1. M. Manns, 1 H. Reesink, 2 C. Moreno, 3 T. Berg, 4 Y. Benhamou, 5 Y. Horsmans, 6 G. Dusheiko, 7 R. Flisiak, 8 P. Meyvisch, 9 O. Lenz, 9 V. Sekar, 10 G. van ’t Klooster, 9 K. Simmen, 9 R. Verloes 9 OPERA-1 trial (Study TMC435-C201): interim analysis of safety and antiviral activity of TMC435 in treatment-naïve genotype-1 HCV patients 1 Medizinische Hochschule Hannover, Germany; 2 Amsterdam Medical Center, Amsterdam, The Netherlands; 3 Erasme Hospital, Université Libre de Bruxelles, Belgium; 4 Charité-Universitätsmedizin Berlin, Campus Virchow- Klinikum, Germany; 5 Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France; 6 Saint-Luc Université Catholique de Louvain, Belgium; 7 Royal Free Hospital, London, UK; 8 Medical University of Bialystok, Poland; 9 Tibotec, Mechelen, Belgium; 10 Tibotec Pharmaceuticals, USA

2. OPERA-1: TMC435 is a potent HCV NS3/4A inhibitor Non-covalent binding NS3/4A protease inhibitor EC 50 = 8 nM in genotype-1 replicon In vitro: synergistic with IFNα and an NS5B inhibitor; additive with RBV 3.9 log 10 IU/mL decline in HCV RNA after 5 days’ monotherapy with TMC435 200 mg QD in genotype-1 infected treatment-experienced patients Pharmacokinetic profile allows for QD dosing HCV, hepatitis C virus; IFNα, interferon α; QD, once daily; RBV, ribavirin Lin et al. AAC 2009; Reesink et al. EASL 2008; Van ’t Klooster et al. AASLD 2008

3. OPERA-1 (Study TMC435-C201) Phase IIa, double-blind, placebo-controlled, proof-of-concept trial treatment-naïve and treatment-experienced patients, genotype-1 infection Data presented for treatment-naïve patients Cohort 1: TMC435 25 and 75 mg QD Cohort 2: TMC435 200 mg QD Standard entry criteria for PEG-IFN/RBV studies documented chronic HCV infection compensated liver disease including cirrhosis PEG-IFN, pegylated interferon

4. OPERA-1 (Cohorts 1 and 2): objectives To study the dose dependency of the antiviral effect of TMC435 QD in treatment-naïve genotype-1 HCV-infected patients Panel A: during 1 week of monotherapy, plus 3 weeks combined with SoC Panel B: combined with SoC over 4 weeks of treatment To determine the antiviral activity, safety and tolerability of TMC435 QD SoC, standard of care (pegylated interferon  -2a + ribavirin)

5. SoC = pegylated interferon  -2a + ribavirin (PEG-IFN  -2a + RBV) ITT, intent-to-treat population OPERA-1 (Cohorts 1 and 2): study design Treatment-naïve, genotype-1 HCV-infected patients Cohort 1: TMC435 25 and 75 mg QD Cohort 2: TMC435 200 mg QD Placebo + SoCSoC N=10 Week 01424 or 48 TMC435 25 mg QD TMC435 25 mg QD + SoCSoC Panel A Panel B N=9 TMC435 75 mg QD TMC435 75 mg QD + SoCSoC N=10 TMC435 200 mg QD TMC435 200 mg QD + SoCSoCN=8 TMC435 25 mg QD+ SoCSoC N=9 TMC435 75 mg QD+ SoCSoC N=9 TMC435 200 mg QD+ SoCSoC N=10 PlaceboPlacebo + SoCSoC N=9 N=ITT

6. OPERA-1 (Cohorts 1 and 2): demographics and baseline disease characteristics PARAMETER Cohort 1Cohort 2 Placebo (N=13) 25 mg QD (N=18) 75 mg QD (N=19) Placebo (N=6) 200 mg QD (N=18) Patient demographics Male, % Caucasian, % 76.9 92.3 72.2 94.4 57.9 100.0 83.3 100.0 55.6 88.9 Disease characteristics HCV subtype*, % 1a 1b 1 other 58.3 41.7 0 33.3 61.1 5.6 36.8 63.2 0 83.3 16.7 0 27.8 66.7 5.6 HCV RNA, log 10 IU/mL, median <800 000, %  800 000, % 6.6 15.4 84.6 6.7 5.6 94.4 6.4 26.3 73.7 6.4 33.3 66.7 6.6 11.1 88.9 Duration of HCV infection, years, median 13.012.38.45.52.5 Cirrhosis, %53.861.147.433.316.7 *Based on part of NS5B sequence

7. -1.72 -3.47 -4.55 -4.68 0.02 -2.63 -3.43 -4.13 OPERA-1 (Cohorts 1 and 2): mean change in HCV RNA from baseline to Day 7 (mono- and triple therapy) Mean HCV RNA (log 10 IU/mL) change from baseline 0237 Day Placebo Panel A TMC435 25 mg TMC435 75 mg TMC435 200 mg Placebo Panel B TMC435 25 mg TMC435 75 mg TMC435 200 mg Panel A: TMC435 monotherapy phase Panel B: TMC435 combined with SoC

8. OPERA-1 (Cohorts 1 and 2): mean change in HCV RNA from baseline to Day 28 (mono- and triple therapy) Mean (± SE) HCV RNA (log 10 IU/mL) change from baseline 1 037142128 Day 0 -2 Placebo Panel B TMC435 25 mg Panel A TMC435 25 mg TMC435 75 mg TMC435 200 mg TMC435 75 mg TMC435 200 mg -3 -4 -5 -6 -3.64 -4.74 -5.52 -5.44 -2.74 -4.26 -4.48 -4.60 Panel A: 1 week of TMC435 monotherapy followed by 3 weeks combined with SoC Panel B: 4 weeks of TMC435 combined with SoC

9. OPERA-1 (Cohorts 1 and 2): response to treatment at Day 28 6/9 patients in the 25 mg arm, 9/9 patients in the 75 mg arm and 10/10 patients in the 200 mg arm of Panel B had HCV RNA <10 IU/mL at Week 12 (4-weeks TMC435 + SoC, 8-weeks SoC only) Patients (%) Placebo25 mg75 mg200 mg Panel A Placebo25 mg75 mg200 mg Panel B TMC435 QD n=8n=9 n=8n=9 n=10 _ Panel A: 1 week of TMC435 monotherapy followed by 3 weeks combined with SoC Panel B: 4 weeks of TMC435 combined with SoC

10. No viral breakthroughs were observed in Panel B (4 weeks TMC435 + SoC) 5 viral breakthroughs were observed in Panel A (1 week TMC435 monotherapy followed by 3 weeks TMC435 + SoC) 2 patients in 25 mg group 2 patients in 75 mg group 1 patient in 200 mg group Among the viral breakthroughs in Panel A, emerging NS3 mutations † were observed in all 5 patients R155K (intermediate FC ‡ ) R155K + D168N (intermediate FC ‡ ) D168E (intermediate FC ‡ ) Q80R/K + D168E (high FC ‡ ) D168V (high FC ‡ ) Viral breakthrough: >1 log 10 IU/mL increase in HCV RNA from nadir or >100 IU/mL in patients with previous HCV RNA 10-100; high FC: >100 † based on in vitro passage experiments; ‡ based on in vitro replicon SDM data for TMC435 OPERA-1 (Cohorts 1 and 2): virology findings during the first 4 weeks of treatment

11. OPERA-1 (Cohorts 1 and 2): adverse event (AE) summary Parameter, % Cohort 1Cohort 2 Placebo (N=13) 25 mg QD (N=18) 75 mg QD (N=19) Placebo (N=6) 200 mg QD (N=18) Any AE Grade 3 or 4 Discontinuation due to AE Serious AE Death 0 7.7 0 00000000 10.5 * 0 00000000 11.1 * 0 Most common AEs † Headache Fatigue Nausea Influenza-like illness 38.5 30.8 7.7 15.4 50.0 44.4 27.8 47.4 21.1 26.3 31.6 50.0 16.7 0 16.7 27.8 22.2 * Neutropenia in 4 subjects, related to PEG-IFN  -2a, not or doubtfully related to TMC435 † Reported in >10 patients (all TMC435 groups combined) No evidence of hepatobiliary, renal, haematopoietic or cardiac disturbances

12. Mean  mol/L (± SE) 280 0 0 0 Placebo25 mg75 mg200 mg n=7n=9 n=10 280 0 0 0 Placebo25 mg75 mg200 mg n=6n=9*n=10n=8 Panel APanel B OPERA-1 (Cohorts 1 and 2): total bilirubin at baseline (Day 0) and Day 28 ULN Bilirubin levels decreased after the end of treatment with TMC435 Elevations in direct and indirect bilirubin levels were also observed, particularly in the highest dose group Day * Baseline sample missing from 1 patient; ULN, upper limit of normal = 21  mol/L

13. OPERA-1 (Cohorts 1 and 2): ALT at baseline (Day 0) and Day 28 280 0 0 0 Placebo25 mg75 mg200 mg n=6n=9**n=10n=8 280 0 0 0 Placebo25 mg75 mg200 mg n=6n=9*n=10n=8 Day Mean U/L (± SE) ALT, alanine aminotransferase * Baseline sample missing from 1 patient; ** baseline sample missing from 2 patients Panel APanel B ULN

14. OPERA-1 (Cohorts 1 and 2): summary TMC435 demonstrated potent antiviral activity in monotherapy and in combination with SoC over 4 weeks of treatment TMC435 25, 75 and 200 mg QD resulted in greater HCV RNA reductions than SoC alone Dose-dependent antiviral activity was observed after 1 week of TMC435 monotherapy In the 75 and 200 mg groups, all patients achieved HCV RNA levels <25 IU/mL and 8/9 and 7/10 respectively were undetectable at the end of 4-week triple therapy (Panel B) Once-daily administration of TMC435 in combination with SoC in treatment- naïve genotype-1 patients over 28 days was generally safe and well tolerated TMC435 was not associated with AE-related treatment discontinuations Most reported AEs were mild to moderate Most common AEs included headache, fatigue, nausea and influenza-like illness Bilirubin elevations were observed in some patients receiving TMC435, mostly with the 200 mg dose, and were generally mild and reversible in nature Substantial decreases in transaminases were observed in patients receiving TMC435

15. OPERA-1 (Cohorts 1 and 2): conclusions In treatment-naïve patients infected with HCV genotype-1, TMC435 in combination with SoC over 4 weeks of treatment: demonstrated potent antiviral activity was generally safe and well tolerated was not associated with AE-related treatment discontinuations These results support the development of TMC435 for treatment-naïve patients infected with HCV genotype-1

16. The patients and their families The OPERA-1 investigators and their study staff Belgium Yves HORSMANS, Brussels Christophe MORENO, Brussels Hans ORLENT, Bruges Hans VAN VLIERBERGHE, Ghent Germany Thomas BERG, Berlin Michael BIERMER, Berlin Peter BUGGISCH, Hamburg Andreas ERHARDT, Düsseldorf Atef HALABI, Kiel Michael Peter MANNS, Hannover Karl-Heinz MOLZ, München Jens RASENACK, Freiberg Medivir AB, Sweden Tibotec France Yves BENHAMOU, Paris Patrice COUZIGOU, Pessac Patrick MARCELLIN, Clichy Jean-Michel MOLINA, Paris Stanislas POL, Paris Anne RACHLINE, Paris Christian TREPO, Lyon Netherlands Henk REESINK, Amsterdam Poland Robert FLISIAK, Bialystok Andrzej HORBAN, Warszawa Maciej JABLKOWSKI, Lodz Wieslaw KRYCZKA, Kielce UK Matthew CRAMP, Plymouth Geoffrey DUSHEIKO, London Graham FOSTER, London Mark NELSON, London Acknowledgements