Transcript Maraviroc slide set

Presentation Number 40LB
15th CROI
Boston, USA, February 3–6, 2008
Virological Correlates Associated with Treatment
Failure at Week 48 in the Phase 3 Study of Maraviroc in
Treatment-Naive Patients
Jayvant Heera1, Mike Saag2, Prudence Ive3, Jeannette Whitcomb4,
Marilyn Lewis5, Lynn McFadyen5, James Goodrich1, Howard
Mayer1, Elna van der Ryst5, and Mike Westby5
1Pfizer
Global Research and Development, New London, CT, USA
2University of Alabama at Birmingham, Birmingham, AL, USA
3University of the Witwatersrand, Johannesburg, South Africa
4Monogram Biosciences Inc., South San Francisco, CA, USA
5Pfizer Global Research and Development, Sandwich, UK
MERIT Study: Phase 3 Trial Design
Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)*
Randomization
1:1
Screening
(6 weeks)
Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)*
0
*Patients experiencing toxicity to ZDV or 3TC were permitted to substitute
an alternative nucleoside reverse transcriptase inhibitor
Week 48
Week 96
Primary
analysis
Patient eligibility criteria:
• ≥16 years of age • HIV-1 RNA ≥2,000 copies/mL
• Treatment naive • No evidence of resistance to EFV, zidovudine (ZDV), or lamivudine (3TC)
• CCR5-tropic (R5) HIV-1 infection
Patients stratified by
• HIV-1 RNA < and ≥100,000 copies/mL at screening
• Geographic location: Northern Hemisphere and Southern Hemisphere
MVC QD arm discontinued at end of Phase 2b (Week 16) for failure to meet
protocol-defined criteria to continue (205 patients completed 16 weeks)
MERIT Study
Heera J, et al. 15th CROI 2008; Presentation 40LB
Saag M, et al. 4th IAS 2007. Abstract WESS104
2
Week 48 Efficacy Results
Includes all patients who received at least one dose of study medication
HIV-1 RNA
<50 copies/mL (ITT)
100
69.3
Patients (%)
70
65.3
60
50
40
30
20
0
N=
361
360
EFV + CBV MVC + CBV
140
142 cells/mm3
120
100
80
60
EFV + CBV
MVC + CBV
40
20
0
0
*Difference (adjusted for randomization strata)
†Lower bound of 1-sided 97.5% confidence interval; non-inferiority margin = –10%
CBV = Combivir
MERIT Study – 48 weeks
169 cells/mm3
160
Mean change in from baseline in
CD4+ count (cells/mm3)
80
10
180
–4.2* (–10.9†)
90
Change in CD4+
cell count (LOCF)
8
16
24
32
Time (weeks)
40
48
Heera J, et al. 15th CROI 2008; Presentation 40LB
Saag M, et al. 4th IAS 2007. Abstract WESS104
3
Summary of Discontinuations Through 48 Weeks
Includes all patients who received at least one dose of study medication
EFV + CBV
N=361
MVC + CBV
N=360
91 (25.2)
97 (26.9)
Adverse event, n (%)
49 (13.6)
15 (4.2)
Lack of efficacy, n (%)
15 (4.2)
43 (11.9)
Other reason, n (%)
9 (2.5)
14 (3.9)
Withdrew consent or lost to follow-up, n (%)
18 (5.0)
25 (6.9)
Reason for discontinuation
All, n (%)
MERIT Study – 48 weeks
Heera J, et al. 15th CROI 2008; Presentation 40LB
Saag M, et al. 4th IAS 2007. Abstract WESS104
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Objectives
● To understand the virological correlates associated with treatment
failure at Week 48
Methods
● Tropism was measured throughout the study using the Trofile™ assay
● Resistance to NRTIs and EFV was evaluated by the PhenoSense GT™
assay
● Resistance to MVC was evaluated using the PhenoSense Entry™ assay,
with plateaus in maximum percent inhibition (MPI) <95% as a marker of
resistance
● MVC plasma concentrations were determined using sparse PK sampling
and combined with adherence data
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Percentage of Patients with HIV-1 RNA <50 Copies/mL at
Week 48 by Tropism Result at Baseline
Includes all patients who received at least one dose of study medication
● 25 (3.5%) patients had D/M virus at baseline
● In both treatment groups the proportion of patients with D/M virus at baseline who
achieved undetectable HIV-1 RNA was reduced relative to patients with R5 virus
100
R5
90
80
69.3
Patients (%)
70
D/M
EFV + CBV
MVC + CBV
68.0
60
54.6
50
40
30
20
7.1
10
0
N=
MERIT Study – 48 weeks
339
331
11
14
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Possible Correlates of Tropism Changes From Screening to
Baseline: Combined Treatment Groups
Tropism change from
screening to baseline, N=24
R5 at screening and
baseline, N=697
Mean screening HIV-1 RNA,
log10 copies/mL
4.79
4.84
Mean screening CD4+ count,
cells/mm3 (min, max)
201
(23, 431)
271
(3, 1,528)
B
17 (4.2%)
390 (95.8%)
C
4 (1.9%)
212 (98.1%)
Other/undetermined
3 (4.2%)
68 (95.8%)
Viral subtype
MERIT Study – 48 weeks
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Analysis of Virological Correlates Associated with Lack of
Efficacy
● Virological analysis of patients who discontinued due to lack of
efficacy
– 43 patients on MVC
– 15 patients on EFV
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Tropism Shift and NRTI Resistance at Failure for Patients
on MVC (n=43)
Tropism
Baseline
R5
(32)
Missing
(1)
NR/NP
(2)
DM/X4
(8)
Tropism
Failure
R5
(13)
BLQ
(9)
NR/NP
(5)
D/M or X4
(16)
NRTI res
(7)
(2)
(2)
(16)
27*
NR/NP = no result/non-phenotypable
BLQ = HIV-1 RNA <500 copies/mL tropism tests were cancelled or censored for these samples
*Excludes two patients with no resistance data at the last timepoint on treatment, but with resistance at earlier visits
Heera J, et al. 15th CROI 2008; Presentation 40LB
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RTI Resistance Selected in Virus from Patients with
Treatment Failure
Tropism at
failure*
MVC (300 mg BID)
n
M184V
22
10 (45%)
R5
N
22
D/M or X4
19
19
19 (100%)
5 (26%)
Other
Total
2
43
0
7 (16%)
R5
N
14
2
0
43
29 (67%)
EFV (600 mg QD)
n
EFVres
13
8
+M184V
3
+2NRTIres
0
Other
Total
1
15
1
14
1
4 (29%)
1
1 (7%)
Tropism at
failure*
1
9 (64%)
2NRTIres
2 (9%)
* Last valid tropism result while on treatment
N = total patients in group; n = total patients with a valid resistance test; 2NRTIres = genotypic resistance to 3TC
and ZDV (or substituted NRTI); EFVres = genotypic resistance to EFV; Other = missing baseline tropism result
(n=1) or no valid tropism data during failure (n=2)
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Incomplete Adherence is a Significant Contributor to
Treatment Failure in Patients with R5 Virus at Baseline
Tropism
Baseline
R5
(32)
Tropism
Failure
R5
(11)
BLQ
(6)
NR/NP
(5)
D/M or X4
(10)
PK BLQ
(4*)
(5)
(2)
(1)
50%
NR/NP = no result/non-phenotypable
BLQ = HIV-1 RNA <500 copies/mL tropism tests were cancelled or censored for these samples
PK BLQ = MVC plasma concentrations below the limit of quantification corresponding to a rebound in viral load
* Includes one patient with no BLQ PK but with documented interruption between visits corresponding to rebound in VL.
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Characteristics of Patients who Failed 300 mg BID MVC
with R5 Virus
Country
Race
Sex
Clade
MVC
resistance*
NRTI
resistance**
Belgium
Black
M
AG
Yes
M184V
Argentina
White
M
BF
Yes
M184V, M41M/L
Poland
White
M
B
M184V
USA
White
M
B
M184V
South Africa
Black
M
C
M184V
Australia
White
M
B
Yes
Puerto Rico
White
M
B
(Note 1)
South Africa
Black
M
C
Yes
South Africa***
Black
M
C
Yes
South Africa
Black
F
C
Yes
UK
White
M
B
South Africa
Other
M
C
PK BLQ
*By phenotype;**By genotype; *** Tropism was recorded as “BLQ” at last on-treatment timepoint, but ‘R5’ at all other timepoints
PK BLQ = serum levels of MVC during periodic sampling were below limit of quantification Heera J, et al. 15th CROI 2008; Presentation 40LB
Note 1: documented non-adherence between visits coinciding with viral load rebound
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Example Patient Profile 1
Treatment start
Treatment end
M184V
R5
R5
NR
NR NR NR
R5 R5
R5
6
800
MPI 99
5
MPI 92
600
4
400
3
200
2
FPV/r + TDF + 3TC
MVC + CBV
1
0
100
200
CD4+ count (cells/mm3)
HIV-1 RNA (log10 copies/mL)
R5
0
300
Time since first administration (day)
FPV = fosamprenavir; TDF = tenofovir
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Mean Change from Baseline in CD4+ Count (cells/mm3)
by Tropism Result at Baseline and Time of Failure
EFV + CBV
MVC + CBV
Total
R5R5
140
Mean change from baseline
in CD4+ count (cells/mm3)
120
R5NR non-R5Any
128
111
101
100
83
86
N=10
N=9
80
80
60
R5D/M
or X4
44
40
20
0
-20
N=15 N=42
N=11
N=0
N=11
N=0
N=10
N=6
-18
-40
NR = not-reported, non-phenotypable, below limit of quantification, or missing
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Tropism Summary
● 13 patients (3.8%) receiving MVC had a change in tropism result from R5
to D/M between screening and baseline
– The response to MVC was significantly reduced in this subgroup
– Tropism changes were 50% less frequent in patients with clade C HIV-1 than
in patients with clade B or other clades
● For subjects with R5 virus at baseline, no appreciable difference in
treatment response was seen between the MVC and EFV treatment
groups
● A retrospective analysis will be performed to investigate the impact of
an enhanced tropism assay on MERIT outcomes
● CXCR4-using virus was detected at failure in 10/32 (31.3%) MVC-treated
(300 mg BID) subjects with R5 virus at baseline
● Patients failing MVC had higher CD4+ cell counts at failure than EFV,
irrespective of tropism result at failure
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Resistance Summary
● Lamivudine resistance mutation (M184V/I) was most common in patients
failing in the MVC arm
– 19/19 patients failing with D/M or X4 virus
– 10/22 patients failing with R5 virus
● EFV-related resistance mutations were most common in patients failing
in the EFV arm
– 9/14 patients with resistance test data
● Resistance to MVC in patients failing with R5 virus was uncommon
– 2/12 patients studied
● Viral load rebound in patients failing the MVC arm was more commonly
associated with BLQ plasma levels of MVC at the time of failure
Heera J, et al. 15th CROI 2008; Presentation 40LB
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Acknowledgements
● The patients participating in the MERIT study
● The investigators and study site staff
● The Pfizer MERIT study team
Heera J, et al. 15th CROI 2008; Presentation 40LB
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