48-week primary analysis of trial TMC278-C204: TMC278 demonstrates potent and sustained efficacy in ARV-naïve patients

1. 48-week primary analysis of trial TMC278-C204:TMC278 demonstrates potent and sustained efficacy in ARV-naïve patients A Pozniak, J Morales-Ramirez, L Mohapi, M Santoscoy, P Chetchotisakd, M Hereygers, S Vanveggel, M Peeters, B Woodfall and K Boven 14th Conference on Retroviruses and Opportunistic Infections Los Angeles, USA, 25–28 February 2007 Abstract: J-1010, Paper: 144LB

2. TMC278 • TMC278, a next generation NNRTI, has demonstrated in vitro and in vivo activity against wild-type and NNRTI resistant isolates1 • TMC278 has a terminal half-life of 45 hours in humans • All doses (25–150mg) of TMC278 significantly reduced viral load in a Phase IIa study in ARV-naïve patients2 1de Bethune M-P, et al. CROI 2005. Abstract 5562Goebel F, et al. CROI 2005. Abstract 160

3. TMC278-C204 Phase IIb, ARV-naïve patients 96 weeks VL 5,000 copies/mL Sensitive to NRTIs and no NNRTI RAMs • Randomized controlled study • TMC278 blinded for all 3 dose groups versus open label efavirenz • Stratification factors • Investigator-selected NRTI backbone: Combivir® (75.3%) or Truvada® (24.7%) (given as combination or individual components) • Region (Asia and Africa; US, Europe and Russia; Latin America) EFV 600mg qd + 2 NRTIs (n=89) TMC278 25mg qd + 2 NRTIs (n=93) Screening TMC278 75mg qd + 2 NRTIs (n=95) TMC278 150mg qd + 2 NRTIs (n=91) VL = viral load; RAM = resistance associated mutation; EFV = efavirenz

4. Demographic and baseline characteristics *No differences between TMC278 dose groups †Median values and (range)

5. Patient disposition at Week 48Primary efficacy endpoint, ITT population *TLOVR = time to loss of virologic response; NC=F = non-completer = failure; ITT = intent to treat. Virologic response and loss of response need confirmation with subsequent VL measurement. †Not related to TMC278

6. VL <50 copies/mL through 48 weeks (observed) TMC278 25mg qd TMC278 75mg qd TMC278 150mg qd EFV 600mg qd 96% 100 80 60 40 20 0 93% 92% 89% Virologic responders (%, 95% CI) 0 2 4 8 12 16 20 24 32 40 48 56 Time (weeks) TMC278 25mg N = 89 TMC278 75mg N = 93 TMC278 150mg N = 89 EFV 600mg N = 83 90 88 81 84 81 81 81 80 78 28 92 90 92 88 88 87 83 81 81 26 87 86 83 81 80 79 77 74 75 23 84 82 83 79 80 80 80 79 76 27

7. 100 80 60 40 20 0 0 2 4 8 12 16 20 24 32 40 48 VL <50 copies/mL through 48 weeks (TLOVR)Primary efficacy endpoint, ITT population (NC=F) TMC278 25mg qd (n=93) TMC278 75mg qd (n=95) TMC278 150mg qd (n=91) EFV 600mg qd (n=89) 81% 81% 80% 77% Virologic responders (%, 95% CI) Time (Weeks) CI = confidence interval

8. 0 2 4 8 12 16 20 24 32 40 48 Change in log10 plasma VL through 48 weeks TMC278 25mg qd (n=93) TMC278 75mg qd (n=95) TMC278 150mg qd (n=91) EFV 600mg qd (n=89) 0.0 –0.5 –1.0 –1.5 –2.0 –2.5 –3.0 –3.5 Mean change in log10 VL (95% CI) Time (weeks) For premature discontinuations: data imputed with baseline value (NC=F)For missing values: last observation carried forward (LOCF)

9. 0 2 4 8 12 16 20 24 32 40 48 Change in CD4 cell count through 48 weeks TMC278 25mg qd (n=93) TMC278 75mg qd (n=95) TMC278 150mg qd (n=91) EFV 600mg qd (n=89) 180 160 145 140 143 127 120 125 Mean change (95% CI) from baseline in CD4 cell counts (x 106/L) 100 80 60 40 20 0 Time (weeks) For premature discontinuations: data imputed with baseline value (NC=F)For missing values: last observation carried forward (LOCF)

10. Most common AEs* at least possibly related to TMC278 or efavirenz *Occurring in >5% of patients in all TMC278 groups combined or control

11. NNRTI class effects, any grade, irrespective of causality *All rashes were grade 1/2 except one patient with grade 3 rash plus fever (75mg TMC278 group) probably related to dapsone

12. Serious adverse events (SAEs) and grade 3/4 adverse events (AEs) • SAEs at least possibly related to treatment • TMC278 25mg: 3 patients; 75mg: 0 patients; 150mg: 2 patients and EFV: 1 patient • One death in TMC278 75mg qd group (not related) due to pneumonia, septic shock • Difference in G3 and G4 AEs largely due to investigations reported as AE (11.1% in TMC278 and 6.7% in EFV) but no difference in G3 and G4 lab abnormalities

13. Treatment-emergent grade 3/4 laboratory abnormalities All grade 3/4 lab abnormalities: TMC278 22%, efavirenz 20% *Relative to the number of patients with available data for that parameter

14. Laboratory data over time Lipids • No TMC278 dose relationship for mean changes in lipid parameters Endocrine tests • No clinically relevant changes in endocrine laboratory parameters LDL = low density lipoprotein; HDL = high density lipoprotein

15. TMC278-C204: conclusions • TMC278 demonstrated potent and sustained antiviral efficacy over 48 weeks: 77–81% (TLOVR, NC= F, <50 copies/mL) • TMC278 was generally safe and well-tolerated • Incidence of rash and nervous system-related events and total cholesterol/triglycerides were lower with TMC278 than with EFV • The 75mg dose, one pill once daily, has been selected for further development in treatment-naïve HIV patients

16. TMC278-C204: acknowledgements The authors would like to thank the patients that participated in the study, the study center staff, DSMB members, Tibotec study personnel and the principal investigators: