104bLB
Efficacy and Safety of Maraviroc plus Optimized Background Therapy in Viremic ART-experienced Patients Infected with CCR5-tropic HIV-1: 24-Week Results of a Phase 2b/3 Study in the US and Canada
J Lalezari1, J Goodrich2, E DeJesus3, H Lampiris4, R Gulick5, M Saag6, C Ridgway7, M McHale7, E van der Ryst7, and Howard Mayer*2
1Quest Clin Res, Univ of California, San Francisco, US; 2Pfizer Global R&D, New London, CT, US; 3Orlando Immunology Ctr, FL, US; 4San Francisco VAMC, Univ of California, US; 5Weill Med Coll of Cornell Univ, New York, NY, US; 6Univ of Alabama at Birmingham, US; and 7Pfizer Global R&D, Sandwich, UK
Background:
Maravic (MVC) is an oral CCR5 antagonist
with activity against R5-tropic HIV-1 in
vitro and significant antiviral efficacy in 10-day monotherapy. MOTIVATE 1 is an ongoing, double-blind, placebo-controlled,
phase 2b/3 trial assessing the safety and efficacy of MVC
in treatment-experienced HIV-infected patients. These are the results of a
planned week-24 interim analysis.
Methods:
Triple-class-experienced patients
(±triple-class resistance) with only R5-tropic HIV-1 (Trofile assay) and HIV-1 RNA >5000 copies/mL were randomized 1 : 2 : 2 to receive placebo, MVC
once daily or MVC twice daily +
optimized background therapy (OBT) (3 to 6 antiretroviral drugs ± low-dose
ritonavir). With a protease inhibitor (PI) (other than tipranavir) and/or
delavirdine, MVC 150 mg once or
twice daily was administered; otherwise 300 mg once daily or twice daily was
used. The primary endpoint was the mean reduction in HIV-1 RNA from baseline to week 24.
Results:
Of 601 patients randomized, 585
received ≥1 dose of study drug. Baseline characteristics were similar
across treatment arms. At baseline, median CD4 count was 163, 168,
and 150 cells/mm3 and mean HIV-1 RNA
was 4.84, 4.85, and 4.86 log10 copies/mL in the placebo, MVC once daily, and MVC
twice daily arms, respectively. OBT contained ≤2 active drugs in 66.1,
68.5, and 75.7% of patients in the placebo, MVC
once daily, and MVC twice daily
arms, respectively. Adverse events, severe adverse events,
AIDS-defining events, and laboratory (including liver enzyme) abnormalities
occurred with similar frequency across groups. The
following analyses are based on all randomized patients who received ≥1
dose of study drug:
|
|
Placebo + OBT
(n
= 118)
|
MVC Once Daily +
OBT
(n
= 232)
|
MVC Twice Daily +
OBT
(n
= 235)
|
|
Mean
change in viral load from baseline (log10 copies/mL)
Treatment
difference placebo
(97.5%CI)
|
1.03
N/A
|
1.82
0.79
(1.14,
0.44)
|
1.95
0.92
(1.28,
0.57)
|
|
%
<400 copies/mL
p value vs placebo
|
31.4%
N/A
|
54.7%
<0.0001
|
60.4%
<0.0001
|
|
%
<50 copies/mL
p
value vs placebo
|
24.6%
N/A
|
42.2%
0.0006
|
48.5%
<0.0001
|
|
Mean
change in CD4 from baseline§ (cells/mm3)
p
value vs placebo
(95%CI)
|
+52
(n = 116)
N/A
|
+107
(n = 227)
<0.0001
(+30,
+79)
|
+111
(n = 233)
<0.0001
(+35,
+83)
|
|
Category
C AIDS-defining events, n
|
5
|
12
|
8
|
|
Discontinuations
due to adverse events, n (%)
|
6
(5.1)
|
11
(4.7)
|
10
(4.3)
|
|
Deaths*,
n (%)
|
1
(0.8)
|
2
(0.9)
|
1
(0.4)
|
Mean of all pre-dose assessments Discontinuations=no
change from BL
§Last Observation Carried Forward *No deaths were related to study drug
according to investigators
Conclusions: In this treatment-experienced population, MVC (twice daily or
once daily) + OBT provided significantly superior virologic control and
increases in CD4 cell count compared with placebo + OBT. There were no clinically
relevant differences in the safety profile between the MVC
(twice daily or once daily) + OBT and placebo + OBT treatment groups.
|
