1. TMC278 (rilpivirine), an investigational next-generation NNRTI, demonstrates long-term efficacy and tolerability in ARV-naïve patients: 96-week results of study C204
M Santoscoy,1 P Cahn,2 C Gonsalez,3 W Hao,4 A Pozniak,5 P Shalit,6 S Vanveggel,7 K Boven8
1Hospital Carlos Mac Gregor IMSS, Mexico City, Mexico; 2Hospital Juan A Fernández and Fundación Huesped, Buenos Aires, Argentina; 3Hospital das Clíncias, Pinheiros, Brazil; 4Beijing You’an Hospital, Beijing, China; 5Chelsea and Westminster NHS Foundation Trust and PKR/SSR, London, UK; 6Swedish Medical Center, Seattle, WA, USA; 7Tibotec BVBA, Mechelen, Belgium; 8Tibotec Inc., Yardley, PA, USA.

2. TMC278: a next-generation NNRTI with potent anti-HIV-1 activity
TMC278 has demonstrated potent in-vitro anti-HIV-1 activity against wild-type and NNRTI-resistant isolates1
Half-life of 45 hours
48-week results from the global Phase IIb TMC278-C204 study showed potent and sustained efficacy at all doses (25, 75 and 150mg qd) in ARV-naïve patients, and was generally well tolerated2,3
Currently in Phase III trials
1de Bethune M-P, et al. CROI Abstract 556 2Pozniak A, et al. CROI Abstract 144LB
3Yeni P, et al. EACS Abstract P7.2/08
ARV = antiretroviral

3. Screening and randomization 1:1:1:1 ARV-naïve patients (N=368)
TMC278-C204: study design
96 weeks
Ongoing (extended to 5 years), randomized, active-controlled, dose-ranging Phase IIb study in ARV-naïve patients
Primary objective to evaluate the TMC278 efficacy (ITT-TLOVR) and safety dose-response relationship at Week 48
Primary analysis at 48W
Analysis at 96W
Screening and randomization 1:1:1:1
ARV-naïve patients (N=368)
HIV RNA 5,000 copies/mL
EFV 600mg qd + 2 NRTIs N=89
TMC mg qd + 2 NRTIs N=93
TMC mg qd + 2 NRTIs N=95
TMC mg qd + 2 NRTIs N=91
EFV = efavirenz; ITT = intent to treat; TLOVR = time to loss of virologic response; NRTI backbone chosen by investigator and is either AZT/3TC or TDF/FTC administered as fixed-dose combinations where available

4. Demographic and baseline characteristics
TMC278 groups
All TMC278 (n=279)
EFV 600mg (n=89)
25mg qd (n=93)
75mg qd (n=95)
150mg qd (n=91)
Male, % 70 67 64
Caucasian, % 44 43 47
Age, years* 36 35
Viral load, log10 copies/mL*
4.83
4.86
4.85
4.84
4.88
CD4 cell count, cells/mm3*‡
176
216
196
200
207
Duration of known HIV infection, years*
1.4
1.3
0.9
1.0
1.2
*Median values
‡n=88 for EFV 600mg

5. Virologic responders (%, 95% CI)
TMC278: high response rate and sustained virologic response over 96 weeks similar to EFV
HIV-1 RNA <50 copies/mL to Week 96 (ITT-TLOVR algorithm)
TMC278 25mg qd (n=93) TMC278 75mg qd (n=95)
TMC mg qd (n=91) EFV 600mg qd (n=89)
100 80 60 40 20
76%
72%
71%
71%
Virologic responders (%, 95% CI)
Time (weeks)
CI = confidence interval

6. TMC278: potent antiviral efficacy at Week 48 sustained to Week 96
Parameter
TMC278 groups
All TMC278 (n=279)
EFV 600mg qd (n=89)
25mg qd (n=93)
75mg qd (n=95)
150mg qd (n=91)
Viral load <50 copies/mL (ITT-TLOVR), %
Week 48 80 77 79 81
Week 96 76 72 71 73
Virologic failure, %* 10 5 7 6 9 8
Discontinuations, % 23 25 24 27
AE = adverse event *Patients with loss of virologic response, patients who never achieved confirmed viral load <50 copies/mL or patients who discontinued before reaching Week 96 due to lack of virologic efficacy

7. TMC278: continued CD4 increases through Week 96
Hatched bars: Week 48
Solid bars: Week 96
122
146
145
172
143
159
127
160
200
150
Mean change in CD4 cell count from baseline (cells/mm3, 95% CI)
100 50
TMC278 25mg qd (n=93)
TMC278 75mg qd (n=95)
TMC mg qd (n=91)
EFV 600mg qd (n=88)
For premature discontinuations, subsequent timepoints were imputed with baseline value up to week 96 (non-completer status equals failure imputation algorithm)
Intermediate missing values were imputed using last observation carried forward

8. A limited number of patients experienced virologic failure and developed RAMs on TMC278-based therapy
Very few patients experienced virologic failure with RAMs
6% (17/279) in the TMC278 arms
7% (6/89) in the EFV arm
The proportion* of patients in whom treatment-emergent NNRTI RAMs developed was similar across arms
56% (5/8) in the TMC278 25mg qd group
60% (3/5) in the TMC278 75mg qd group
33% (1/3) in the TMC mg qd group
60% (3/5) in the EFV arm
Resistance findings to be explored further in Phase III trials
*Sequence information not available in 2 VF failures (1 in TMC278 75mg arm and 1 in EFV arm)

9. All TMC278 doses were safe and well tolerated, with no consistent association between safety assessments and TMC278 dose
Summary of treatment-emergent AEs, regardless of severity and causality
AE (%)
TMC278 groups
All TMC278 (n=279)
EFV 600mg qd (n=89)
25mg qd (n=93)
75mg qd (n=95)
150mg qd (n=91)
Any AE 90 97 92 93
AEs leading to discontinuation 9 12 14
Any serious AEs 13 10 15
Any grade 3/4 AEs 30 25 26 27 21
Investigations reported as grade 3/4 AEs* 16 8
Grade 3/4 laboratory abnormalities 33 22 24
*Investigations included laboratory assessments and electrocardiograms

10. Incidences of rash, nervous system- and psychiatric-related AEs were lower with TMC278 than with EFV
Summary of NNRTI AEs of interest, regardless of severity and causality*
Incidence (%)
TMC278 groups
All TMC278 (n=279)
EFV 600mg qd (n=89)
25mg qd (n=93)
75mg qd (n=95)
150mg qd (n=91)
Any rash† 5 10 13 9‡ 21
Nervous system disorders
Headache
Dizziness
Somnolence 32 17 3 23 30 19 4
31‡ 20
11‡ 4§ 48 16 11
Psychiatric disorders
Insomnia
Depression
Abnormal dreams/nightmares 8 7 1 6 14 3§
*Well-described AEs associated with current NNRTIs and occurring in ≥5% of TMC278- or EFV-treated patients †All rashes were grade 1 or 2, except for one patient with grade 3 rash in the TMC278 75mg group (associated with fever) probably related to dapsone ‡p<0.01 vs EFV; §p<0.05 vs EFV (Fisher’s exact test)

11. Increases in lipid parameters were lower with TMC278 than with EFV
No TMC278 dose relationship for mean changes in lipid parameters
Mean change from baseline (SD) at 96 weeks
Parameter
Combined TMC278 group
EFV 600mg qd
TC (mg/dL)*
9.0 (30.5)
34.5 (31.2)
LDL-C (mg/dL)*
4.5 (26.7)
18.2 (28.3)
HDL-C (mg/dL)*
6.2 (10.6)
11.3 (11.8)
Ratio TC/HDL-C‡
–0.4 (1.1)
–0.1 (0.9)
TG (mg/dL)*
–9.9 (80.9)
29.2 (86.7)
TC = total cholesterol; LDL-C = low-density lipoprotein-cholesterol; HDL-C = high-density lipoprotein-cholesterol; TG = triglycerides *p<0.01, ‡p=0.19 for EFV vs TMC278 (nonparametric Wilcoxon rank sum test, post-hoc analysis) 11

12. Additional investigations
Endocrine
No clinically relevant changes in adrenal and thyroid parameters were observed
ECG
Increases in QTc interval were seen with all TMC278 doses and EFV up to 48 weeks, which then stabilized up to Week 96
increases were primarily seen with the AZT/3TC backbone
mean increase was lowest with TMC278 25mg 12

13. Conclusions
Once-daily oral TMC278 at all doses demonstrated a high response rate and sustained virologic response over 96 weeks
TMC278 was generally safe and well tolerated
Incidences of rash, nervous system- and psychiatric-related AEs and increase in lipids were significantly lower with TMC278 than with EFV
There were trends suggesting a favourable profile of TMC278 25mg compared with the higher dose groups
Both efficacy and safety of TMC278 were well maintained between 48 and 96 weeks
TMC278 is being further evaluated in Phase III trials at a dose of 25mg qd

14. Acknowledgements
The authors would like to thank the patients who participated in the study, the study centre staff, DSMB members, Tibotec study personnel and the following principal investigators:
Argentina
W Belloso
P Cahn
I Cassetti
A Cassiro
M Losso
S Lupo
Austria
A Rieger
N Vetter
Brazil
C Cunha
C Gonsalez
B Grinsztejn
J Madruga
P Rogerio
A Timerman
China
Li Xingwang
Wu Hao
France
P-M Girard
J-M Molina
D Salomon
Y Yazdanpanah
P Yeni
Germany
K Arastéh
G Fätkenheuer
F Goebel
J-A Rump
Mexico
M Santoscoy
Puerto Rico
J Morales-Ramirez
Russia
B Gruzdev
O Kozyrev
G Moshkovich
A Pronin
O Romanenko
E Vinogradova
A Yakovlev
South Africa
P Ive
S Miller
L Mohapi
D Steyn
R Wood
Thailand
P Chetchotisakd
K Ruxrungtham
K Supparatpinyo
W Techasatit
A Vibhagool
Uganda
E Katabira UK
A Pozniak
E Wilkins
USA
N Bellos
P Chiliade K Sathasivam
C Farthing
J Nadler B Casanas
P Shalit
M Thompson
A Wilkin