Transcript 47th ICAAC Chicago, USA, September 17–20, 2007 Efficacy and Safety of Maraviroc in AntiretroviralExperienced Patients Infected With CCR5-Tropic HIV-1: 48-Week Results of MOTIVATE.

47th ICAAC
Chicago, USA, September 17–20, 2007
Efficacy and Safety of Maraviroc in AntiretroviralExperienced Patients Infected With CCR5-Tropic
HIV-1: 48-Week Results of MOTIVATE 1
J Lalezari1, J Goodrich2 , E DeJesus3, R Gulick4, H Lampiris5, M Saag6,
N Bellos7, J Nadler8, P Tebas9, B Trottier10, M Wohlfeiler11, C Ridgeway12,
M McHale12, E van der Ryst12, H Mayer2, on behalf of the MOTIVATE 1
Study Team
1Quest
Clinical Research, UCSF, San Francisco, CA, USA
Global Research and Development, New London, CT, USA
3Orlando Immunology Center, Orlando, FL, USA
4Weill Medical College of Cornell University, New York, NY, USA
5San Francisco Veterans Affairs Medical Center, UCSF, San Francisco, CA, US
6University of Alabama at Birmingham, Birmingham, AL, USA
7Southwest Infectious Disease Associates, Dallas, TX, USA
8University of South Florida, Tampa, FL, USA
9University of Pennsylvania, Philadelphia, PA, USA
10Clinique Medicale L'Actuel, Montreal, QC, CANADA
11Wohlfeiler, Piperato & Associates, North Miami Beach, FL, USA
12Pfizer Global Research and Development, Sandwich, UK
2Pfizer
2
Background
● MOTIVATE 1 is one of two randomized, double-blind, placebo-controlled,
Phase 3 studies investigating the safety and efficacy of the CCR5
antagonist maraviroc, in treatment-experienced patients with R5 HIV-1
● In a planned interim analysis at 24 weeks1, maraviroc (QD and BID)
+ OBT vs OBT alone demonstrated
– significantly greater virologic suppression rates
– significantly greater increases in CD4+ count
– no clinically relevant differences in safety profile
● The MOTIVATE 1 primary efficacy endpoint is the change from baseline
in HIV-1 RNA at 48 weeks
1. Lalezari J et al. 14th CROI 2007; Presentation 104bLB
3
MOTIVATE 1 Trial Design
OBT* + placebo
Randomization
1:2:2
N=601
OBT* + maraviroc (150 mg† QD)
OBT* + maraviroc (150 mg† BID)
Screening
(6 weeks)
0
24w
48w
Patient eligibility criteria:
• R5 HIV-1 infection
• Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeks
• HIV-1 RNA ≥5,000 copies/mL • Resistance to and/or ≥ 6 months’ experience with ≥ one ARV
from three classes (≥ two for PIs)
Patients stratified by:
• Enfuvirtide use in OBT
• HIV-1 RNA < and ≥100,000 copies/mL at screening
* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of RTV not counted as an ARV)
† Patients receiving a PI (except TPV) and/or delavirdine in their OBT received 150 mg dose of MVC,
all other patients received 300 mg dose of MVC
4
Demographics and Baseline Characteristics
Includes all patients who received at least one dose of study medication (full analysis set)
OBT alone
N=118
MVC QD + OBT
N=232
MVC BID + OBT
N=235
46 (31–71)
46 (19–75)
46 (25–69)
Male, n (%)
106 (90)
210 (91)
212 (90)
White, n (%)
99 (84)
187 (81)
197 (84)
160
(1675)
4.84
(3.466.02)
42
65
11
168
(1812)
4.85
(3.206.75)
44
69
10
Not Permitted
150
(2678)
4.86
(3.266.88)
46
75
11
Treated N=585
§
Mean age, yrs (range)
Median CD4+ count*,
cells/mm3 (range)
Mean HIV-1 RNA*,
log10 copies/mL (range)
Enfuvirtide in OBT, %
≤2 active drugs in OBT†, %
Tipranavir use in OBT, %
Darunavir use in OBT
§ Two
MOTIVATE 1-Week 48
patients (1 MVC QD, 1 OBT alone) were assigned to the
wrong treatment group due to a transcription error
* Calculated for each patient as the mean of up to three pre-dose
assessments (screening, randomization, and baseline)
† According to overall susceptibility score
5
Mean Change from Baseline in HIV-1 RNA
Includes all patients who received at least one dose of study medication
OBT alone (N=118)
MVC QD + OBT (N=232)
MVC BID + OBT (N=235)
Mean change in HIV-1 RNA
from baseline (log10 copies/mL)
Study week
24
0.0
48
-0.5
-1.0
-0.80
-1.03
-1.5
-2.0
-2.5
MOTIVATE 1-Week 48
-1.82
-1.66
-1.95
Difference: -0.85*
(97.5% CI: -1.22, -0.49)
Difference: -0.79*
(97.5% CI: -1.14, -0.44)
Difference: -0.92*
(97.5% CI: -1.28, -0.57)
-1.82
Difference: -1.02*
(97.5% CI: -1.39, -0.66)
HIV-1 RNA value imputed as baseline if patient discontinued before 48 weeks
*Treatment difference vs OBT alone
6
Percentage of Patients with Undetectable HIV-1 RNA
Includes all patients who received at least one dose of study medication
Number of patients remaining on study treatment at Week 48:
OBT alone, 27 (30%); MVC QD + OBT, 109 (60%); MVC BID + OBT, 127 (66%)
100
90
<400 copies/mL
Patients (%)
80
70
60.4%*
60
50
40
30
54.7%*
57.5%*
50.9%*
31.4%
20
10
0
100
90
22.0%
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (weeks)
MOTIVATE 1-Week 48
MVC BID + OBT (N=235)
MVC QD + OBT (N=232)
OBT alone (N=118)
<50 copies/mL
80
70
60
50
40
30
20
10
0
48.5%*
46.8%*
42.2%#
41.8%*
24.6%
16.1%
0 4 8 12 16 20 24 28 32 36 40 44 48
Time (weeks)
HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 48 weeks
*P<0.0001 vs OBT alone
#P<0.0006 vs OBT alone
7
Mean Change from Baseline in CD4+ Count
Includes all patients who received at least one dose of study medication
OBT alone (N=116)
Mean change from
baseline in CD4+ count (cells/mm3)
MVC QD + OBT (N=227)
MVC BID + OBT (N=233)
150
Difference: +55 *
(95% CI: +30, +79)
107
100
50
Difference: +59 *
(95% CI: +35, +83)
Difference: +69 *
Difference: +59 * (95% CI: +44, +93)
(95% CI: +34, +84)
113
111
122
54
52
0
24
48
Study week
MOTIVATE 1-Week 48
Last observation carried forward
* P<0.0001 vs OBT alone
Percentage of Patients With HIV-1 RNA <50 copies/mL at
Week 48 According to Screening HIV-1 RNA*
8
Includes all patients who received at least one dose of study medication and had a post-baseline observation
OBT alone
Patients (%)
MVC QD + OBT
MVC BID + OBT
100
90
80
70
60
50
40
30
20
10
0
N=
MOTIVATE 1-Week 48
<100,000
copies/mL
55
≥100,000
copies/mL
Total
population
60
45
31
27
49
32
19
7
70
135 139
46
93
95
116
228
234
Last observation carried forward
* Protocol-defined randomization stratum
MOTIVATE 1 and 2: Proportion of Patients Receiving ENF With
Undetectable HIV-1 RNA at Week 48 According to ENF First Use
Patients (%)
OBT alone
N=
100
90
80
70
60
50
40
30
20
10
0
Maraviroc QD + OBT
9
Maraviroc BID + OBT
<400 copies/mL
<50 copies/mL
71 71
64
61
43
36
35
32
27
3
59 91 108
30 75 72
ENF first use ENF experienced/
resistance
MOTIVATE 1 & 2-Week 48
25
3
59 91 108
30 75 72
ENF first use ENF experienced/
resistance
Last observation carried forward
10
Safety Analyses Unadjusted for Duration of Exposure
Includes all patients who received at least one dose of study medication
All causalities and severities
OBT
alone
N=118
64
MVC QD
+ OBT
N=232
168
MVC BID
+ OBT
N=235
169
Patients with AEs
Patients discontinuing due to AEs
86%
6%
90%
6%
92%
5%
Patients with grade 3 AEs
25%
17%
23%
Patients with grade 4 AEs
7%
9%
10%
Patients with SAEs
16%
14%
17%
Patients with Category C events
Deaths*
5%
1%
5%
1%
5%
2%
Total exposure, patient-years
MOTIVATE 1-Week 48
AEs = adverse events; SAEs = serious adverse events
*Includes deaths reported up to 28 days after stopping study drug
No deaths were related to study drug according to the investigator
Incidence of Adverse Events Occurring in ≥10% of Patients
in Any Group, Unadjusted for Exposure
11
Includes all patients who received at least one dose of study medication
Total exposure in patient-years: OBT alone 64, MVC QD + OBT 168, MVC BID + OBT 169
OBT alone (N=118)
MVC QD + OBT (N=232)
MVC BID + OBT (N=235)
50
Patients (%)
40
30
20
10
MOTIVATE 1-Week 48
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RTI = respiratory tract infection; ISR = injection site reaction
12
Number of Category C Events
Includes all patients who received at least one dose of study medication
OBT
alone
N=118
MVC QD
+ OBT
N=232
MVC BID
+ OBT
N=235
Total exposure, patient-years
Cryptosporidial gastroenteritis
Cytomegalovirus infection*
Herpes simplex
64
0
0
2
168
1
1
2
169
0
1
5
Mycobacterium avium
0
0
1
Esophageal candidiasis
0
6
1
Pneumocystis jiroveci pneumonia
0
0
1
Pneumonia
Progressive multifocal
leukoencephalopathy
Kaposi’s sarcoma
0
2
1
0
0
1
2
0
0
Lymphoma*
2
1
1
Event, n
Total number of events
Total number of patients, n (% )
MOTIVATE 1-Week 48
6
6 patients (5.1%)
13
12
11 patients (4.7%) 12 patients (5.1%)
* Includes T-cell and diffuse large B-cell lymphomas
Maximum Liver Function Test Values Over 48 Weeks
Without Regard to Baseline
13
OBT
alone
N=116*
MVC QD
+ OBT
N=228*
MVC BID
+ OBT
N=234*
AST:
Grade 3 (5–10 x ULN†)
Grade 4 (>10 x ULN†)
4 (3.4)
0
7 (3.1)
3 (1.3)
7 (3.0)
4 (1.7)
ALT:
Grade 3 (5–10 x ULN†)
Grade 4 (>10 x ULN†)
2 (1.7)
0
11 (4.8)
1 (0.4)
5 (2.1)
3 (1.3)
Total bilirubin:
Grade 3 (2.5–5 x ULN†)
Grade 4 (>5 x ULN†)
4 (3.4)
2 (1.7)
17 (7.4)
2 (0.9)
10 (4.3)
2 (0.9)
All causalities, n (%)
Unadjusted for duration of exposure
* Total patients evaluated for each laboratory parameter
MOTIVATE 1-Week 48
†
Upper limit of normal
MOTIVATE 1 and 2: Change in CD4+ Cell Count from
Baseline by Tropism Result at Time of Failure
14
Mean change from baseline in CD4+ count in
patients with treatment failure (cells/mm3 )
Tropism result,
Baseline → Treatment Failure
All treatment failures*
R5 → R5
R5 → D/M or X4
MOTIVATE 1 & 2-Week 48
OBT alone
N=271
MVC QD + OBT
N=477
MVC BID + OBT
N=487
+24
(n=111)
+25
(n=89)
+61
(n=6)
+64
(n=92)
+77
(n=33)
+47
(n=35)
+74
(n=96)
+133
(n=24)
+57
(n=41)
* Includes patients with non-reportable/non-phenotypable tropism result at baseline and
patients with non-reportable/non-phenotypable/missing tropism result at time of failure
15
MOTIVATE 1: Summary of 48-Week Primary Analysis
● Maraviroc (BID or QD) + OBT provided significantly greater virologic
suppression rates and increases in CD4+ count compared to OBT alone
at 48 weeks in this treatment-experienced population
● No new or unique safety findings emerged
– Adverse events, serious adverse events, and lab abnormalities (including grade 3/4
transaminase elevations) occurred with similar frequency between treatment groups
– Category C (AIDS-defining events) were balanced across treatment groups
● These results demonstrate that treatment with maraviroc + OBT
provides sustained antiretroviral efficacy and tolerability in treatmentexperienced patients
16
Acknowledgments
● Investigators and study site staff
● Patients who participated in the study
● Colleagues from Monogram Biosciences: J Whitcomb, E Coakley,
C Petropoulos
● R Harrigan, BC Centre for Excellence in HIV
● Colleagues from Quintiles
● Colleagues from Pfizer: S Felstead, A Bullivant, I Oborska, K George,
M Westby, K Turner, D Lindell, D Paige, S Nuttall, J Merson, L Kapili,
M Dunne