Transcript Protecting cognitive function in hematological cancers

DUET-1 and DUET-2:
TMC125 versus placebo
in treatment-experienced
HIV-1-infected patients
DUET-1: Anthony Mills, Pedro Cahn, Beatriz Grinsztejn, Richard Haubrich,
Jacob Lalezari, José Valdez Madruga, Gilles Pialoux, Timothy Wilkin,
Monika Peeters, Johan Vingerhoets, Goedele De Smedt, Lorant Leopold,
Roberta Trefiglio and Brian Woodfall
DUET-2: Christine Katlama, Thomas Campbell, Bonaventura Clotet,
Margaret Johnson, Adriano Lazzarin, Keikawus Arastéh, William Towner, Benoit
Trottier, Monika Peeters, Johan Vingerhoets, Goedele De Smedt,
Benny Baeten, Greet Beets, Rekha Sinha and Brian Woodfall
DUET-1: Thailand, France, North and South America. Madruga JV, et al. Lancet 2007:370;29–38
DUET-2: Australia, Europe, North America. Lazzarin A, et al. Lancet 2007:370;39–48
DUET-11 and DUET-22 trials:
design and inclusion criteria
Screening
6 weeks
48-week treatment period
with optional 48-week extension
Follow up
4 weeks
24-week primary analysis
600 patients
target per trial
TMC125 + BR* (including DRV/r)
Placebo + BR* (including DRV/r)
*BR = DRV/r with optimised NRTIs and optional enfuvirtide




Viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks
≥1 NNRTI RAM, at screening or in documented historical genotype
≥3 primary PI mutations at screening
Primary endpoint was the proportion of patients achieving viral load
<50 HIV-1 RNA copies/mL when all patients had reached Week 24 or
discontinued
1. Madruga, et al. Lancet 2007;370:29–38
2. Lazzarin, et al. Lancet 2007;370:39–48
DUET-1 and DUET 2:
baseline characteristics and background ARVs
DUET-1
DUET-2
TMC125 + BR Placebo + BR TMC125 + BR Placebo + BR
(n=304)
(n=308)
(n=295)
(n=296)
Parameter
Patient
demographics
Male
87
86
94
92
Caucasian
65
65
77
76
Disease
characteristics
Viral load (log10 c/mL)*
4.8 (2.7–6.2)
4.9 (2.4–6.5)
4.8 (3.0–6.8)
4.8 (2.2–6.3)
99 (1–789)
109 (1–694)
100 (1–708)
108 (0–912)
CDC category C
61
63
55
55
10–15 ARVs (%)
67
65
62
67
Darunavir/r (%)
5
5
3
5
Detectable
mutations
≥2 NNRTI RAMs (%)
66
67
65
65
≥4 primary PI RAMs (%)
60
59
65
66
Background
regimen
Used ENF (total) (%)
40
41
52
53
Used ENF de novo (%)
24
26
27
27
PSS = 0 (%)
15
15
16
16
PSS = 1 (%)
35
31
35
42
Prior ARV use
CD4 cells (cells/µL)*
c/mL = HIV-1 RNA copies/mL; PSS = phenotypic sensitivity score
DUET-1 and DUET-2 primary endpoint: patients
with viral load <50 copies/mL at Week 24 TLOVR
DUET-1
100
TMC125 + BR (n=304)
Placebo + BR (n=308)
80
p=0.0050
56%
60
40
39%
20
0
Responders (%) + 95% CI
Responders (%) + 95% CI
100
DUET-2
TMC125 + BR (n=295)
Placebo + BR (n=296)
80
p=0.0003
62%
60
40
44%
20
0
0
4
8 12 16 20
Time (weeks)
24
0
4
8 12 16 20
Time (weeks)
24
CI = confidence interval; intent-to-treat (ITT) population;
TLOVR = time to loss of virological response imputation algorithm
DUET-1 and -2: patients with HIV-RNA <400
copies/mL to week 24
DUET-1
TMC125 + BR (n=304)
Placebo + BR (n=308) 74%
80
60
40
p=0.0001
51%
20
0
100
Responders (%) + 95% CI
Responders (%) + 95% CI
100
DUET-2
TMC125 + BR (n=295)
Placebo + BR (n=296)
75%
80
60
40
54%
p=0.0001
20
0
0
4
8 12 16 20
Time (weeks)
24
0
4
8 12 16 20
Time (weeks)
24
CI = confidence interval; intent-to-treat (ITT) population;
time to loss of virological response (TLOVR) imputation algorithm
DUET-1 and DUET-2:
viral load reduction from baseline to week 24
0.0
DUET-2
TMC125 + BR (n=304)
Placebo + BR (n=308)
–1.0
p<0.0001
–1.7
–2.0
–2.4
–3.0
0
4
8
12 16
Time (weeks)
20
24
Mean change in viral load from
baseline (log10 copies/mL) + SE
Mean change in viral load from
baseline (log10 copies/mL) + SE
DUET-1
0.0
TMC125 + BR (n=295)
Placebo + BR (n=296)
–1.0
p<0.0001
–1.7
–2.0
–2.3
–3.0
0
4
8
12 16
Time (weeks)
20
24
CI = confidence interval; intent-to-treat (ITT) population;
time to loss of virological response (TLOVR) imputation algorithm
DUET-1 and DUET-2:
change in CD4 cell count from baseline
DUET-2
+89
100
p=0.0002
80
60
+64
40
20
TMC125 + BR (n=304)
Placebo + BR (n=308)
0
Mean change in CD4 cell count
from baseline (cells/μL) + SE
Mean change in CD4 cell count
from baseline (cells/μL) + SE
DUET-1
100
p=0.3692
+78
80
60
+66
40
20
TMC125 + BR (n=295)
Placebo + BR (n=296)
0
0
4
8 12 16 20
Time (weeks)
24
0
4
8 12 16 20
Time (weeks)
24
SE = standard error; intent-to-treat (ITT) population; non-completer = failure (NC=F) imputation
DUET-1 and DUET-2: response (VL <50 copies/mL)
according to number of active background ARVs
DUET-1
DUET-2
47%
0
9%
59%
1
24%
2
68%
61%
3
66%
65%
0
20
40
60
80
100
Patients with viral load
<50 copies/mL at Week 24 (%)
TMC125 + BR (n=295)
Placebo + BR (n=296)
Number of active
background ARVs (PSS)
Number of active
background ARVs (PSS)
TMC125 + BR (n=304)
Placebo + BR (n=308)
44%
0
7%
62%
1
35%
2
82%
70%
3
80%
73%
0
20
40
60
80
100
Patients with viral load
<50 copies/mL at Week 24 (%)
Darunavir and enfuvirtide are counted as active if FC<10 or used de novo, respectively;
PSS = phenotypic sensitivity score
DUET-1 and DUET-2: response according to
enfuvirtide use (primary analysis)
DUET-1
DUET-2
80
60
40
60%
55%
56%
33%
20
0
Re-using or
not using
enfuvirtide
Using
enfuvirtide
de novo
p<0.0001
p=0.7935
Patients with viral load
<50 copies/mL at Week 24 (%)
Patients with viral load
<50 copies/mL at Week 24 (%)
TMC125 + BR (n=304)
Placebo + BR (n=308)
80
60
40
TMC125 + BR (n=295)
Placebo + BR (n=296)
73%
68%
58%
34%
20
0
Re-using or
not using
enfuvirtide
Using
enfuvirtide
de novo
p<0.0001
p=0.3838
DUET-1 and DUET-2: virological response
(<50 copies/mL) according to baseline mutations


13 baseline ResistanceAssociated Mutations were
associated with a decreased
response to TMC125
(TMC125 RAMs):
V90I
A98G
L100I
K101E/P
V106I
V179D/F
Y181C/I/V G190A/S
When 3 of these TMC125
RAMs were present the
response rate was comparable
to the overall placebo response*
Only 14% of patients had
3 or more TMC125 RAMs
†analysis
80
% patients with confirmed
<50 HIV-1 RNA copies/mL

60
40
20
0
0
1
2
3
4
5
Number of TMC125 RAMs
Pts† (%) = 40
30
16
8
5
9
performed in n=406 (100%); *overall placebo response = 36%
What is the effect of Y181C on TMC125
response rates?
What is the effect of Y181C on TMC125
response rates?


Y181C is a common
mutation conferring
resistance to currently
available NNRTIs
The TMC125 response rate
is not compromised when
Y181C is present, with
either 0 or 1 other TMC125
RAM
When Y181C is present with
two or more TMC125 RAMs
(13% of all patients),
response rates were
substantially reduced
80
% patients with confirmed
<50 HIV-1 RNA copies/mL

60
40
20
0
Overall Y181C Y181C Y181C Y181C Y181C
+1
+2
+3
+4
TMC125 + 0
TMC125 RAMs
N = 406
23
36
26
17
8
DUET-1 and DUET-2:
overview of adverse events (AEs)
DUET-1
DUET-2
DUET-1
Parameter, %
Parameter
Any AE (any cause)
Grade 3/4 AE
Grade 3/4 AE
Discontinuation due to AE
Discontinuation due to AE, %
Serious AE
Serious AE, %
Death (any cause), n (%)
Death (any cause), n (%)
AEs*
AEs of
AEs
of
interest
interest
TMC125
Placebo
TMC125
Placebo
(n=304)
(n=308)
(n=295)
(n=296)
93
92
TMC125
+ BR Placebo
+ BR
+ BR+ BR TMC125
+ BR+ BR Placebo
+ BR+ BR
(n=304)
(n=308)
(n=295)
(n=296)
Any AE (any cause)
Most
Most
common
common
AEs*
DUET-2
Rash (any type)
Rash
(any type), %
Nausea
Nausea,
%
Diarrhoea
Diarrhoea,
Headache %
Headache
Injection site reaction
Injection
site reaction
Nervous system disorders
Nervous
disorders
Psychiatricsystem
disorders
Psychiatric
Hepatic AEs disorders
Hepatic AEs
93
93
21
21
5
5
12
12
4 (1.3%)
4 (1.3%)
92
93
28
28
5
5
20
20
7 (2.3%)
8 (2.6%)
92
28
28
6
6
15
15
4 (1.4%)
4 (1.4%)
92
27
27
4
4
17
17
7 (2.4%)
7 (2.4%)
7
10
12
12
20
20
13
13
7
7
20
14
14
18
9
13
9
10
20
11
15
5
20
14
14
7
7
15
16
5
17
17
4
20
20
14
14
12
12
10
710
15
15
10
510
10
No deaths in the TMC125 group were considered at least possibly related to trial medication;
*In >10% patients in TMC125 group in either trial
DUET-1 and DUET-2:
summary of rash







Overall incidence
– 17% in TMC125 group vs 9% in placebo group
Onset: most frequent in 2nd week of therapy
Severity
– usually mild to moderate; 1% grade 3 and 0% grade 4
– no rashes with mucosal involvement
Infrequently lead to discontinuation (2%)
– most self-limiting with continued treatment
Higher incidence in women, but no gender difference in severity or
treatment discontinuations
No association between rash and baseline CD4 cell count
In patients with a history of NNRTI-related rash, there was no
apparent increased risk
DUET-1 and DUET-2: incidence of treatmentemergent lipid and liver abnormalities
DUET-1
TMC125
+ BR
(n=304)
Placebo
+ BR
(n=308)
TMC125
+ BR
(n=295)
Placebo
+ BR
(n=296)
Triglycerides
increased, %
7
5
7
4
Total cholesterol
increased, %
6
5
5
4
LDL increased, %
3
4
7
7
ALT, %
3
2
2
1
AST, %
2
2
3
1
Grade 3/4
abnormalities

DUET-2
The profile of abnormalities was generally similar between the TMC125 and
placebo groups with no consistent or clinically-relevant trends in
laboratory, vital signs or ECG data
Conclusions

In treatment-experienced patients, including those with NNRTI resistant virus,
TMC125 consistently demonstrated superiority over placebo
–
56% (DUET-1) and 62% (DUET-2) of patients achieved confirmed
undetectable VL (<50 copies/mL) with TMC125 plus BR at Week 24

Even in the absence of any other fully active background agents, with
TMC125, over 40% of patients achieved undetectable (<50 copies/mL)
viral load
–



response rates increased as more active agents were used in the
background regimen
Thirteen TMC125 resistance-associated mutations (TMC125 RAMs) were
identified
–
in the presence of 0, 1 and 2 TMC125 RAMs, virological responses were
greater than the overall placebo response
–
only 14% of all patients had ≥3 TMC125 RAMs
Except for rash, incidence and severity of AEs with TMC125 were similar to
placebo
TMC125 has the ability to extend and enhance the NNRTI class and provide a
new treatment option for patients with resistance to and/or unable to tolerate
other NNRTI’s
DUET-1 and DUET-2: acknowledgements

We express our gratitude to the patients that participated in the study, as well as the
study centre staff, DSMB, Tibotec personnel and following principal investigators:
DUET-1
DUET-2
Argentina: H Ariza, J Benetucci, L Calanni,
L Cassetti, J Corral, D David, A Krolewiecki,
M Losso, P Patterson, R Teijeiro; Brazil:
C A da Cunha, E Kallas, E Netto, J H Pilotto,
M Schechter, J Suleiman, A Timerman; Chile:
J Ballesteros, R Northland; Costa Rica:
A Alvilés Montoya, G Herrera Martinez, A Solano
Chinchilla; France: M Dupon, C Katlama,
J M Livrozet, P Morlat, C Piketty, I Poizot-Martin;
Mexico: J Andrade-Villanueva, G Reyes-Terán,
J Sierra-Madero; Panama: A Canton,
A Rodriguez, N Sosa; Puerto Rico: J O Morales
Ramirez, J L Santana Bagur, R Soto-Malave;
Thailand: T Anekthananon, P Mootsikapun,
K Ruxrungtham; USA: M Albrecht, N Bellos,
R Bolan, P Brachman, C Brinson, F Cruickshank,
R Elion, W J Fessel, T Hawkins, S Hodder,
T Jefferson, H Katner, C Kinder, M Kozal,
J Leider, D McDonough, K Mounzer, D Norris,
W O’Brien, G Pierone, K Raben, B Rashbaum,
M Rawlings, B Rodwick, P Ruane, J Sampson,
S Schrader, A Scribner, M Sension, D Sweet,
B Wade, D Wheeler, A Wilkin, T Wills,
M Wohlfeiler, K Workowski.
Australia: J Chuah, D Cooper, B Eu, J Hoy,
C Workman; Belgium: N Clumeck, R Colebunders,
M Moutschen; Canada: J Gill, K Gough, P Junod,
D Kilby, J Montaner, A Rachlis, C M Tsoukas,
S L Walmsley; France: C Arvieux, L Cotte,
J F Delfraissy, P M Girard, B Marchou, J M Molina,
D Vittecoq, Y Yazdanpanah, P Yeni; Germany:
S Esser, G Fätkenheuer, H Gellermann, K Göbels,
F D Goebel, H Jäger, A Moll, J K Rockstroh,
D Schuster, S Staszewski, A Stoehr; Italy:
A Antinori, G Carosi, G Di Perri, R Esposito,
F Mazzotta, G Pagano, E Raise, S Rusconi,
L Sighinolfi, F Suter; Netherlands: P H J Frissen,
J M Prins, B J A Rijnders; Poland: A Horban;
Portugal: F Antunes, M Miranda, J Vera; Spain:
P Domingo, G Garcia, J M Gatell, J GonzálezLahoz, J López-Aldeguer, D Podzamczer; UK:
P Easterbrook, M Fisher, C Orkin, E Wilkins; USA: B
Barnett, J Baxter, G Beatty, D Berger, C Borkert, C
Cohen, M Conant, J Ernst, C Farthing, T File,
M Frank, J E Gallant, A E Greenberg, C Hicks,
D T Jayaweera, S Kerkar, N Markowitz, C Martorell,
C McDonald, D McMahon, M Mogyoros, R A Myers
Jr, G Richmond, K Sathasivam, S Schneider,
H Schrager, P Shalit, F P Siegal, L Sloan, K Smith, S
Smith, P Tebas, L S Tkatch.