Transcript 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.

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
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 556
2Goebel F, et al. CROI 2005. Abstract 160
TMC278-C204 Phase IIb, ARV-naïve patients
VL 5,000 copies/mL
Sensitive to NRTIs
and no NNRTI RAMs
96 weeks
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)

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)
VL = viral load; RAM = resistance associated mutation; EFV = efavirenz
Demographic and baseline characteristics
All TMC278*
n=279
EFV 600mg
n=89
33.0
32.6
44
47
35
(19–67)
35
(21–63)
4.84
(2.16–7.13)
4.88
(3.37–6.41)
69,300
(144–13,600,000)
75,100
(2,320–2,570,000)
CD4 cell count, cells/mm3†
200
(5–758)
207
(3–970)
Duration of known HIV infection,
years†
1.0
(0–21)
1.0
(0–15)
Characteristic
Gender, % female
Race, % Caucasian
Age, years†
VL, log10 copies/mL†
VL, copies/mL†
*No
differences between TMC278 dose groups
†Median values and (range)
Patient disposition at Week 48
Primary efficacy endpoint, ITT population
25mg qd
n=93
75 (81)
TMC278
75mg qd
n=95
76 (80)
150mg qd
n=91
70 (77)
EFV 600mg
n=89
72 (81)
8 (9)
5 (5)
6 (7)
5 (6)
0
1 (1)†
0
0
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)
Parameter, n (%)
VL <50 copies/mL*
Virologic failure
Death
*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 qd
TMC278 150mg qd
EFV 600mg qd
96%
93%
92%
89%
Virologic responders
(%, 95% CI)
100
80
60
40
20
0
TMC278 25mg N =
TMC278 75mg N =
TMC278 150mg N =
EFV 600mg N =
0 2 4
8
12
16
20 24
32
Time (weeks)
40
48
56
89 90
93 92
89 87
83 84
88
90
86
82
81
92
83
83
84
88
81
79
81
88
80
80
80
81
74
79
78
81
75
76
28
26
23
27
81
87
79
80
81
83
77
80
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)
Virologic responders
(%, 95% CI)
100
81%
81%
80%
77%
80
60
40
20
0
0 2 4
8
12
16
20
24
Time (Weeks)
32
40
48
CI = confidence interval
Change in log10 plasma VL through 48 weeks
Mean change in log10 VL (95% CI)
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
0 2 4
8
12
16
20
24
32
40
48
Time (weeks)
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
Mean change (95% CI) from baseline
in CD4 cell counts (x 106/L)
TMC278 25mg
qd (n=93)
TMC278 75mg
qd (n=95)
TMC278 150mg
qd (n=91)
EFV 600mg
qd (n=89)
180
160
145
143
127
125
140
120
100
80
60
40
20
0
0 2 4
8
12
16
20 24
Time (weeks)
32
40
48
For premature discontinuations: data imputed with baseline value (NC=F)
For missing values: last observation carried forward (LOCF)
Most common AEs* at least possibly related to
TMC278 or efavirenz
AE preferred term, %
25mg
n=93
TMC278
75mg
150mg
n=95
n=91
All TMC278 EFV 600mg
n=279
n=89
Nausea
Headache
15.1
6.5
25.3
11.6
20.9
5.5
20.4
7.9
18.0
7.9
Dizziness
Vomiting
Somnolence
Vertigo
Abnormal dreams
Rash
5.4
3.2
2.2
1.1
1.1
0
5.3
7.4
3.2
2.1
4.2
0
5.5
3.3
4.4
0
0
1.1
5.4
4.7
3.2
1.1
1.8
0.4
27.0
9.0
10.1
10.1
5.6
5.6
*Occurring in >5% of patients in all TMC278 groups combined or control
NNRTI class effects, any grade, irrespective of
causality
TMC278
AE, system organ class,
preferred term, %
25mg
n=93
75mg
n=95
150mg
n=91
All TMC278 EFV 600mg
n=279
n=89
Skin and subcutaneous tissue
disorders
All rash*
22.6
5.4
29.5
6.3
29.7
12.1
27.2
7.9
33.7
19.1
Nervous system disorders
Headache
Dizziness
Somnolence
34.4
15.1
10.8
3.2
34.7
22.1
7.4
3.2
30.8
17.6
7.7
4.4
33.3
18.3
8.6
3.6
52.8
15.7
30.3
11.2
Ear and labyrinth disorders
Vertigo
1.1
2.1
0
1.1
11.2
Psychiatric disorders
Insomnia
Depression
Abnormal dreams/nightmares
14.0
6.5
4.3
1.1
12.6
5.3
6.3
6.3
13.2
5.5
3.3
0
13.3
5.7
4.7
2.5
15.7
4.5
2.2
10.1
*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)
TMC278
25mg
n=93
75mg
n=95
150mg
n=91
All
TMC278
n=279
Any SAE
10.8
10.5
9.9
10.4
9.0
Any grade 3/4 AE
25.8
24.2
24.2
24.7
15.7
%



EFV
600mg
n=89
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
Treatment-emergent grade 3/4 laboratory
abnormalities
TMC278
Grade 3/4 laboratory
abnormalities, %*
25mg
n=93
75mg
n=95
150mg
n=91
All
TMC278
n=279
EFV
600mg
n=89
AST and/or ALT
G3
G4
3.3
2.2
2.1
3.2
2.2
2.2
2.5
2.5
1.2
1.2
Creatinine
G3
G4
0
0
0
0
1.1
0
0.4
0
0
0
Hemoglobin
G3
G4
1.1
1.1
1.1
1.1
0
2.2
0.7
1.5
0
0
All grade 3/4 lab abnormalities: TMC278 22%, efavirenz 20%
*Relative to the number of patients with available data for that parameter
Laboratory data over time
Lipids
 No TMC278 dose relationship for mean changes in lipid parameters
Serum lipids (change from baseline)
TMC278
EFV
Total cholesterol (mg/dL)
5 (±30)
31 (±30)
LDL cholesterol (mg/dL)
0 (±24)
16 (+26)
HDL cholesterol (mg/dL)
5 (±9)
12 (±10)
- 0.45 (±0.99)
- 0.30 (±0.85)
-10 (±79)
18 (±66)
Mean (SD)
Ratio total cholesterol/HDL cholesterol
Triglycerides (mg/dL)
Endocrine tests
 No clinically relevant changes in endocrine laboratory parameters
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
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:
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