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H. W. Reesink, J. F. Bergmann, J. de Bruijne, C. J. Weegink, J. van Lier, A. van Vliet, A. Keung, J. Li, PowerPoint Presentation
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H. W. Reesink, J. F. Bergmann, J. de Bruijne, C. J. Weegink, J. van Lier, A. van Vliet, A. Keung, J. Li,

H. W. Reesink, J. F. Bergmann, J. de Bruijne, C. J. Weegink, J. van Lier, A. van Vliet, A. Keung, J. Li,

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H. W. Reesink, J. F. Bergmann, J. de Bruijne, C. J. Weegink, J. van Lier, A. van Vliet, A. Keung, J. Li,

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  1. 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 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 44th European Association for the Study of the Liver (EASL) Meeting Copenhagen, Denmark, April 24, 2009

  2. 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

  3. 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)

  4. Study Design and Treatment Regimens Period 1 Period 2 800 mg SCH 900518 TID Tx-Naive [n = 10] Tx-Experienced [n = 10] >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 400 mg SCH 900518 BID + 200 mg RTV BID + PEG-IFN alfa-2b (1.5 mg/kg) 7 days 14 days • Randomized 4:1 (Active: Placebo) • SCH 900518 dosed as amorphous suspension with food • RTV = ritonavir • 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)

  5. Baseline Characteristics

  6. SafetyAEs ≥10% During 7 Days of Monotherapy with SCH 900518 (± Ritonavir) *Reported by ≥50% of patients

  7. SafetyAEs ≥10% During 14 Days of Combination TherapySCH 900518 + PEG-IFN alfa-2b (± Ritonavir) *Reported by ≥50% of patients *reported by ≥50% of patients

  8. 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

  9. Pharmacokinetics of SCH 900518 (± Ritonavir) at Steady-State in Combination With PEG-IFN alfa-2b 3500 400 mg BID + RTV 800 mg TID 3000 2500 Trough 61 x EC90 Plasma ConcentrationSCH 900518 (ng/mL) 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)

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

  11. SCH 900518 (± Ritonavir)+ PEG-IFN alfa-2b Mean Change From Baselinein HCV RNA (Log10 IU/mL) 0 -1 Placebo (n = 8) 800 mg TID Tx-Naive (n = 8) -2 800 mg TID Tx-Exper (n = 8) Mean Change in HCV RNA (Log10 IU/mL) 400 mg BID/RTV Tx-Naive (n = 8) 400 mg BID/RTV Tx-Exper (n = 8) -3 -4 -5 0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 Hours = PEG-IFN alfa-2b Dose Morning Day 15

  12. Resistance AnalysisIndividual 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 Plasma HCV RNA (Log10 IU/mL) -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

  13. SCH 900518: Antiviral Activity in Combination With PEG-IFN alfa-2b at Day 15

  14. SCH 900518 Pharmacokinetic/Pharmacodynamic Relationship (Monotherapy ± Ritonavir) Median Cmin (ng/mL) by Quartile 170 296 1150 1725 0 n = 7 n = 8 n = 8 n = 8 -1 -2 Mean Change in HCV-RNA Log10 (lU/mL) on Day 7 -3 -4 -5 (62 × EC90) (41 × EC90) (11 × EC90) (6 × EC90)

  15. Modeled SCH 900518 Tablet + Ritonavir Pharmacokinetics for Phase 2 Study 3500 Doses Tested in Phase 2 3000 SCH 900518 200 mg QD/RTV SCH 900518 400 mg QD/RTV 2500 SCH 900518 100 mg BID/RTV Plasma ConcentrationSCH 900518 (ng/mL) 2000 Trough Values 1500 1000 ~16 x EC90 500 ~12 x EC90 ~8 x EC90 0 0 5 10 15 20 25 Time (hr)

  16. 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 100,000,000 10,000,000 1,000,000 100,000 HCV RNA (Log10 IU/mL) 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

  17. 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

  18. Study Investigators and Colleagues