INTELENCE (Etravirine) UPDATE
Global Clinical Research
Rekha Sinha, MD
January 30, 2009
Overview of Presentation

Etravirine (ETR) Safety and Tolerability
- Pooled Data from Phase III Trials
- Short-term safety in Pediatric Population

Planned Trials with Etravirine

Etravirine Resistance
Clinical Data: Previous Human Experience
Phase I (57 trials)
Additional
ongoing trials
Total N=1167 (healthy)
96 (HIV-1 infected)
Phase IIa (POP)
3 trials
Phase IIb
Total N=48
6 trials
Total N= 442
Phase III (Pivotal)
DUET: 2 trials (C206 and C216)
Total N=599
NDA 2007
FDA approval January 2008
• Worldwide
Expanded Access
and CU
(9000)
• DUET rollover
trial (N - 300)
------------------Pediatric Study
Phase I completed
N= 41
Phase II ongoing
N= 100
ETR Safety and Tolerability:
DUET Trials (TMC125-C206/C216)
Design and Major 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*
Placebo + BR*
*BR = darunavir/ritonavir with optimized NRTIs and optional enfuvirtide



DUET-1 and -2 differed only in geographical location; pooled analysis was pre-specified
Major inclusion criteria:
–
Plasma 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
Patients recruited from Thailand, Australia, Europe and the Americas
*From extended list of 41 NNRTI RAMs (Tambuyzer et al. Abstract 67 EHDRW 2007);
BR = background regimen; RAM = resistance-associated mutation
Patients with viral load <50 copies/mL
at Week 48 (%) (± 95% CIs)
Response (<50 copies/mL)
at Week 48 (ITT-TLOVR)
100
Placebo + BR (n=604)
ETR + BR (n=599)
90
80
70
61%
60
p<0.0001
50
40%
40
30
20
10
0
02 4
8
12 16 20 24
32
40
48
Time (weeks)

61% of patients in the ETR group achieved a confirmed undetectable viral load
(<50 copies/mL) compared with 40% in the placebo group (p<0.0001)
ITT-TLOVR = intent-to-treat time-to-loss of virologic response; ETR = etravirine;
BR = background regimen CIs = confidence intervals; p value from logistic regression model
Modified from Johnson M et al., 15th CROI 2008. Abstract 791
Overview of AEs
(regardless of causality)
ETR + BR
(n=599)
Placebo + BR
(n=604)
Any AE (any cause)
96
96
Grade 3 or 4 AE
33
35
Serious AE
20
23
Discontinuation due to AE
7
6
Death (any cause)
2
3
Most
common
AEs
Rash (any type)
19
11
Diarrhea
18
24
Nausea
15
13
Headache
11
13
Nervous system disorders
17
20
Psychiatric disorders
17
20
Hepatic AEs
7
6
Parameter, %
AEs of
interest


There were no consistent or clinically relevant trends in laboratory, vital signs or ECG data
The profile of laboratory abnormalities, including hepatic and lipid parameters, was generally similar
between the ETR and placebo groups
Johnson M et al., 15th CROI 2008. Abstract 791
Rash (1)
Investigator assessment of
cause of rash, %
Any cause

ETR group
(n = 599)
19.2
Placebo group
(n = 604)
10.9
Significance
P = 0.0001
In the ETR group
–
–
–
–
early onset: median 14 days
limited duration: median 15 days
low severity: mostly mild-to-moderate; 1.3% grade 3, no grade 4
● mostly maculopapular; no mucosal involvement
infrequently led to permanent discontinuation: 2.2% of ETR group, 0%
in placebo group
● mostly resolved with continued treatment
Rash with etravirine: usually mild-to-moderate and infrequently led to
permanent discontinuation
Nervous system* & Psychiatric
disorders
Most common Nervous system events (reported in ≥ 1.0% of patients in the ETR group)
Headache
10.9
12.7
Dizziness
3.2
4.3
Somnolence
1.8
2.3
*Selected based on the nervous system events commonly associated with approved NNRTIs.
Most common psychiatric events (reported in ≥ 1.0% of patients in the ETR group)
Insomnia
Depression
Anxiety
Sleep disorder



7.2
4.2
3.8
1.3
8.3
6.6
4.1
0.8
No increased risk in patients with a history of psychiatric disorders
Abnormal dreams/nightmares were similar in incidence to placebo (0.8% vs 1.0% for the ETR and
Placebo groups respectively)
No episodes of hallucinations, suicidal ideation, or manic symptoms in the ETR group
AEs: similar incidence to placebo, low severity,
did not lead to discontinuation
Hepatic AEs and laboratory
abnormalities
ETR group
(n = 599)
Placebo group
(n = 604)
Any cause or severity
Grade 3/4
6.5
3.0
6.1
3.0
Leading to discontinuation
1.0
0.7
Laboratory abnormalities
ALT elevated (grade 3/4)
AST elevated (grade 3/4)
1.6/0.8
1.2/0.2
1.8/0.4
1.2/0.2
Hepatic AEs, %
Hepatic disorders: similar incidence to placebo, low severity, infrequently led to
discontinuation
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
Safety conclusions

Safety and tolerability of ETR were generally comparable to
placebo, except for the incidence of rash (any type)

Overall, most AEs were of low severity and infrequently led to
discontinuation

Rash, the only AE to occur more frequently with ETR
–
generally mild-to-moderate
–
most often resolved with continuing treatment
–
infrequently led to discontinuation

Nature and incidence of nervous system and psychiatric AEs
were similar to placebo

ETR was not associated with any increase in laboratory
abnormalities, including hepatic and lipid parameters
Safety in Pediatric population
• Phase I trial in children (6-17 years)
TMC125-C126 Trial Design
40 treatment experienced children on a Stable ARV
& Virologically suppressed
Group 1
 6 to  12 years
Screening
up to 28 days
Stage I
20 subjects (10/Group)
Dose: 4 mg/kg b.i.d
Group 2
 12 to  17 years
Treatment Phase
7 days
Interim analysis
Follow-up
1 month
Stage II
20 subjects (10/Group)
Dose: 5.2 mg/kg b.i.d
Stable ARV: LPV/rtv and a minimum of 2 NRTIs +/- ENF
Most Common AEs
TMC125-C126
AE regardless of causality*, N ( %)
Infections and infestations
Rhinitis
Stage I
Stage II
N=21
4 (19.0)
2 (9.5)
N=21
3 (14.3)
2 (9.5)
Nervous system disorders
3 (14.3)
3 (14.3)
Headache
3 (14.3)
3 (14.3)
--------------------------------------------------------------- ----------------------- ----------------------Gastrointestinal disorders
Diarrhoea
Nausea
2 (9.5)
0
1 (4.8)
2 (9.5)
1 (4.8)
1 (4.8)
Skin and subcutaneous tissue disorders
Rash
2 (9.5)
1 (4.8)
1 (4.8)
0
1(4.8)
0
Rash maculopapular
*10.0% in TMC125 group
Conclusion
Based on the comparable exposures of TMC125 in
children to that seen in adults from the DUET trials and
the overall safety of TMC125 in Stage II of TMC125-C126
The recommended dose per weight band for children and
adolescents aged between 6 and 17, inclusive, will be
based on 5.2 mg/kg b.i.d.
Planned trials with ETR
- New target population
- New ARV regimen
ETR, RAL plus 3TC in HIV-infected Early
Treatment-Experienced Patients
Phase IV Single arm open label design
Population: First or Second line failure, VL > 500 c/mL, Sensitive to ETR,
Naïve to integrase
N= 50
ARV regimen: ETR 200mg/ RAL 400mg/ lamivudine 150mg each b.i.d
Duration: 48 week study
Objective: To assess the percentage of early treatmentexperienced HIV-infected patients that have achieved an HIV RNA <50
copies/mL at week 24
Study of Efavirenz Neuropsychiatric
Symptoms versus Etravirine (SENSE)
Double blind, active controlled trial
Population: Treatment naive, VL > 5000 cp/mL, sensitive to ETR and
background regimen (2 NRTIs), no NNRTI resistance
N= 150
ARV regimen: ETR 400 mg q.d ( 4 ETR tablets 100 mg each) versus
efavirenz 600 mg q.d
Duration: 48 week study
Objective: To compare neuropsychiatric adverse event profile of
ETR versus efavirenz in combination with 2 N(t)RTIs as assessed at Wk 12
ETR in a Nucleoside Sparing Regimen
Open label, active controlled trial
Population: Treatment experienced, NNRTI resistant, VL > 500 cp/mL,
sensitive to ETR and background regimen
N= 520
ARV regimen: ETR 200 mg b.i.d plus PI/rtv versus PI/rtv plus 2
N(t)RTIs
Duration: 48 week study
Objective: Efficacy of ETR given in a PI-containing N(t)RTI-sparing
regimen in terms of the proportion of subjects achieving a plasma viral
load < 50 HIV-1 RNA copies/mL at Week 24.
ETR Resistance
Table 1. Overview of
the NNRTI mutations

The list of 44 NNRTI RAMs was
expanded to 57 mutations by addition of
all mutations at NNRTI resistance amino
acid positions
17 NNRTI related mutations that blunt
response to ETR identified based on
the DUET analysis

The frequency and virologic response in
patients with the mutations at baseline is
shown (if n5), along with the ETR FC in
a site-directed mutant (SDM)
ETR RAMs 2008
Response rate below threshold (<51.9%)
ETR FC >3.0
Mutation
V90I
A98G
A98S
L100I
K101E
K101H
K101P
K101Q
K101R
K103N
K103R
K103S
V106I
V108I
E138A
E138Q
V179D
V179F
V179I
V179T
Y181C
Y181I
Y181V
Y188L
V189I
G190A
G190S
H221Y
P225H
F227L
M230L
K238T
Y318F
N348I
No. of
No. of
patients
patients Response rate
with
with
(<50 cps/mL)
mutation at <50 cps/mL in pooled
ETR FC in
baseline
at Week 24 DUET (%)
single SDM
22
11
50.0
1.5
59
29
49.2
2.5
38
26
68.4
0.4
34
18
52.9
1.8
53
24
45.3
1.7
26
11
42.3
1.3
9
4
44.4
6.2
35
20
57.1
3.4
5
3
60.0
0.7
118
82
69.5
0.7
9
2
22.2
0.8
16
12
75.0
0.9
24
9
37.5
NA
66
42
63.6
0.5
12
6
50.0
2.0
10
8
80.0
5.1
5
2
40.0
2.6
7
1
14.3
0.1
97
60
61.9
0.8
8
3
37.5
0.8
110
50
45.5
3.9
8
4
50.0
12.5
6
2
33.3
17.4
32
24
75.0
0.9
24
13
54.2
0.8
115
58
50.4
0.8
14
3
21.4
0.2
35
23
65.7
2.5
5
3
60.0
1
20
13
65.0
0.4
4
2
50.0
3.4
10
9
90.0
2.4
13
10
76.9
1.4
60
35
58.3
NA
The following mutations were present in <5 patients at baseline: K101N, K103H, K103T, V106A, V106M, E138G, E138K, V179A,
V179E, V179G, Y181F, Y188C, Y188F, Y188H, G190C, G190E, G190Q, G190R, F227C, M230I, M230L, P236L, K238N and N348T
Figure 1. Effect of the ETR RAMs 2008
(n=17) on virologic response
Patients with confirmed VL
HIV-1 RNA <50 copies/mL (%)
80
70
60
75% of response in
patients without NNRTI RAMs
50
40
30
20
10
0
52
34
34
115
22
12
12
88
4
59
59
110
53
9
26
26
5
24
88
6
14
14
77
*No detectable baseline NNRTI RAM from the list of 44;
Mutations in the ETR RAM list of 2008 but not 2007 are underlined
Etravirine Weighted Genotype Score to
Predict Response
Mutation
Y181I
Y181V
K101P
L100I
Y181C
M230L
E138A
V106I
G190S
V179F §
V90I
V179D
K101E
K101H
A98G
V179T
G190A
ETR FC in the subset of HIV-1
clinical isolates with 1 ETR RAM
(n=1,619), regardless of the
Prevalence (%)
presence of other NRTI or
in the panel of
NNRTI RAMs*
4,248 HIV-1
Q1–Q3
n
clinical isolates Median
1.5
0.9
2.6
8.4
32.0
1.1
2.5
4.4
3.7
0.7
6.8
2.1
9.9
2.2
9.5
0.6
23.3
42.0
10.4
22.3
6.7
4.4
4.3
2.9
2.6
0.8
–
2.0
1.7
1.5
1.1
1.0
0.9
0.8
23.2–129.7
3.9–60.6
5.6–42.9
2.7–17
2.1–11.6
2.7–10.5
1.4–10.6
1.4–5.2
0.6–1.7
–
0.8–3.6
1.0–4.7
0.8–2.5
0.6–2.8
0.5–1.9
0.7–1.2
0.5–1.5
§V179F
34
28
65
264
552
20
44
63
32
0
97
33
24
8
127
2
226
ETR FC in Effect on FC
in linear
a single
SDM
model
12.5
17.4
6.2
1.8
3.9
3.4
2.0
NA
0.2
0.1
1.5
2.6
1.7
1.3
2.5
0.8
0.8
High
High
High
Medium
Medium
High
Medium
Low
Low
Medium
Low
Low
Low
Low
Low
Low
Low
Weight
factor
3
3
2.5
2.5
2.5
2.5
1.5
1.5
1.5
1.5
1
1
1
1
1
1
1
*Median (Q1–Q3) FC for all isolates was 3.0 (1.1–9.3);
was never present as single ETR RAM (always with Y181C)
Effect of ETR FC
Increasing ETR FC was associated with a
gradual loss in virological response

CCOs as defined by Tibotec: FC = 3 and FC = 13
Modified from Peeters, M, et al. IHDRW 2008. Poster 121
Figure 6. Relation between the weighted score and the
virologic response (<50 copies/mL)
Patients with confirmed VL
HIV-1 RNA <50 copies/mL (%)
100
80
Highest
response
Intermediate
response
Reduced
response
Response category
74.4%
60
52.0%
37.7%
40
20
0
N
0.0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
115/148 37/53
6/11
11/15
32/59
2/7
19/36
1/5
14/27
3/9
4/9
4/13
1/3
2/11
Weighted score for the 17 ETR RAMs 2008
Hatched bars indicate virologic response for the entire category
Understanding Etravirine Susceptibility
The virologic response is a function of the number and weight of the
baseline ETR RAMs


Among the 17 ETR RAMs, Y181I and Y181V had the highest weight,
followed by L100I, K101P, Y181C and M230L
Among the 17 ETR RAMs, mutations with the highest weight had a
low prevalence
Weighted mutation score of 0-2
Highest response rates (74%)
Weighted mutation score of 2.5-3.5
Intermediate response rates (52%)
Weighted mutation score of >/=4
Reduced response rates (74%)
·