Transcript A4001078 and A4001095

48-week results of once-daily maraviroc (MVC)
150 mg in combination with ritonavir-boosted
atazanavir (ATV/r) compared to emtricitabine/tenofovir
(FTC/TDF) + ATV/r in treatment-naïve patients infected
with R5 HIV-1 (Study A4001078)
Simon Portsmouth,1 Charles Craig,2 Anthony Mills,3
Donna Mildvan,4 Daniel Podzamczer,5
Gerd Fätkenheuer,6 Manuel Leal,7 Hernan Valdez,1
Srinivas Rao Valluri,1 Jayvant Heera1
1Pfizer
Inc., New York, NY, USA; 2Pfizer, Sandwich, Kent, UK; 3Anthony Mills MD, Los Angeles,
CA, USA; 4Beth Israel Medical Center Division of Infectious Diseases, New York, NY, USA;
5HIV Unit, Infectious Disease Service, Hospital Universitari de Bellvitge, Barcelona, Spain;
6University Hospital of Cologne Köln, Germany; 7Laboratory of Immunovirology,
Biomedicine Institute of Seville (IBIS), Infectious Disease Service, Virgen del Rocio
University Hospital, Seville, Spain
Rationale for MVC + boosted PI regimen
• Potential for early use: prevalence of CCR5
tropic virus is greatest in treatment-naïve
individuals1
• Nucleoside-sparing regimen
• Good penetration of MVC in CSF and genital
secretions2-4
• MOTIVATE and PK studies support use of MVC
150 mg QD with selected ritonavir-boosted PIs
Study A4001078: an exploratory pilot study of a low pill
burden QD dual-therapy regimen, MVC + ATV/r
1. Hoffmann, Eur J Med Res, 2007. 2. Tiraboschi et al, J Acquir Immune Defic Syndr, 2010
3. Dumond et al, J Acquir Immune Defic Syndr, 2009. 4. Brown et al, J Infect Dis, 2011
Study design
Open-label, 48-week Phase 2b pilot study
FTC/TDF + ATV/r (300/100 mg QD)
Randomization
1:1
N=121
Screening
(6 weeks)
MVC (150 mg QD) + ATV/r (300/100 mg QD)
0
Week 2
First 15 US patients
Serial PK of MVC
•
16 wk
24 wk
Interim analyses
48 wk
Primary analysis
Patient eligibility criteria
–
–
–
–
–
R5 HIV (ESTA) at screening
≥16 years of age
HIV-1 RNA ≥1000 copies/mL
CD4 ≥100 cells/mm3
No evidence of resistance to ATV/r, TDF,
or FTC
–
–
–
–
Study has iDMC
Ongoing study: USA, Spain, Germany
Extended to 96 weeks
Study is not powered to show a
treatment difference and no formal
comparative statistics will be performed
*Sparse PK sampling on all patients at Weeks 2 (non-PK substudy), 12 and 24 (Vourvahis. Abstract 37 IWCPHIV, 2010)
Study disposition
Screening n=220
Enrolled into study n=121
Discontinued n=7
MVC + ATV/r
n=60
FTC/TDF + ATV/r
n=61
• 2 AE (vomiting,
jaundice)
• 2 lost to follow-up
• 1 withdrew consent
• 3 lost to follow-up
• 2 protocol
violations
• 1 withdrew consent
• 1 insufficient
clinical response
(VL 934 copies/mL)
• 1 pregnancy
Continuing in
study n=53
•
Discontinued n=7
Continuing in
study n=54
• 1 other: possible
TDF-related kidney
failure
Two patients in each arm experienced protocol defined treatment failure
VL, HIV-1 RNA, viral load
Summary of baseline characteristics
MVC + ATV/r
n=60
FTC/TDF + ATV/r
n=61
38.3 (21–61)
35.3 (18–68)
Male, n (%)
56 (93.3)
52 (85.2)
Race, n (%)
White
Black
Asian
Other
45 (75.0)
13 (21.7)
0
2 (3.3)
46 (75.4)
11 (18.0)
3 (4.9)
1 (1.6)
Median CD4+ count,
cells/mm3 (range)
344
(160–744)
358
(110–902)
4.6 (3.4–5.9)
4.7 (3.3–5.9)
16 (27)
22 (36)
Mean age, years (range)
Mean HIV-1 RNA, log10
copies/mL (range)
HIV-1 RNA ≥100,000 copies/mL,
n (%)
HIV-1 RNA <400 copies/mL at Week 48
Patients with HIV-1 RNA
<400 copies/mL (%)
100
89.8%
90
80
86.9%
70
60
50
40
MVC + ATV/r (N=59)
30
20
FTC/TDF + ATV/r (N=61)
10
0
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
Study week
Intent-to-treat. Missing=failure
HIV-1 RNA <50 copies/mL at Week 48
Patients with HIV-1 RNA
<50 copies/mL (%)
100
90
80
83.6%
74.6%
70
60
50
40
MVC + ATV/r (N=59)
30
20
FTC/TDF + ATV/r (N=61)
10
0
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
Study week
Intent-to-treat. Missing=failure
Patients with HIV-1 RNA <50 copies/mL (%)
HIV-1 RNA <50 copies/mL at Week 24 and
Week 48 according to baseline viral load
100
94.9
80
FTC/TDF + ATV/r
37/39
90
81.4
81.3
35/43
13/16
70
77.3
17/22
60
50
40
30
20
10
0
Week 24
Week 48
<100,000 copies/mL
Week 24
Week 48
≥100,000 copies/mL
Baseline HIV-1 RNA
Intent-to-treat. Missing=failure
MVC + ATV/r
Patients with HIV-1 RNA <50 copies/mL (%)
HIV-1 RNA <50 copies/mL at Week 24 and
Week 48 according to baseline viral load
100
94.9
37/39
90
80
35/43
34/39
76.7
33/43
70
FTC/TDF + ATV/r
87.2
81.4
81.3
13/16
77.3
17/22
77.3
68.8
17/22
11/16
60
50
40
30
20
10
0
Week 24
Week 48
<100,000 copies/mL
Week 24
Week 48
≥100,000 copies/mL
Baseline HIV-1 RNA
Intent-to-treat. Missing=failure
MVC + ATV/r
Patients with HIV-1 RNA <400 copies/mL (%)
HIV-1 RNA <400 copies/mL at Week 24 and
Week 48 according to baseline viral load
100
90
90.7
94.9
93.8
37/39
15/16
39/43
90.9
20/22
80
70
60
50
40
30
20
10
0
Week 24
Week 48
<100,000 copies/mL
Week 24
Week 48
≥100,000 copies/mL
Baseline HIV-1 RNA
Intent-to-treat. Missing=failure
MVC + ATV/r
FTC/TDF + ATV/r
Patients with HIV-1 RNA <400 copies/mL (%)
HIV-1 RNA <400 copies/mL at Week 24 and
Week 48 according to baseline viral load
100
90
90.7
94.9
37/39
39/43
80
93.8
88.4
87.2
38/43 34/39
15/16
90.9
20/22
93.8
15/16
FTC/TDF + ATV/r
86.4
19/22
70
60
50
40
30
20
10
0
Week 24
Week 48
<100,000 copies/mL
Week 24
Week 48
≥100,000 copies/mL
Baseline HIV-1 RNA
Intent-to-treat. Missing=failure
MVC + ATV/r
Outcomes for all patients with VL >50 copies/mL
at Week 48
HIV-1 RNA, copies/mL
MVC+ATV/r
Aa
B
C
D
E
Fb
G
H
I
FTC/TDF+ATV/r
J
K
L
aPatient
bPatient
Week 48
Post Week 48
69
144
57
81
167
87
61
51
58
497 (W84)
<50 (W96)
<50 (W72)
<50 (W84)
<50 (W96)
274 (W96)
<50 (W72)
<50 (W84)
<50 (W84)
52
780
55
<50 (W84)
<50 (W96)
<50 (W84)
discontinued at Week 84 due to insufficient clinical response
discontinued at Week 96
Median change from baseline
in CD4 cell count (cells/μL)
Change in median CD4+ cell count over time
(LOCF)
250
200
187
173
150
100
MVC + ATV/r (N=59)
50
FTC/TDF + ATV/r (N=61)
0
0
2
4
6
8
10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
Study week
Intent-to-treat. LOCF, last observation carried forward
No genotypic or phenotypic resistance
observed through Week 48
• 3 patients in the MVC arm and 3 patients in the FTC/TDF
arm were identified for virologic analysesa
Change in
tropism
0
aPatients
Susceptibility to
drug retained
Development of resistance mutations
MVC
FTC/TDF
MVC
ATV
TDF
FTC
3
3
0
0
0
0
who discontinued from the study early with sufficient VL (≥500 copies/mL). Assays (ESTA,
Monogram GenoSeq and/or PhenoSenseGT) performed at screening/baseline and at the last on-treatment
time point were available
Safety
MVC + ATV/r
n=60
FTC/TDF + ATV/r
n=61
Any AE, n (%)
58 (96.7)
60 (98.7)
Serious AE, n (%)
10 (16.7)
12 (19.7)
Grade 3 or 4 AE, n (%)
29 (48.3)
18 (29.5)
Discontinued due to AE, n (%)
2 (3.3)
0
Hyperbilirubinemia, n (%)
AE related
Grade 3 or 4 AE related
Grade 3 or 4 laboratory*
27 (45.0)
22 (36.7)
39 (65.0)
21 (34.4)
12 (19.7)
32 (52.5)
• 7 patients in the MVC + ATV/r group and 3 patients in the FTC/TDF group switched off of ATV/r
therapy per protocol due to either tolerability or unconjugated hyperbilirubinemia
*DAIDS grading
Modern dual-therapy studies: 48-week results
No. of patients with post-BL
resistance mutations/no. of
virologic failuresa
HIV-1 RNA <50 copies/mL
ACTG 51421
N=500
22/46
39/56
16/78
EFV + 2 NRTI
EFV + LPV/r
LPV/r + 2 NRTI
COOL2
N=143
EFV + TDF/3TC
0/0
3/3
EFV +TDF
0
afrom
10
20
evaluable samples
BL, baseline
30
40
50
% of patients
60
70
80
90
100
1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J
Antimicrob Chemother, 2009.
Modern dual-therapy studies: 48-week results
No. of patients with post-BL
resistance mutations/no. of
virologic failuresa
HIV-1 RNA <50 copies/mL
ACTG 51421
N=500
22/46
39/56
16/78
EFV + 2 NRTI
EFV + LPV/r
LPV/r + 2 NRTI
COOL2
N=143
EFV + TDF/3TC
EFV +TDF
0/0
3/3
SPARTAN3
N=94 (2:1)
ATV/r QD + FTC/TDF
0/8
4/11
PROGRESS4
N=206
LPV/r BID + FTC/TDF
LPV/r BID + RAL BID
1/3
1/4
ACTG 52625
N=112
DRV/r QD + RAL
DRV/r QD + RAL BID
5/28
ATV BID + RAL BID
0
afrom
10
20
evaluable samples
BL, baseline
30
40
50
% of patients
60
70
80
90
100
1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob
Chemother, 2009. 3. Kozal THLBB204, IAS 2010.
4. Reynes MOAB0101, IAS, 2010. 5. Taiwo Abstract 551, CROI, 2011.
Modern dual-therapy studies: 48-week results
No. of patients with post-BL
resistance mutations/no. of
virologic failuresa
HIV-1 RNA <50 copies/mL
ACTG 51421
N=500
22/46
39/56
16/78
EFV + 2 NRTI
EFV + LPV/r
LPV/r + 2 NRTI
COOL2
N=143
EFV + TDF/3TC
EFV +TDF
0/0
3/3
SPARTAN3
N=94 (2:1)
ATV/r QD + FTC/TDF
0/8
4/11
PROGRESS4
N=206
LPV/r BID + FTC/TDF
LPV/r BID + RAL BID
1/3
1/4
ACTG 52625
N=112
DRV/r QD + RAL
DRV/r QD + RAL BID
5/28
VEMAN6
N=37
1078
N=121
ATV BID + RAL BID
0/0
0/0
LPV/r BID + FTC/TDF
LPV/r BID + MVC QD
0/2
0/2
ATV/r QD + FTC/TDF
ATV/r QD + MVC QD
0
afrom
10
20
evaluable samples
BL, baseline
30
40
50
% of patients
60
70
80
90
100
1. Riddler et al, N Engl J Med, 2008.
2. Girard et al, J Antimicrob Chemother, 2009. 3. Kozal THLBB204, IAS 2010.
4. Reynes MOAB0101, IAS, 2010. 5. Taiwo Abstract 551, CROI, 2011. 6. Nozza CDB325, IAS, 2011
Conclusions
• 48-week results of this pilot study of MVC + ATV/r support
the antiviral activity of this once-daily, two-drug
combination in treatment-naïve patients
• No resistance nor change in phenotypic tropism was
observed
• No new unexpected safety events
• A Phase III study (A4001095; NCT01345630) will start in
Q3/4 2011
– MVC + DRV/r QD vs FTC/TDF + DRV/r QD
– Estimated enrollment of 804
Acknowledgments
• Thanks to the patients and investigators who participated in this
study
• Editorial support was provided by Clemence Hindley of
Complete Medical Communications and was funded by ViiV
Healthcare
Backups
Creatinine clearance
Study week
0
4
8
12
16
20
24
28
32
36
40
44
Mean change from baseline in
creatinine clearance (mL/min)
0
-2
-4
MVC + ATV/r (N=60)
-6
-8
-10
-12
-14
FTC/TDF + ATV/r (N=61)
48
Pharmacokinetics
MVC concentration (ng/mL)
10,000
1000
*
100
10
7.65 ng/mL (in vivo IC50)1
1
0
4
8
12
16
20
24
Hours
• All 15 patients had plasma MVC concentrations above the in vivo IC50 across the dosing Interval (150 mg QD +
ATV/r)2
• There were 139 sparse PK samples with full dose and time data collected at the 2,12 and 24 week visits yielding
concentrations from 13.7 to 933 ng/mL with samples taken from 0-32 hours after dose3
* One patient accidentally dosed with MVC prior to the
1. Rosario et al, J Acquir Immune Defic Syndr, 2006.
2. Vourvahis, Abstract 37 IWCPHIV, 2010.
24-hour 3.
sample
draw
Weatherley,
Abstract P_05 IWCPHIV, 2011
Definition of Virologic Failure
• HIV-1 RNA <1.0 log10 decrease from Baseline at Week 4
or thereafter (confirmed by a second measurement
taken no more than 14 days after the first measurement);
or
• Failure to achieve HIV-1 RNA <400 copies/mL at Week 24,
(confirmed by asecond measurement taken no more
than 14 days after the first measurement);
• An increase in HIV-1 RNA to detectable levels (1,000
copies/mL on 2 consecutive measurements taken no
more than 14 days apart) in subjects previously
confirmed to have undetectable levels of <400
copies/mL on 2 consecutive visits.
Patients switching from ATV/r
• 10 patients switched from ATV/r (7 in the MVC arm and
3 in the FTC/TDF arm) due to either tolerability issues or
unconjugated hyperbilirubinemia
– 8 switched to DRV/r
– 2 switched to LPV/r
• All 10 patients had reached HIV-1 RNA <50 copies/mL
prior to switching
HIV-1 RNA <50 copies/mL at Week 24 and
Week 48 according to baseline CD4 count
n/N
4/5
5/5
40/48
46/49
Median CD4 cell count (cells/mm3)
Median CD4+ cell count over time (LOCF)
600
550
Week 48
500
450
400
Week 24
MVC + ATV/r = 580
MVC + ATV/r = 537
FTC/TDF + ATV/r = 580
FTC/TDF + ATV/r = 536
350
300
MVC + ATV/r (N=59)
250
FTC/TDF + ATV/r (N=61)
200
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48
Study week
Intent-to-treat. LOCF, last observation carried forward
Responders at Week 24 but not Week 48
HIV-1 RNA, copies/mL
Week 24
Week 32
Week 40
Week 48
<50
<50
<50
<50
<50
56
<50
<50
<50
57
<50
<50
144
81
61
58
<50
<50
<50
<50
<50
<50
<50
<50
N/A
<50
<50
<50
N/A
780b
55
N/A
MVC+ATV/r
A
B
C
D
FTC/TDF+ATV/r
Ea
F
G
Ha
N/A, not available; W, week
aPatient discontinued prior to Week 48
bResult of repeat test 13 days later was <50 copies/mL
Responders at Week 24 but not Week 48
HIV-1 RNA, copies/mL
Week 24
Week 32
Week 40
Week 48
Post Week 48
<50
<50
<50
<50
<50
56
<50
<50
<50
57
<50
<50
144
81
61
58
<50 (W96)
<50 (W84)
<50 (W72)
<50 (W84)
<50
<50
<50
<50
<50
<50
<50
<50
N/A
<50
<50
<50
N/A
780b
55
N/A
N/A
<50 (W96)
<50 (W84)
N/A
MVC+ATV/r
A
B
C
D
FTC/TDF+ATV/r
Ea
F
G
Ha
N/A, not available; W, week
aPatient discontinued prior to Week 48
bResult of repeat test 13 days later was <50 copies/mL
• 7/9 (MVC + ATV/r) and 3/3 (FTC/TDF + ATV/r) patients with HIV-1 RNA ≥50 copies/mL at
Week 48 had HIV-1 RNA <50 copies/mL at their latest visit. HIV-1 RNA levels for the remaining
2 patients were 274 copies/mL (W96), and 497 copies/mL (W84)