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

TMC278 TMC278, a next generation NNRTI, has demonstrated in vitro and in vivo activity against wild-type and NNRTI resistant isolates 1 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 patients 2 1 de Bethune M-P, et al. CROI Abstract Goebel F, et al. CROI Abstract 160

Screening EFV 600mg qd + 2 NRTIs (n=89) TMC278 25mg qd + 2 NRTIs (n=93) TMC278 75mg qd + 2 NRTIs (n=95) VL  5,000 copies/mL Sensitive to NRTIs and no NNRTI RAMs TMC mg qd + 2 NRTIs (n=91) 96 weeks VL = viral load; RAM = resistance associated mutation; EFV = efavirenz TMC278-C204 Phase IIb, ARV-naïve patients 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)

Demographic and baseline characteristics Characteristic All TMC278 * n=279 EFV 600mg n=89 Gender, % female Race, % Caucasian4447 Age, years † 35 (19–67) 35 (21–63) VL, log 10 copies/mL † 4.84 (2.16–7.13) 4.88 (3.37–6.41) VL, copies/mL † 69,300 (144–13,600,000) 75,100 (2,320–2,570,000) CD4 cell count, cells/mm 3† 200 (5–758) 207 (3–970) Duration of known HIV infection, years † 1.0 (0–21) 1.0 (0–15) * No differences between TMC278 dose groups † Median values and (range)

Patient disposition at Week 48 Primary efficacy endpoint, ITT population Parameter, n (%) TMC278 EFV 600mg n=89 25mg qd n=93 75mg qd n=95 150mg qd n=91 VL <50 copies/mL* 75 (81) 76 (80)70 (77)72 (81) Virologic failure8 (9)5 (5)6 (7)5 (6) Death01 (1) † 00 Discontinuation due to adverse event (AE) 6 (6)5 (5)9 (10)5 (6) Discontinuation for other reasons 4 (4)8 (8)6 (7)7 (8) * 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

VL <50 copies/mL through 48 weeks (observed) TMC278 25mg qd TMC278 75mg qdTMC mg qdEFV 600mg qd Virologic responders (%, 95% CI) Time (weeks) TMC278 25mg N = 89 TMC278 75mg N = 93 TMC mg N = 89 EFV 600mg N = 83 93% 92% 89% 96%

VL <50 copies/mL through 48 weeks (TLOVR) Primary efficacy endpoint, ITT population (NC=F) Time (Weeks) Virologic responders (%, 95% CI) CI = confidence interval TMC278 25mg qd (n=93) TMC278 75mg qd (n=95) TMC mg qd (n=91) EFV 600mg qd (n=89) 81% 80% 77%

Change in log 10 plasma VL through 48 weeks Mean change in log 10 VL (95% CI) TMC278 25mg qd (n=93) TMC278 75mg qd (n=95) TMC mg qd (n=91) EFV 600mg qd (n=89) Time (weeks) –0.5 –1.0 –1.5 –2.0 –2.5 –3.0 –3.5 For premature discontinuations: data imputed with baseline value (NC=F) For missing values: last observation carried forward (LOCF)

Change in CD4 cell count through 48 weeks For premature discontinuations: data imputed with baseline value (NC=F) For missing values: last observation carried forward (LOCF) Mean change (95% CI) from baseline in CD4 cell counts (x 10 6 /L) TMC278 25mg qd (n=93) TMC278 75mg qd (n=95) TMC mg qd (n=91) EFV 600mg qd (n=89) Time (weeks)

Most common AEs* at least possibly related to TMC278 or efavirenz AE preferred term, % TMC278 All TMC278 n=279 EFV 600mg n=89 25mg n=93 75mg n=95 150mg n=91 Nausea Headache Dizziness Vomiting Somnolence Vertigo Abnormal dreams Rash *Occurring in >5% of patients in all TMC278 groups combined or control

NNRTI class effects, any grade, irrespective of causality AE, system organ class, preferred term, % TMC278 All TMC278 n=279 EFV 600mg n=89 25mg n=93 75mg n=95 150mg n=91 Skin and subcutaneous tissue disorders All rash* Nervous system disorders Headache Dizziness Somnolence Ear and labyrinth disorders Vertigo Psychiatric disorders Insomnia Depression Abnormal dreams/nightmares *All rashes were grade 1/2 except one patient with grade 3 rash plus fever (75mg TMC278 group) probably related to dapsone

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 % TMC278 All TMC278 n=279 EFV 600mg n=89 25mg n=93 75mg n=95 150mg n=91 Any SAE Any grade 3/4 AE

Treatment-emergent grade 3/4 laboratory abnormalities Grade 3/4 laboratory abnormalities, % * TMC278 All TMC278 n=279 EFV 600mg n=89 25mg n=93 75mg n=95 150mg n=91 AST and/or ALTG3 G CreatinineG3 G HemoglobinG3 G *Relative to the number of patients with available data for that parameter All grade 3/4 lab abnormalities: TMC278 22%, efavirenz 20%

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 Serum lipids (change from baseline) Mean (SD) TMC278EFV Total cholesterol (mg/dL)5 (±30)31 (±30) LDL cholesterol (mg/dL)0 (±24)16 (+26) HDL cholesterol (mg/dL)5 (±9)12 (±10) Ratio total cholesterol/HDL cholesterol Triglycerides (mg/dL) (±0.99) -10 (±79) (±0.85) 18 (±66) LDL = low density lipoprotein; HDL = high density lipoprotein

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

TMC278-C204: acknowledgements Argentina Dr W Belloso Dr P Cahn Dr I Cassetti Dr A Cassiro Dr M Losso Dr S Lupo Austria Dr A Rieger Dr N Vetter Brazil Dr C Cunha Dr C Gonzales Dr B Grinsztejn Dr J Madruga Dr P Rogerio Dr A Timerman China Dr Li Xingwang Dr Wu Hao France Dr P-M Girard Dr J-M Molina Dr D Salomon Dr Y Yazdanpanah Dr P Yeni Germany Dr K Arastéh Dr G Fätkenheuer Dr F Goebel Dr J-A Rump Mexico Dr M Santoscoy Russia Dr B Gruzdev Dr O Kozyrev Dr G Moshkovich Dr A Pronin Dr O Romanenko Dr E Vinogradova Dr A Yakovlev South Africa Dr P Ive Dr S Miller Dr L Mohapi Dr D Steyn Dr R Wood Thailand Dr P Chetchotisakd Dr K Ruxrungtham Dr K Supparatpinyo Dr W Techasatit Dr A Vibhagool Uganda Dr E Katabira UK Dr A Pozniak Dr E Wilkins US Dr N Bellos Dr P Chiliade/ Dr K Sathasivam Dr C Farthing Dr J Morales Dr J Nadler/ Dr B Casanas Dr P Shalit Dr M Thompson Dr A Wilkin 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: