Transcript Abstract Number WESS104 4th IAS, Sydney, July 2007 A Multicenter, Randomized, Double-Blind, Comparative Trial of a Novel CCR5 Antagonist, Maraviroc Versus Efavirenz, both.

Abstract Number WESS104
4th IAS, Sydney, July 2007
A Multicenter, Randomized, Double-Blind, Comparative Trial of a Novel
CCR5 Antagonist, Maraviroc Versus Efavirenz, both in Combination with
Combivir (Zidovudine/Lamivudine), for the Treatment of Antiretroviral-Naive
Subjects Infected with R5 HIV 1: Week 48 Results of the MERIT Study
Michael Saag1, Prudence Ive2, Jayvant Heera3, Margaret Tawadrous3, Edwin DeJesus4,
Nathan Clumeck5, David Cooper6, Andrzej Horban7, Lerato Mohapi8, Horacio Mingrone9,
Gustavo Reyes-Teran10, Sharon Walmsley11, Frances Hackman12, Elna van der Ryst12,
Howard Mayer3
of Alabama at Birmingham, Birmingham, USA
of the Witwatersrand, Clinical HIV Research Unit, Johannesburg, South Africa
3Pfizer Global Research and Development, New London, USA
4Orlando Immunology Center, Orlando, USA
5Saint-Pierre University Hospital, Infectious Diseases, Brussels, Belgium
6University of New South Wales, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia
7Hospital of Infectious Diseases, Warsaw, Poland
8University of the Witwatersrand, Perinatal HIV Research Unit, Johannesburg, South Africa
9HIV Outpatient Care Unit, Muñiz Hospital, Buenos Aires City, Argentina
10Instituto Nacional de Enfermedades Respiratorias, Center for Research in Infectious Diseases, Tlalpan, Mexico
11University of Toronto, Toronto, Canada
12Pfizer Global Research and Development, Sandwich, UK
2University
1University
2
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
48 wk
First
patient visit
Nov 2004
Primary
analysis
96 wk
Patient eligibility criteria:
• ≥16 years of age • HIV-1 RNA ≥2,000 copies/mL
• Treatment naive • No evidence of resistance to EFV, ZDV, or 3TC
• 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 pts completed 16 weeks)
*Patients experiencing toxicity to ZDV or 3TC were permitted to substitute an alternative NRTI
3
Demographics and Baseline Characteristics
Randomized: N=740
Treated: N=721
Mean age, yrs (range)
Male, n (%)
Race, n (%)
White
Black
Asian
Other
Median CD4+ count, cells/mm3 (range)
Mean HIV-1 RNA, log10 copies/mL (SD)
MERIT Study 48 weeks
EFV + CBV
N=361
37.4 (18–77)
MVC + CBV
N=360
36.7 (20–69)
259 (71.7)
256 (71.1)
198 (54.8)
133 (36.8)
5 (1.4)
25 (6.9)
254
(8–1,053)
4.88
(0.699)
204 (56.7)
123 (34.2)
6 (1.7)
27 (7.5)
241
(5–1,422)
4.86
(0.640)
4
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
5
Percentage of Patients with Undetectable HIV-1 RNA by Visit
Includes all patients who received at least one dose of study medication
<400 copies/mL
100
90
80
72.6%
70
40
30
40
30
20
10
10
0
0
MERIT Study 48 weeks
24
32
16
Time (weeks)
40
48
64.4%
50
20
24 8
69.0%
60
Patients (%)
50
80
70
70.0%
60
Patients (%)
<50 copies/mL
100
90
EFV + CBV (N=361)
MVC + CBV (N=360)
24 8
24
16
32
Time (weeks)
40
48
Missing values classified as failures/non-responders
Percentage of Patients with Undetectable HIV-1 RNA at Week 48
(Primary Endpoint)
Includes all patients who received at least one dose of study medication
100
90
80
<50 copies/mL
–3.0* (–9.5†)
–4.2* (–10.9†)
70
Patients (%)
EFV + CBV
<400 copies/mL
73.1
70.6
69.3
360
361
6
MVC + CBV
65.3
60
50
40
30
20
10
0
N=
361
360
*Difference (adjusted for randomization strata)
†Lower bound of 1-sided 97.5% confidence interval; noninferiority margin = –10%
Per-protocol analysis: <400 copies/mL difference = -4.1 (-10.5†), <50 copies/mL difference = -4.4 (-11.2†)
Intent-to-treat (ITT) analysis
MERIT Study 48 weeks
7
Mean Change in CD4+ Count from Baseline by Visit
Includes all patients who received at least one dose of study medication
Mean change in CD4+ count
from baseline (cells/mm3)
180
169 cells/mm3
160
142 cells/mm3
140
120
EFV + CBV
MVC + CBV
100
80
60
40
20
0
0 2 4
N=
N=
331 346
336 350
MERIT Study 48 weeks
8
348
351
12
348
352
16
348
352
20
24
32
348
352
348
352
Time (weeks)
348
352
40
48
348
352
348
352
LOCF
8
Mean Change in CD4+ Count from Baseline to Week 48
Includes all patients who received at least one dose of study medication
Mean change in CD4+ count
from baseline (cells/mm3)
200
150
144
*Difference: +26
(95% CI: +7, +46)
170
100
50
0
EFV + CBV
N=348
MVC + CBV
N=352
* Difference adjusted for randomization strata
MERIT Study 48 weeks
LOCF
Percentage of Patients with HIV-1 RNA <50 copies/mL
by HIV-1 RNA at Screening
Includes all patients who received at least one dose of study medication
EFV + CBV
MVC + CBV
100
<100,000 copies/mL
90
80
71.6
70
Patients (%)
9
69.6
≥100,000 copies/mL
66.6
60
59.6
50
40
30
20
10
0
N=
MERIT Study 48 weeks
211
204
150
156
Missing values classified as failures/non-responders
Percentage of Patients with HIV-1 RNA <50 copies/mL
by Geographic Region
Includes all patients who received at least one dose of study medication
EFV + CBV
MVC + CBV
100
Northern Hemisphere*
90
80
70
Patients (%)
10
Southern Hemisphere†
67.8
68.0
71.0
199
194
162
62.1
60
50
40
30
20
10
0
N=
166
*Patients at study centers in North America and Europe
†Patients at study centers in Argentina, South Africa and Australia
MERIT Study 48 weeks
Missing values classified as failures/non-responders
11
Safety Analyses
Includes all patients who received at least one dose of study medication
All causalities and severities
EFV + CBV
N=361
MVC + CBV
N=360
Patients with adverse events
340 (94.2)
331 (91.9)
Patients with grade 3 AEs, n (%)
66 (18.3)
51 (14.2)
Patients with grade 4 AEs, n (%)
24 (6.6)
22 (6.1)
Patients with SAEs, n (%)†
46 (12.7)
41 (11.3)
Patients with Category C events, n (%)
12 (3.3)
6 (1.7)
Malignancies
16 (4.4)
10 (2.8)
1
1
Deaths†*, n (%)
MERIT Study 48 weeks
AEs = adverse events; SAEs = serious adverse events
†Based on all data through 21 June 2007
*Deaths reported up to 28 days after stopping study drug; one additional death on EFV
within 28 days, date of death not captured in database
Incidence of Adverse Events Occurring in
≥10% of Patients in Any Group, Unadjusted for Exposure
Includes all patients who received at least one dose of study medication
50
Patients (%)
40
30
20
10
0
MERIT Study 48 weeks
EFV + CBV (N=361)
MVC + CBV (N=360)
12
13
Incidence of Category C AIDS-Defining Events
Includes all patients who received at least one dose of study medication
Number of patients
EFV + CBV
N=361
MVC + CBV
N=360
Category C events
12 (3.3)
6 (1.7)
Infections
8 (2.2)
5 (1.4)
8
1
1
1
0
2
0
1
4 (1.1)
1 (0.3)
2
1
1
0
1
0
Tuberculosis
Herpes simplex
Lobar pneumonia/Lower respiratory
tract infection
Pneumocystis jiroveci pneumonia
Malignancies
Hodgkin’s disease
NHL/Diffuse large B-cell lymphoma
Kaposi’s sarcoma
MERIT Study 48 weeks
14
Median Maximum Change in Fasting Lipids
EFV + CBV
MVC + CBV
30
27
Median change (mg/dL)
25
20
15
10
9
10
5
1
10
4
0
-5
N=
332
321
Total
cholesterol
MERIT Study 48 weeks
327
319
HDL
cholesterol
-3
318 311
LDL
cholesterol
-4
332
321
Triglycerides
Proportion of Patients with Grade 3 or 4 Liver Function Test
Values Without Regard to Baseline
All causalities, n (%)
Unadjusted for duration of exposure
AST:
Grade 3 >5.0 to 10.0 ULN*
Grade 4 >10.0 x ULN*
EFV + CBV
MVC + CBV
9/350 (2.6%)
2/350 (0.6%)
7/353 (2.0%)
5/353 (1.4%)
ALT:
Grade 3 >5.0 to 10.0 ULN*
Grade 4 >10.0 x ULN*
9/350 (2.6%)
2/350 (0.6%)
9/353 (2.5%)
2/353 (0.6%)
Total bilirubin:
Grade 3 >2.5 to 5.0 x ULN*
Grade 4 >5.0 x ULN*
0/345
0/345
3/352 (0.9%)†
0/352
†All
MERIT Study 48 weeks
15
*Upper limit of normal
three patients had hyperbilirubinemia not associated with transaminase elevations,
two associated with Gilbert’s syndrome.
16
Summary of 48-Week Primary Analyses (1)
● The percentage of subjects discontinuing from the study prior to
Week 48 was similar in the MVC (26.9%) and EFV (25.2%) arms
– The rate of discontinuation due to lack of efficacy was higher with MVC (11.9%) than
with EFV (4.2%)
– The rate of discontinuation due to adverse events was lower with MVC (4.2%) than
with EFV (13.6%)
● Based on the pre-planned statistical analysis (noninferiority margin of
–10%), MVC was:
– Noninferior to EFV based on <400 copies/mL endpoint (70.6% vs 73.1%)
– But not the <50 copies/mL endpoint (65.3% vs 69.3%)
● CD4+ cell count increases were higher in patients receiving MVC
compared to EFV (+170 vs +144 cells/mm3)
MERIT Study 48 weeks
17
Summary of 48-Week Primary Analyses (2)
● Fewer patients experienced grade 3 or 4 adverse events in the MVC arm
than in the EFV arm
● Fewer patients experienced Category C events in the MVC arm (n=6)
than in the EFV arm (n=12)
– The incidence of AIDS-defining malignancies and malignancies in general was lower
in the MVC arm than in the EFV arm
● Grade 3/4 transaminase elevations were infrequent and occurred at a
similar rate in the two treatment arms
● Median lipid increases from baseline were greater in the EFV arm
MERIT Study 48 weeks
18
Acknowledgements
● Patients participating in the MERIT study
● Investigators and study site staff
● Pfizer MERIT study team
● Monogram Biosciences