Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 1 SAFETY AND ANTIVIRAL ACTIVITY OF SCH 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 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 2 Background: SCH   Mechanism-based inhibitor of the HCV NS3 serine protease   Replicon assay activity (HCV genotype 1b)   EC 50 = 20 nM, EC 90 = 40 nM   IFN-alfa–enhanced antiviral activity   Resistance profile of SCH   Similar to other protease inhibitors   Decreased resistance in combination with IFN- alfa in vitro   Primarily CYP3A4-mediated metabolism

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 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   400 mg BID SCH with ritonavir 200 mg BID (metabolic inhibition)

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 4 Study Design and Treatment Regimens 800 mg SCH TID Tx-Naive [n = 10] Tx-Experienced [ n = 10] 400 mg SCH BID mg RTV BID Tx-Naive [ n = 10] Tx-Experienced [ n = 11] >28-Day Washout 800 mg SCH TID + PEG-IFN alfa-2b (1.5  g/kg) >28-Day Washout 400 mg SCH BID mg RTV BID + PEG-IFN alfa-2b (1.5  g/kg) SOC Period 1Period 2 7 days14 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 dosed as amorphous suspension with food RTV = ritonavir

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 5 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) Male, n (%)6 (60)7 (70)8 (80)10 (91) Race, n (%) Caucasian9 (90)8 (80) 7 (64) Black1 (10) 0 Other01 (10) 4 (36) Age, mean (SD), y51.1 (3.9)47.9 (7.4)43.6 (9.2)51.1 (7.2) Weight, mean (SD), kg73.5 (11.5)82.2 (12.5)79.4 (14.8)84.4 (13.2) BMI, mean (SD), kg/m (2.1) 27.8 (4.4) 25.3 (4.1) 26.3 (5.2) Patients receiving methadone, n (%) 1 (10)0 1 (9) Patients with hemophilia, n (%)001 (10)1 (9) Baseline HCV RNA, mean (SD) 4.8 x 10 6 (3.2 x 10 6 ) 6.3 x 10 6 (4.4 x 10 6 ) 3.8 x 10 6 (2.9 x 10 6 ) 4.3 x 10 6 (4.6 x 10 6 )

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 6 Safety AEs ≥10% During 7 Days of Monotherapy with SCH (± Ritonavir) Tx-Naive 800 mg TID (n = 8) Tx-Exper 800 mg TID (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* Headache304*400 Diarrhea Anorectal Discomfort4*21200 Nausea5*12010 Dizziness Somnolence4*20010 Abdominal Discomfort111003* Influenza-like Illness Abdominal Distension *Reported by ≥50% of patients

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 7 Safety AEs ≥10% During 14 Days of Combination Therapy SCH PEG-IFN alfa-2b (± Ritonavir) Tx-Naive 800 mg TID (n = 8) Tx-Exper 800 mg TID (n = 8) Tx-Naive 400 mg BID + RTV (n = 8) Tx-Exper 400 mg BID + RTV (n = 8) Placebo (n = 4) Placebo + RTV (n = 4) SUBJECTS REPORTING ANY AE, n 8* 3*4* Influenza-like Illness 8* 7* 3* Diarrhea2114*00 Headache Dyspepsia Injection Site Erythema Nausea *reported by ≥50% of patients *Reported by ≥50% of patients

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 8 SCH Overall 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 related SAEs   No deaths

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 9 Pharmacokinetics of SCH (± Ritonavir) at Steady-State in Combination With PEG-IFN alfa-2b Trough 11 x EC 90 Trough 61 x EC 90 t ½ ≈ 16 hours (+ RTV) t ½ ≈ 5 hours (alone) Hours After SCH Dose Plasma Concentration SCH (ng/mL) 400 mg BID + RTV 800 mg TID

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 10 SCH Monotherapy (± Ritonavir) Mean Change From Baseline in HCV RNA (Log 10 IU/mL) Morning Day Hours Mean Change in HCV RNA (Log 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)

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 11 SCH (± Ritonavir) + PEG-IFN alfa-2b Mean Change From Baseline in HCV RNA (Log 10 IU/mL) = PEG-IFN alfa-2b Dose Mean Change in HCV RNA (Log 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

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 12 Resistance Analysis Individual Patient Plots of Treatment-Experienced Subjects Receiving SCH mg BID + Ritonavir Plasma HCV RNA (Log 10 IU/mL) = PEG-IFN alfa-2b Dose Hours Morning Day Resistant variants detected in these subjects at loci: V36, R155, A156

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 13 SCH : Antiviral Activity in Combination With PEG-IFN alfa-2b at Day 15 SCH (± 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) ExperiencedNaiveExperiencedNaive 800 mg TID SCH % (4/8) 75% (6/8) 0% (0/8) 38% (3/8) 400 mg BID SCH 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 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 14 SCH Pharmacokinetic/Pharmacodynamic Relationship (Monotherapy ± Ritonavir) (6 × EC 90 ) (11 × EC 90 ) (41 × EC 90 ) (62 × EC 90 ) n = 7n = Median C min (ng/mL) by Quartile Mean Change in HCV-RNA Log 10 (lU/mL) on Day 7

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 15 Modeled SCH Tablet + Ritonavir Pharmacokinetics for Phase 2 Study ~12 x EC 90 ~16 x EC 90 Trough Values Time (hr) SCH mg QD/RTV SCH mg QD/RTV SCH mg BID/RTV ~8 x EC 90 Plasma Concentration SCH (ng/mL) Doses Tested in Phase 2

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 16 Preliminary Phase 2 Data in Naïve Patients SCH /Ritonavir + PEG-IFN alfa-2b/RBV (n=25) Once-Daily Dosing = PEG-IFN alfa-2b/RBV = 200 mg SCH QD 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%) , ,000 1,000,000 10,000, ,000, Days HCV RNA (Log 10 IU/mL) LLQ <25 IU/mL

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 17 Conclusions   SCH (± ritonavir ± PEG-IFN alfa-2b) was safe and well tolerated   No SCH related SAEs   SCH 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 with metabolic inhibition

Reesink H, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 23, 2009, Copenhagen, Denmark.04/28/09 18 Study Investigators and Colleagues AMC:SPRI: H. W. ReesinkE. A. Hughes J. de BruijneM. A. Treitel C. J. WeeginkE. O’Mara J. Li A. Keung EMC:PRA: H. L. A. JanssenJ. van Lier R. J. de KnegtA. van Vliet J. F. BergmannM. Ypey