reesink h, et al. presented at the 44 th annual meeting of the european association for the study of...

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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

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

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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 IFN-

alfa in vitro

Primarily CYP3A4-mediated metabolism

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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)

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Study Design and Treatment Regimens

800 mg SCH 900518 TID Tx-Naive [n = 10]

Tx-Experienced [n = 10]

400 mg SCH 900518 BID

+ 200 mg RTV BID Tx-Naive [n = 10]

Tx-Experienced [n = 11]

>28-Day Washout 800 mg SCH 900518 TID

+ PEG-IFN alfa-2b (1.5 g/kg)

>28-Day Washout 400 mg SCH 900518 BID

+ 200 mg RTV BID + PEG-IFN alfa-2b (1.5 g/kg)

SOC

Period 1 Period 2

7 days 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)

•Randomized 4:1 (Active: Placebo)

•SCH 900518 dosed as amorphous suspension with food

•RTV = ritonavir

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Baseline CharacteristicsTx-Naive

800 mg TID(n = 10)

Tx-Experienced800 mg TID

(n = 10)

Tx-Naive400 mg BID

+ RTV(n = 10)

Tx-Experienced 400 mg BID

+ RTV(n = 11)

Male, n (%) 6 (60) 7 (70) 8 (80) 10 (91)

Race, n (%)

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)24.1 (2.1) 27.8 (4.4)27.8 (4.4) 25.3 (4.1)25.3 (4.1) 26.3 (5.2)26.3 (5.2)

Patients receiving methadone, n (%)

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)

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SafetyAEs ≥10% During 7 Days of Monotherapy

with SCH 900518 (± Ritonavir)

Tx-Naive800 mg TID

(n = 8)

Tx-Exper800 mg TID

(n = 8)

Tx-Naive400 mg

BID+RTV

(n = 8)

Tx-Exper400 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

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SafetyAEs ≥10% During 14 Days of Combination Therapy

SCH 900518 + PEG-IFN alfa-2b (± Ritonavir)

Tx-Naive800 mg TID

(n = 8)

Tx-Exper800 mg TID

(n = 8)

Tx-Naive400 mg BID

+ RTV(n = 8)

Tx-Exper400 mg BID

+ RTV(n = 8)

Placebo(n = 4)

Placebo + RTV(n = 4)

SUBJECTS REPORTINGANY 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

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SCH 900518Overall Safety

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

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Pharmacokinetics of SCH 900518 (± Ritonavir) at Steady-State in Combination With PEG-IFN alfa-2b

Trough11 x EC90

Trough61 x EC90

t½ ≈ 16 hours (+ RTV)t½ ≈ 5 hours (alone)

0

500

1000

1500

2000

2500

3000

3500

0 0.5 2 4 6 8 12

Hours After SCH 900518 Dose

Pla

sma

Co

nce

ntr

atio

nS

CH

900

518

(ng

/mL

)

400 mg BID + RTV

800 mg TID

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SCH 900518 Monotherapy (± Ritonavir) Mean Change From Baseline in HCV RNA (Log10 IU/mL)

Morning Day 8

-5

-4

-3

-2

-1

0

0 24 48 72 96 120 144 168

Hours

Mea

n C

han

ge

in

HC

V R

NA

(L

og

10 IU

/mL

)

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)

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SCH 900518 (± Ritonavir) + PEG-IFN alfa-2b Mean Change From Baseline in HCV RNA (Log10 IU/mL)

= PEG-IFN alfa-2b Dose

-5

-4

-3

-2

-1

0

0 24 48 72 96 120 144 168 192 216 240 264 288 312 336

Mea

n C

han

ge

in

HC

V R

NA

(L

og

10 IU

/mL

)

Hours

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)

Morning Day 15

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Resistance AnalysisIndividual Patient Plots of Treatment-Experienced

Subjects Receiving SCH 900518 400 mg BID + Ritonavir

-6

-5

-4

-3

-2

-1

0

Pla

sma

HC

V R

NA

(L

og

10 IU

/mL

)

= PEG-IFN alfa-2b Dose

HoursMorning Day 15

0 24 48 72 96 120 144 168 192 216 240 264 288 312 336

Resistant variants detected in these subjects at loci: V36, R155, A156

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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)

Placebo0% (0/4)

0% (0/4)

0% (0/4)

0% (0/4)

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SCH 900518 Pharmacokinetic/Pharmacodynamic Relationship (Monotherapy ± Ritonavir)

(6 × EC90) (11 × EC90) (41 × EC90) (62 × EC90)

n = 7 n = 8 n = 8 n = 8

-5

-4

-3

-2

-1

0170 296 1150 1725

Median Cmin (ng/mL) by Quartile

Mea

n C

han

ge

in H

CV

-RN

A

Lo

g10

(lU

/mL

) o

n D

ay 7

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Modeled SCH 900518 Tablet + Ritonavir Pharmacokinetics

for Phase 2 Study

~12 x EC90

~16 x EC90

Trough Values

0

500

1000

1500

2000

2500

3000

3500

0 5 10 15 20 25

Time (hr)

SCH 900518 200 mg QD/RTV

SCH 900518 400 mg QD/RTV

SCH 900518 100 mg BID/RTV

~8 x EC90

Pla

sma

Co

nce

ntr

atio

nS

CH

900

518

(ng

/mL

)

Doses Tested in Phase 2

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Preliminary Phase 2 Data in Naïve Patients SCH 900518/Ritonavir + PEG-IFN alfa-2b/RBV (n=25)

Once-Daily Dosing

= PEG-IFN alfa-2b/RBV

= 200 mg SCH 900518 QD + 100 mg RTV + PEG-IFN alfa-2b/RBV

*Excludes one subject because of noncompliance with study medications

Treatment Week 4<LLQ = 19/20 (95%)<LLD = 15/20 (75%)

10

100

1000

10,000

100,000

1,000,000

10,000,000

100,000,000

-1 0 5 10 15 20 25 30

Days

HC

V R

NA

(L

og

10 IU

/mL

)

LLQ <25 IU/mL

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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 treatment-experienced patients

Pharmacokinetic and pharmacodynamic modeling, as well as preliminary in-treatment antiviral data, support once-daily dosing of SCH 900518 with metabolic inhibition

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Study Investigators and Colleagues

AMC: SPRI:

H. W. Reesink E. A. Hughes

J. de Bruijne M. A. Treitel

C. J. Weegink E. O’Mara

J. Li

A. Keung

EMC: PRA:

H. L. A. Janssen J. van Lier

R. J. de Knegt A. van Vliet

J. F. Bergmann M. Ypey

reesink h, et al. presented at the 44 th annual meeting of the european association for the study of...

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