DUET week 48 TLR

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INTELENCE (Etravirine) UPDATE
Rekha Sinha, MD January 30, 2009
Global Clinical Research
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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

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Clinical Data Previous Human Experience
Phase I (57 trials) Total N1167 (healthy) 96
(HIV-1 infected)

• Additional ongoing trials
• Worldwide Expanded Access and CU
• (9000)
• DUET rollover trial (N - 300)
• -------------------Pediatric Study Phase I
  completed
• N 41
• Phase II ongoing
• N 100

Phase IIa (POP) 3 trials Total N48
Phase IIb 6 trials Total N 442
Phase III (Pivotal) DUET 2 trials (C206 and
C216) Total N599
FDA approval January 2008
NDA 2007
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ETR Safety and Tolerability DUET Trials
(TMC125-C206/C216)
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Design and Major Inclusion Criteria
48-week treatment period with optional 48-week
extension
24-week primary analysis
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 gt5,000 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
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Response (lt50 copies/mL) at Week 48 (ITT-TLOVR)
Placebo BR (n604)
ETR BR (n599)
100
90
80
70
61
60
plt0.0001
Patients with viral load lt50 copies/mL at Week
48 () ( 95 CIs)
50
40
40
30
20
10
0
Time (weeks)

• 61 of patients in the ETR group achieved a
  confirmed undetectable viral load (lt50
  copies/mL) compared with 40 in the placebo group
  (plt0.0001)

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
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Overview of AEs (regardless of causality)
Parameter, Parameter, ETR BR(n599) Placebo BR(n604)
Any AE (any cause) Any AE (any cause) 96 96
Grade 3 or 4 AE Grade 3 or 4 AE 33 35
Serious AE Serious AE 20 23
Discontinuation due to AE Discontinuation due to AE 7 6
Death (any cause) Death (any cause) 2 3
Most common AEs Rash (any type) 19 11
Most common AEs Diarrhea 18 24
Most common AEs Nausea 15 13
Most common AEs Headache 11 13
AEs of interest Nervous system disorders 17 20
AEs of interest Psychiatric disorders 17 20
AEs of interest Hepatic AEs 7 6

• 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
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Rash (1)
Investigator assessment of cause of rash, ETR group (n 599) Placebo group (n 604) Significance
Any cause 19.2 10.9 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
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Nervous system Psychiatric disorders
Most common Nervous system events (reported in 1.0 of patients in the ETR group) Most common Nervous system events (reported in 1.0 of patients in the ETR group) 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) Most common psychiatric events (reported in 1.0 of patients in the ETR group) Most common psychiatric events (reported in 1.0 of patients in the ETR group)
Insomnia 7.2 8.3
Depression 4.2 6.6
Anxiety 3.8 4.1
Sleep disorder 1.3 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
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Hepatic AEs and laboratory abnormalities
Hepatic AEs, Hepatic AEs, ETR group (n 599) Placebo group (n 604)
Any cause or severity Any cause or severity 6.5 6.1
Grade 3/4 Grade 3/4 3.0 3.0
Leading to discontinuation 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
Laboratory abnormalities ALT elevated (grade 3/4) AST elevated (grade 3/4) 1.8/0.4 1.2/0.2
Hepatic disorders similar incidence to placebo,
low severity, infrequently led to discontinuation
ALT alanine aminotransferase AST aspartate
aminotransferase.
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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

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• Safety in Pediatric population
• Phase I trial in children (6-17 years)

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TMC125-C126 Trial Design
40 treatment experienced children on a Stable ARV
Virologically suppressed
Group 1 ? 6 to ? 12 years
Group 2 ? 12 to ? 17 years
Screening up to 28 days
Treatment Phase 7 days
Follow-up 1 month
Stage I 20 subjects (10/Group) Dose 4 mg/kg b.i.d
Stage II 20 subjects (10/Group) Dose 5.2 mg/kg
b.i.d
Interim analysis
Stable ARV LPV/rtv and a minimum of 2 NRTIs /-
ENF
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Most Common AEs
TMC125-C126 TMC125-C126
AE regardless of causality, N ( ) Stage I N21 Stage II N21
Infections and infestations 4 (19.0) 3 (14.3)
Rhinitis 2 (9.5) 2 (9.5)
Nervous system disorders 3 (14.3) 3 (14.3)
Headache 3 (14.3) 3 (14.3)
--------------------------------------------------------------- Gastrointestinal disorders ----------------------- 2 (9.5) ----------------------- 2 (9.5)
Diarrhoea 0 1 (4.8)
Nausea 1 (4.8) 1 (4.8)
Skin and subcutaneous tissue disorders 2 (9.5) 1 (4.8)
Rash Rash maculopapular 1 (4.8) 1(4.8) 0 0


?10.0 in TMC125 group
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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.
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Planned trials with ETR - New target population -
New ARV regimen
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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 gt
  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
  treatment-
• experienced HIV-infected patients that have
  achieved an HIV RNA lt50
• copies/mL at week 24

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Study of Efavirenz Neuropsychiatric Symptoms
versus Etravirine (SENSE)

• Double blind, active controlled trial
• Population Treatment naive, VL gt 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

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ETR in a Nucleoside Sparing Regimen

• Open label, active controlled trial
• Population Treatment experienced, NNRTI
  resistant, VL gt 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 lt 50 HIV-1 RNA copies/mL at Week 24.

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ETR Resistance
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Table 1. Overview ofthe NNRTI mutations
No. of patientswithmutation at baseline
No. ofpatientswith lt50 cps/mLat Week 24
Response rate (lt50 cps/mL) in pooledDUET ()
ETR FC insingle SDM
Mutation
V90I
22
11
50.0
1.5

• 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)

A98G
59
29
49.2
2.5
A98S
38
26
68.4
0.4
L100I
34
18
52.9
1.8
K101E
53
24
45.3
1.7
K101H
26
11
42.3
1.3
K101P
9
4
44.4
6.2
K101Q
35
20
57.1
3.4
K101R
5
3
60.0
0.7
K103N
118
82
69.5
0.7
K103R
9
2
22.2
0.8
K103S
16
12
75.0
0.9
V106I
24
9
37.5
NA
V108I
66
42
63.6
0.5
E138A
12
6
50.0
2.0
E138Q
10
8
80.0
5.1
V179D
5
2
40.0
2.6
V179F
7
1
14.3
0.1
V179I
97
60
61.9
0.8
V179T
8
3
37.5
0.8
Y181C
110
50
45.5
3.9
Y181I
8
4
50.0
12.5
Y181V
6
2
33.3
17.4
Y188L
32
24
75.0
0.9
V189I
24
13
54.2
0.8
ETR RAMs 2008
G190A
115
58
50.4
0.8
G190S
14
3
21.4
0.2
Response rate below threshold (lt51.9)
H221Y
35
23
65.7
2.5
P225H
5
3
60.0
1
ETR FC gt3.0
F227L
20
13
65.0
0.4
M230L
4
2
50.0
3.4
K238T
10
9
90.0
2.4
Y318F
13
10
76.9
1.4
N348I
60
35
58.3
NA
The following mutations were present in lt5
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
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Figure 1. Effect of the ETR RAMs 2008(n17) on
virologic response
80
70
60
75 of response in patients without NNRTI RAMs
50
Patients with confirmed VL HIV-1 RNA lt50
copies/mL ()
40
30
20
10
52
34
115
4
59
110
26
5
24
8
6
14
7
22
12
8
53
9
52
34
115
4
59
110
26
5
24
8
6
14
7
22
12
8
53
9
0
V90l
L100l
Y181l
A98G
V106l
V179T
Y181V
G190A
M230L
Y181C
K101E
K101P
V179D
G190S
V179F
E138A
K101H
No mutation
No detectable baseline NNRTI RAM from the list
of 44 Mutations in the ETR RAM list of 2008 but
not 2007 are underlined
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Etravirine Weighted Genotype Score to Predict
Response
ETR FC in the subset of HIV-1
clinical isolates with 1 ETR RAM
(n1,619), regardless of the
Prevalence ()
presence of other NRTI or
Effect on FC
in the panel of
ETR FC in
NNRTI RAMs
in linear
Weight
4,248 HIV-1
a single
Median
Q1Q3
n
SDM
model
factor
clinical isolates
Mutation
Y181I
1.5
42.0
34
12.5
High
3
23.2129.7
Y181V
0.9
10.4
3.960.6
28
17.4
High
3
K101P
2.6
22.3
65
6.2
High
2.5
5.642.9
L100I
8.4
6.7
2.717
264
1.8
Medium
2.5
Y181C
32.0
4.4
2.111.6
552
3.9
Medium
2.5
M230L
1.1
4.3
20
3.4
High
2.5
2.710.5
E138A
2.5
2.9
1.410.6
44
2.0
Medium
1.5
V106I
4.4
2.6
63
NA
Low
1.5
1.45.2
G190S
3.7
0.8
0.61.7
32
0.2
Low
1.5

V179F
0.7


0
0.1
Medium
1.5
V90I
6.8
2.0
97
1.5
Low
1
0.83.6
V179D
2.1
1.7
1.04.7
33
2.6
Low
1
K101E
9.9
1.5
24
1.7
Low
1
0.82.5
K101H
2.2
1.1
0.62.8
8
1.3
Low
1
A98G
9.5
1.0
0.51.9
127
2.5
Low
1
V179T
0.6
0.9
2
0.8
Low
1
0.71.2
G190A
23.3
0.8
0.51.5
226
0.8
Low
1
Median (Q1Q3) FC for all isolates was 3.0
(1.19.3) V179F was never present as single ETR
RAM (always with Y181C)
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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
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Figure 6. Relation between the weighted score and
the virologic response (lt50 copies/mL)
Highest response
Intermediateresponse
Reduced response
Response category
74.4
52.0
Patients with confirmed VL HIV-1 RNA lt50
copies/mL ()
37.7
?
Weighted score for the 17 ETR RAMs 2008

• Hatched bars indicate virologic response for the
  entire category

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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 gt/4 Reduced
  response rates (74)
•