Tx-Naive
400 mg
BID+
RTV
(n = 8)
Tx-Exper
400 mg
BID+
RTV
(n = 9)
Placebo
(n = 4)
Placebo+
RTV
(n = 4)
SUBJECTS REPORTING
ANY AE, n
7*
8*
7*
8*
3*
3*
Headache
3
0
4*
4
0
0
Diarrhea
2
1
3
4
0
0
Anorectal Discomfort
4*
2
1
2
0
0
Nausea
5*
1
2
0
1
0
Dizziness
2
2
1
1
0
1
Somnolence
4*
2
0
0
1
0
Abdominal Discomfort
1
1
1
0
0
3*
Influenza-like Illness
0
1
3
0
0
0
Abdominal Distension
0
1
1
1
0
1
*Reported by ≥50% of patients
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Safety
AEs ≥10% During 14 Days of Combination Therapy
SCH 900518 + PEG-IFN alfa-2b (± Ritonavir)
Tx-Naive
Tx-Exper
Tx-Naive
Tx-Exper 400 mg BID 400 mg BID
800 mg TID 800 mg TID
+ RTV
+ RTV
(n = 8)
(n = 8)
(n = 8)
(n = 8)
Placebo
(n = 4)
Placebo
+ RTV
(n = 4)
SUBJECTS
REPORTING
ANY AE, n
8*
8*
8*
8*
3*
4*
Influenza-like
Illness
8*
8*
7*
7*
3*
3*
Diarrhea
2
1
1
4*
0
0
Headache
3
0
1
2
0
1
Dyspepsia
1
1
0
2
0
0
Injection Site
Erythema
1
2
0
1
0
0
Nausea
0
1
2
1
0
0
*Reported by ≥50% of patients
*reported by ≥50% of patients
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
SCH 900518
Overall Safety
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 Safe and well tolerated
 No clinically significant changes in laboratory
values, ECG recordings, or vital signs
 Most AEs were mild or moderate in severity
 One subject discontinued immediately after
first dose because of intolerance to drug
suspension
 No SCH 900518-related SAEs
 No deaths
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Plasma Concentration
SCH 900518 (ng/mL)
Pharmacokinetics of SCH 900518 (± Ritonavir)
at Steady-State in Combination With PEG-IFN alfa-2b
3500
400 mg BID + RTV
3000
800 mg TID
2500
Trough
61 x EC90
2000
1500
1000
Trough
11 x EC90
500
0
0
0.5
2
4
6
8
12
Hours After SCH 900518 Dose
t½ ≈ 16 hours (+ RTV)
t½ ≈ 5 hours (alone)
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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SCH 900518 Monotherapy (± Ritonavir)
Mean Change From Baseline in HCV RNA (Log10 IU/mL)
Mean Change in
HCV RNA (Log10 IU/mL)
0
Placebo (n = 8)
-1
800 mg TID Tx-Naive (n = 8)
800 mg TID Tx-Exper (n = 8)
-2
400 mg BID/RTV Tx-Naive (n = 8)
400 mg BID/RTV Tx-Exper (n = 8)
-3
-4
-5
0
24
48
72
96
120
144
168
Hours
Morning Day 8
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
SCH 900518 (± Ritonavir) + PEG-IFN alfa-2b
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Mean Change From Baseline in HCV RNA (Log10 IU/mL)
Mean Change in
HCV RNA (Log10 IU/mL)
0
-1
Placebo (n = 8)
800 mg TID Tx-Naive (n = 8)
800 mg TID Tx-Exper (n = 8)
400 mg BID/RTV Tx-Naive (n = 8)
400 mg BID/RTV Tx-Exper (n = 8)
-2
-3
-4
-5
0
24 48 72 96 120 144 168 192 216 240 264 288 312 336
Hours
= PEG-IFN alfa-2b Dose
Morning Day 15
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Resistance Analysis
Plasma HCV RNA (Log10 IU/mL)
Individual Patient Plots of Treatment-Experienced
Subjects Receiving SCH 900518 400 mg BID + Ritonavir
Resistant variants detected in these
subjects at loci: V36, R155, A156
0
-1
-2
-3
-4
-5
-6
0
24 48 72 96 120 144 168 192 216 240 264 288 312 336
Hours
= PEG-IFN alfa-2b Dose
Morning Day 15
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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SCH 900518: Antiviral Activity in
Combination With PEG-IFN alfa-2b at Day 15
SCH 900518 (± RTV) + PEG-IFN alfa-2b
Percent of Subjects With
HCV RNA <LLQ
(<25 IU/mL)
Percent of Subjects With
HCV RNA <LLD
(<9.3 IU/mL)
Experienced
Naive
Experienced
Naive
800 mg TID
SCH 900518
50%
(4/8)
75%
(6/8)
0%
(0/8)
38%
(3/8)
400 mg BID
SCH 900518 + RTV
50%
(4/8)
63%
(5/8)
25%
(2/8)
25%
(2/8)
Placebo
0%
(0/4)
0%
(0/4)
0%
(0/4)
0%
(0/4)
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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SCH 900518 Pharmacokinetic/Pharmacodynamic
Relationship (Monotherapy ± Ritonavir)
Median Cmin (ng/mL) by Quartile
Mean Change in HCV-RNA
Log10 (lU/mL) on Day 7
0
170
296
1150
1725
n=7
n=8
n=8
n=8
(6 × EC90)
(11 × EC90)
(41 × EC90)
(62 × EC90)
-1
-2
-3
-4
-5
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Modeled SCH 900518 Tablet + Ritonavir
Pharmacokinetics for Phase 2 Study
Plasma Concentration
SCH 900518 (ng/mL)
3500
Doses Tested in Phase 2
3000
SCH 900518 200 mg QD/RTV
2500
SCH 900518 400 mg QD/RTV
SCH 900518 100 mg BID/RTV
2000
1500
Trough
Values
1000
~16 x EC90
500
~12 x EC90
~8 x EC90
0
0
5
10
15
20
25
Time (hr)
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Preliminary Phase 2 Data in Naïve Patients
SCH 900518/Ritonavir + PEG-IFN alfa-2b/RBV (n=25)
Once-Daily Dosing
= 200 mg SCH 900518 QD + 100 mg RTV + PEG-IFN alfa-2b/RBV
= PEG-IFN alfa-2b/RBV
HCV RNA (Log10 IU/mL)
100,000,000
10,000,000
1,000,000
100,000
10,000
Treatment Week 4
<LLQ = 19/20 (95%)
<LLD = 15/20 (75%)
1000
100
LLQ <25 IU/mL
10
-1
0
5
10
15
20
25
30
Days
*Excludes one subject because of
noncompliance with study medications
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Conclusions
 SCH 900518 (± ritonavir ± PEG-IFN alfa-2b)
was safe and well tolerated
 No SCH900518-related SAEs
 SCH 900518 exhibited potent antiviral activity
in both treatment-naive and treatmentexperienced patients
 Pharmacokinetic and pharmacodynamic
modeling, as well as preliminary in-treatment
antiviral data, support once-daily dosing of
SCH 900518 with metabolic inhibition
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09
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Study Investigators and Colleagues
AMC:
H. W. Reesink
J. de Bruijne
SPRI:
E. A. Hughes
M. A. Treitel
C. J. Weegink
E. O’Mara
J. Li
A. Keung
EMC:
H. L. A. Janssen
PRA:
J. van Lier
R. J. de Knegt
J. F. Bergmann
A. van Vliet
M. Ypey
Reesink H, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.
04/28/09