Transcript Slide 1

9TH INTERNATIONAL CONGRESS
ON DRUG THERAPY IN HIV INFECTION
November 9–13, 2008
Glasgow, UK
Efficacy and Safety of Maraviroc in TreatmentExperienced (TE) Patients Infected with R5 HIV-1:
96-week Combined Analysis of the MOTIVATE 1 &
2 Studies
WD Hardy1, R Gulick2, H Mayer3, G Fätkenheuer4, M Nelson5, J Heera3, N Rajicic6, J Goodrich3 1
Cedars-Sinai Medical Center/Geffen School of Medicine, UCLA, Los Angeles, CA, USA; 2 Weill Medical
College of Cornell University, New York, CA, USA; 3 Pfizer Global Research and Development, New
London, CT, USA; 4 University of Cologne, Köln, Germany; 5 Chelsea & Westminster Hospital, London,
UK; 6 Pfizer Inc., New York, NY, USA
MOTIVATE 1 & 2: Trial Design
OBT* + placebo
Randomization
1:2:2
MOTIVATE 1 N=601
MOTIVATE 2 N=474
OBT* + maraviroc (150 mg† QD)
OBT* + maraviroc (150 mg† BID)
Screening
6 weeks
0
Week 48
Week 96
Patients were stratified by enfuvirtide use and HIV-1 RNA < and ≥100,000 copies/mL
Patient eligibility criteria:
• R5 HIV-1 infection
• HIV-1-RNA ≥5,000 copies/mL
• Stable pre-study antiretroviral (ARV) regimen, or no ARVs for ≥4 weeks
• Resistance to and/or ≥6 months’ experience with ≥one ARV from three classes (≥two for protease
inhibitors[PIs])
* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of ritonavir not counted as an ARV)
† Patients receiving a PI (except tipranavir) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients
received 300 mg dose of MVC
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96
MOTIVATE 1 & 2: Percentage of Patients with
HIV-1 RNA <50 copies/mL at Week 48
100
MVC BID + OBT (N=426)
MVC QD + OBT (N=414)
Placebo + OBT (N=209)
90
80
Patients (%)
70
60
50
45.5%*
43.2%*
40
30
20
16.7%
10
*P<0.0001 vs placebo
0
0
4
8
12
16
20 24 28 32
Time (weeks)
Adapted from Hardy et al. CROI 2008. Abstract 792.
36
40
44
48
MOTIVATE 1 and 2 Week 48
MOTIVATE 1 & 2: Week-96 Analyses
Two analyses were conducted to characterize the Week-96 combined
MOTIVATE 1 and 2 populations:
●
Efficacy Analysis
This analysis includes patients receiving MVC QD and BID who had
undetectable viral load (HIV-1 RNA <50 copies/mL ) at Week 48 and
were followed until Week 96
●
Safety Analysis
This analysis includes all blinded data for study participants
according to their original randomization and includes data from
patients who continued to receive blinded therapy beyond Week 48.
It does not include any open-label treatment data. This results in a
distribution of patients in the study with different exposures to blinded
study drug. The study was unblinded when the last patient to be
randomized reached Week 48
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Efficacy
MOTIVATE 1 & 2: Trial Design
OBT* + placebo
Randomization
1:2:2
MOTIVATE 1 N=601
MOTIVATE 2 N=474
OBT* + maraviroc (150
mg†
QD)
OBT* + maraviroc (150 mg† BID)
Screening
6 weeks
0
Efficacy data include all
patients who reached
Week 48 with HIV-1RNA
<50 copies/mL and
continued on blinded
therapy or
open-label MVC BID
Week 48
Week 96
Patients were stratified by enfuvirtide use and HIV-1 RNA < and ≥100,000 copies/mL
Patient eligibility criteria:
• R5 HIV-1 infection
• HIV-1-RNA ≥5,000 copies/mL
• Stable pre-study antiretroviral (ARV) regimen, or no ARVs for ≥4 weeks
• Resistance to and/or ≥6 months’ experience with ≥one ARV from three classes (≥two for protease
inhibitors [PIs])
* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of ritonavir not counted as an ARV)
† Patients receiving a PI (except tipranavir) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients
received 300 mg dose of MVC
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Efficacy
MOTIVATE 1 & 2: Trial Design
Randomization
1:2:2
MOTIVATE 1 N=601
MOTIVATE 2 N=474
Screening
6 weeks
OBT* + maraviroc (150 mg† QD)
239/414 (57.7%)
open-label MVC BID
OBT* + maraviroc (150 mg† BID)
259/426 (60.8%)
open-label MVC BID
0
Week 48
Week 96
Patients were stratified by enfuvirtide use and HIV-1 RNA < and ≥100,000 copies/mL
Patient eligibility criteria:
• R5 HIV-1 infection
• HIV-1-RNA ≥5,000 copies/mL
• Stable pre-study antiretroviral (ARV) regimen, or no ARVs for ≥4 weeks
• Resistance to and/or ≥6 months’ experience with ≥one ARV from three classes (≥two for protease
inhibitors [PIs])
* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of ritonavir not counted as an ARV)
† Patients receiving a PI (except tipranavir) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients
received 300 mg dose of MVC.
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Efficacy
MOTIVATE 1 & 2: Percentage of Patients with HIV-1
RNA <50 copies/mL at Week 96
Includes all patients who received at least one dose of study medication
MVC BID + OBT (N=426)
MVC QD + OBT (N=414)
Placebo + OBT (N=209)
100
90
Option to switch
to open-label MVC BID
Patients (%)
80
70
60
50
45.1%
40
43.7%
46.5%
41.3%
38.9%
43.5%
30
20
23.0%
16.7%
10
7.2%
0
0
8
16
24
32
40
48
56
64
72
80
88
96
Time (weeks)
In this analysis, non-completers were categorized as failures
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Efficacy
MOTIVATE 1 & 2: Clinical Outcome At Week 96 of
Patients with HIV-1 RNA <50 copies/mL at Week 48
Maraviroc groups include patients on blinded therapy and open-label MVC BID
100
90
80
Patients (%)
70
7.0%
10.5%
0.6%
2.8%
1.2%
81.4%
9.9%
86.7%
Discontinuation due
to lack of efficacy
On study, not failed
60
HIV-1 RNA 50 400 copies/mL
50
HIV-1 RNA <50 copies/mL
40
30
20
10
0
MVC QD + OBT MVC BID + OBT
N=172
N=181
Lack of efficacy = HIV-1 RNA levels of at least three times the baseline HIV-1 RNA level
Does not include patients who discontinued for non-efficacy reasons: adverse events (n=4); withdrew/lost to follow up
(n=8); other reasons (n=4); no discontinuation and no data at 96 weeks (N=4)
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Efficacy
MOTIVATE 1 & 2: Week 96 Analyses
Two analyses were conducted to characterize the Week 96 combined
MOTIVATE 1 and 2 populations:
●
Efficacy Analysis
This analysis includes patients receiving MVC QD and BID, who had
undetectable viral load (HIV-1 RNA <50 copies/mL ) at Week 48 and
were followed until Week 96.
●
Safety Analysis
This analysis includes all blinded data for study participants
according to their original randomization and includes data from
patients who continued to receive blinded therapy beyond Week 48.
It does not include any open-label treatment data. This results in a
distribution of patients in the study with different exposures to blinded
study drug. The study was unblinded when the last patient to be
randomized reached Week 48.
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Safety
9
MOTIVATE 1 & 2: Trial Design
Randomization
1:2:2
MOTIVATE 1 N=601
MOTIVATE 2 N=474
Screening
6 weeks
OBT* + placebo
98/209 (46.9%)
open-label MVC BID
OBT* + maraviroc (150 mg† QD)
239/414 (57.7%)
open-label MVC BID
OBT* + maraviroc (150 mg† BID)
259/426 (60.8%)
open-label MVC BID
0
Week 48
Week 96
Patients were stratified by enfuvirtide use and HIV-1 RNA < and ≥100,000 copies/mL
Patient eligibility criteria:
• R5 HIV-1 infection
• HIV-1-RNA ≥5,000 copies/mL
• Stable pre-study antiretroviral (ARV) regimen, or no ARVs for ≥4 weeks
• Resistance to and/or ≥6 months’ experience with ≥one ARV from three classes (≥two for protease
inhibitors [PIs])
* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of ritonavir not counted as an ARV)
† Patients receiving a PI (except tipranavir) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients
received 300 mg dose of MVC.
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Safety
MOTIVATE 1 & 2:
Duration of Exposure to Study Drug
Median (bars) and range (lines) of study treatment
duration at indicated study time point
20
Week 48
62
Placebo + OBT (N=209)
MVC QD + OBT (N=414)
MVC BID + OBT (N=426)
48
60
48
56
End of Blinded
Therapy
20
132
73
134
73
135
0
8
16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136
Time (weeks)
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Safety
MOTIVATE 1 & 2: Incidence of Malignancies at
Week 48 and End of Blinded Therapy
Includes all patients who received at least one dose of study medication
Placebo + OBT (N=209)
Patients (%)
Unadjusted incidence
10
8
6
4
2
0
MVC QD + OBT (N=414)
MVC BID + OBT (N=426)
5.3
4.8
N=209
2.9
3.3
414
426
Week 48
209
4.3
414
4.5
426
End of blinded therapy
Adjusted incidence
9.3
Rate per 100
patient-years
10
8
6
4
2
0
Total patient-years
7.1
111
4.1
4.6
300
309
Week 48
60
3.5
3.6
522
551
End of blinded therapy
If the same patient in a given treatment arm had more than one occurrence in the same event category,
only the most severe occurrence was taken
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Safety
MOTIVATE 1 & 2: Incidence of Category C (AIDS-defining)
Events at Week 48 and End of Blinded Therapy
Includes all patients who received at least one dose of study medication
Placebo + OBT (N=209)
MVC QD + OBT (N=414)
MVC BID + OBT (N=426)
Patients (%)
Unadjusted incidence
10
8
6
4
2
0
7.7
7.5
5.2
N=
209
18
14.9
16
14
12
10
8
6
4
2
0
Total patient-years 111
Rate per 100
patient-years
8.1
7.0
414
Week 48
426
5.9
209
414
End of blinded therapy
426
Adjusted incidence
11.0
10.0
7.6
300
Week 48
309
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
6.2
5.3
160
522
551
End of blinded therapy
MOTIVATE 1 and 2 Week 96 Safety
MOTIVATE 1 & 2: Incidence of LFT Abnormalities (Without
Regard to Baseline) at Week 48 and End of Blinded Therapy
Incidence (adjusted)
Incidence (unadjusted)
Event counts adjusted to 100 years
of patient exposure
n (%)
Placebo
+ OBT
MVC QD
+ OBT
MVC BID
+ OBT
Placebo
+ OBT
MVC QD
+ OBT
MVC BID
+ OBT
AST: >3.0 x ULN
17 (8)
39 (10)
45 (11)
16.2
13.8
15.7
ALT: >3.0 x ULN
13 (6)
29 (7)
37 (9)
12.4
10.1
12.7
Total bilirubin: >1.5 x
ULN
30 (14)
66 (16)
51 (12)
31.9
25.3
18.5
AST: >3.0 x ULN
19 (9)
45 (11)
46 (11)
13.3
9.4
9.5
ALT: >3.0 x ULN
15 (7)
37 (9)
39 (9)
10.0
7.8
7.8
Total bilirubin: >1.5 x
ULN
31 (15)
68 (17)
54 (13)
23.8
16.0
11.3
Week 48
End of blinded therapy
ULN, upper limit of normal
Total patient-years of exposure to study drug at Week 48: Placebo + OBT 111; MVC QD + OBT 300; MVC BID + OBT 309
Total patient-years of exposure to study drug at at end of blinded therapy: Placebo + OBT 160; MVC QD + OBT 522; MVC BID + OBT 551
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Safety
MOTIVATE 1 & 2: Adverse Events Occurring in
≥5% Patients at End of Blinded Therapy
Includes all patients who received at least one dose of study medication
Placebo + OBT (N=209)
MVC QD + OBT
(N=414)
MVC BID + OBT (N=426)
50
40
Patients
(%)
Unadjusted incidence
30
20
10
0
Nausea
Vomiting
Fatigue
Rate per 100
patient-years
50
NasoUpper RTI
pharyngitis
Dizziness
Headache
Rash
Dizziness
Headache
Rash
Exposure adjusted incidence
40
30
20
10
0
Nausea
Vomiting
Fatigue
NasoUpper RTI
pharyngitis
RTI, respiratory tract infection
If the same patient in a given treatment had more than one occurrence in the same preferred term event category, only the most severe occurrence is
taken. Event counts are adjusted to 100 years of patient exposure. Includes data up to 7 days after last dose of study drug.
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96 Safety
MOTIVATE 1 & 2 Week 96: Summary
Efficacy Analysis
● Maraviroc + OBT results in durable viral suppression through 96
weeks in treatment-experienced patients with R5 HIV-1.
– 87% of patients in the BID arm who were fully suppressed at Week
48 remained suppressed at Week 96.
Safety Analysis
● Pooled analyses revealed no new or unique safety signals between
Week 48 and end of blinded therapy.
– Category C events, malignancies, and LFT abnormalities occurred
with similar frequency among treatment groups when not adjusted for
the longer duration of exposure in the maraviroc groups.
– The incidence of these events decreased between Week 48 and end
of blinded therapy.
– After adjusting for exposure, the incidence of Category C events and
malignancies was lower in the maraviroc groups compared to
placebo.
Adapted from Hardy et al. HIV-9 2008. Presentation 0425.
MOTIVATE 1 and 2 Week 96