Transcript Changes in HIV-1 Co-receptor Tropism for Patients Participating in the Maraviroc MOTIVATE 1 and 2 Clinical Trials E van der Ryst and M.

Changes in HIV-1 Co-receptor Tropism for
Patients Participating in the Maraviroc
MOTIVATE 1 and 2 Clinical Trials
E van der Ryst and M Westby
Pfizer Global Research and Development, Sandwich, UK
47th ICAAC
Chicago, USA, September 17–20, 2007
2
MOTIVATE 1 and 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
24w
48w
Planned
interim analysis
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
3
MOTIVATE 1 and 2: Summary of Week 24 Efficacy Results
Includes all patients who received at least one dose of study medication
OBT alone (N=209)
100
90
80
70
60
50
40
30
20
10
0
P<0.0001*
P<0.0001*
44
23
HIV-1 RNA
<50 copies/mL†
†
MOTIVATE 1 & 2-Week 24
45
P<0.001*
Mean change from
baseline in CD4 count (cells/mm3)
Patients (%)
MVC QD + OBT (N=414)
MVC BID + OBT (N=426)
Difference: +51
(95% CI: 33, 69)
120
109
P<0.001*
Difference: +49
(95% CI: 31, 67)
106
100
80
60
57
40
20
0
Mean Change from
Baseline in CD4 Count‡
* versus OBT alone
HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 24 weeks
‡ Last observation carried forward
van der Ryst, et al. 4th IAS 2007; Poster WEPEB116LB
Characterization of Maraviroc Resistance in MOTIVATE 1
and MOTIVATE 2: Study Overview
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OBJECTIVE: To study changes in HIV-1 tropism in patients who experienced
treatment failure in the MOTIVATE 1 and 2 studies
MOTIVATE 1 and MOTIVATE 2 Phase 3 studies in
treatment-experienced patients (N=1,075)
Tropism determined for all patients at screening,
baseline, and all visits where VL>500 c/mL (Trofile™
assay, Monogram Biosciences)
R5*
Only CCR5-tropic
virus detected
X4†
Only CXCR4-tropic
virus detected
D/M*†
Dual/mixed tropic
virus population
NR/NP
Non-reportable/
non-phenotypable
Assessment of CD4 count at failure, time of
failure, and occurrence of Category C events
by tropism result
* CCR5-using virus; †CXCR4-using virus
Patients With a Change in Tropism Result from R5 at Screening
to D/M at Baseline had a Lower Median CD4+ Count
● Of the 1042 patients with R5 virus at screening, approximately 8% had a
change in tropism result between screening and baseline to non-R5
virus, prior to a change in ARV regimen or administration of study drug
● This subgroup had a lower median CD4+ count and higher mean HIV-1
RNA at screening
Tropism result,
Screening → Baseline
OBT alone
MVC QD +
OBT
MVC BID +
OBT
Mean screening HIV-1 RNA (copies/mL)
R5 → R5
R5 → D/M or X4
4.82
5.09
4.84
5.16
4.86
5.07
Median screening CD4+ count (cells/mm3)
R5 → R5
R5 → D/M or X4
180
92
182
59
170
57
MOTIVATE 1 & 2
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Outcome of Patients with non-R5 Virus at Baseline
(Week 24)
Includes all patients who received at least one dose of study medication
HIV-1 RNA <50 c/mL
OBT alone
CD4+ Count Change
MVC BID + OBT
MVC QD + OBT
100
90
80
Patients (%)
70
Tropism result at baseline:
D/M
R5
60
50
50
50
40
27
30
20
18
26
18
10
0
N=
17
33
MOTIVATE 1 & 2-Week 24
33
187 362 377
Mean change from baseline in
CD4+ count at failure, cells/mm3
OBT
alone
15
(n=5)
MVC QD + MVC BID
OBT
+ OBT
54
26
(n=8)
(n=19)
6
CD4+ Count Increase in Patients Failing Maraviroc is
Greater Even in Patients With D/M or X4 Virus at Failure
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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
OBT alone
N=209
MVC QD + OBT
N=414
MVC BID + OBT
N=426
+14
(n=97)
+15
(n=80)
+67
(n=4)
+49
(n=68)
+61
(n=18)
+37
(n=31)
+71
(n=77)
+138
(n=17)
+56
(n=32)
Data excludes patients who had no tropism result at time of failure
* Includes patients with non-R5 tropism result at baseline
Lalezari J et al. CROI 2007; Abstract 104bLB; Nelson M et al. CROI 2007; Abstract 104aLB
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Patients Failing Maraviroc With D/M or X4 Virus Fail Earlier Than
Those Failing with R5 Virus
100
90
80
Patients (%)
70
Tropism result,
Baseline → Treatment Failure:
R5 → D/M or X4
R5 → R5
62
60
53
50
40
42
37
30
20
10
0
Early failure
(≤ day 70) (N=82)
Late failure
(> day 70) (N=59)
● Time to maraviroc treatment failure with a D/M or X4 virus was
approximately 30 days shorter than for failure with R5 virus
MOTIVATE 1 & 2
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No Association Between Category C Events and Treatment-emergent
D/M or X4 Virus
● The number of patients experiencing CDC Category C events in the
study was low: 14 (6.7%) OBT alone, 26 (6.3%) MVC QD and 18 (4.2%)
MVC BID
● There was no evidence of an increased rate of Category C events in
patients receiving maraviroc + OBT vs those receiving OBT alone
despite the extended treatment duration on maraviroc1,2
● Only 5 patients with R5 virus at baseline who experienced a Category C
event had D/M or X4 virus at the time of the event (3 on MVC QD, 1 on
MVC BID, and 1 on OBT alone)
● All 5 patients had a baseline CD4 count <20 cells/mm3 and were
therefore at high risk of developing a Category C event
● Category C events were therefore not associated with treatmentemergent CXCR4-using virus
MOTIVATE 1 & 2
1. Lalezari J et al. CROI 2007; Abstract 104bLB; 2. Nelson M et al. CROI 2007; Abstract 104aLB
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Reversion to R5 after Cessation of Maraviroc Treatment
Tropism result at last follow-up for patients with DM or X4 virus
at treatment failure
Treatment
N
MVC All
OBT alone
44
3
D/M or X4 virus
at last follow-up
# of Patients Median Days
14
16
2
22
R5 virus
at last follow-up
# of Patients
Median Days
30
203
1
20
●
For maraviroc patients with D/M or X4 virus at treatment failure and with in-study offdrug (ISOD) follow-up data, virus in 68% of patients was R5 at last follow-up
●
Time of follow-up was significantly shorter for patients with D/M or X4 virus at their last
study visit
●
Where follow-up >1 month, virus in 30 out of 31 patients reverted to R5 during ISOD
follow-up
MOTIVATE 1 & 2
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Viral Populations That May Exist Within a Patient
A) Pure
X4
X
R5
X
X
X
X
X
X
X
XX
X
X
X
X X X
X
X
D D
D
D D D D D
D
D
D
D
D
D D
D D D D
D
R
R
R R R R
R
R R R
R
R
RR R R RR
R R R
B) Mixed
Dual/mixed (D/M) tropism
X R
X X X X X
X XX R X X
R X X X XX
X X X
D D R
X R X X
X D X R
R X DX
X X R
X
D
X
X
R
D
R R R
R R XR R
R RR R X
X R R R RR
R R R
Example of a Patient With Treatment-emergent
D/M Virus
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Treatment start
Failure
Treatment end
Patient T6
R5
DM DM
DM DM
DM
DM
R5
HIV-1 RNA (log10 copies/mL)
6
R5
500
5
400
4
300
3
200
2
100
1
CD4 Count (cells/mm3)
R5
0
-100
0
100
200
300
Time Since First Administration (Day)
Lewis M et al. XVI International HIV Drug Resistance Workshop, June 2007, Abstract 56
CXCR4-using env Clones Were Detected at
Low Frequency in the Baseline Sample
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Patient T6
R5
DM DM
DM DM
DM
DM
R5
HIV-1 RNA (log10 copies/mL)
6
R5
500
5
400
4
• CXCR4-using clones
detected at baseline
(7%)
3
2
• No CCR5-tropic
clones on treatment
1
300
200
100
CD4 Count (cells/mm3)
R5
0
-100
0
100
200
300
Time Since First Administration (Day)
Lewis M et al. XVI International HIV Drug Resistance Workshop, June 2007, Abstract 56
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Selective Inhibition of R5 Viruses can Lead to a Change in Tropism
Result to D/M or X4

Trofile™ (like all resistance tests) measures relative proportions (not
absolute amounts) of different viruses (Panel A)

Selective inhibition of a majority virus type, increases the sensitivity
to detect the minor variant (Panel B)
A
B
RRRR RRRR RRRR RRRR
RRRR RRRR RRRR RRRR
RRRD RRRD RRRD RRRD
RRRRRRRR RRRR RRRR
RRRR RRRR RRRR RRRR
RRRR RRRR RRRR RRRR
RRR X RRRD RRRD RRRD
RRRR RRRR RRRR RRRR
R5
MVC
D
D
D
D
X
D
D
D
D/M
Selective Inhibition of R5 Viruses Can Lead to a Change in
Tropism Result to D/M or X4
● Maraviroc selectively inhibits R5 virus
● If maraviroc is administered as part of a sub-optimal regimen, preexisting low (undetected) levels of D/M or X4 virus will emerge as the
dominant viral population
● Since the D/M or X4 virus is pre-existing, time to failure is shorter than
with R5 virus (where maraviroc resistance must be selected de novo)
– Similar to the rapid outgrowth of pre-existing (archived) drug-resistant virus when
failed ARV therapy is reinitiated after treatment interruption
● After withdrawal of maraviroc, selective pressure on R5 virus is
removed, allowing R5 virus to re-emerge as the dominant population
– Reversion to R5 takes approximately 16 weeks, consistent with loss of 3TC1 or
enfuvirtide2 resistance after withdrawal of these ARVs
1. Deeks S, et al. J Infect Dis 2005; 192:1537-44.
2. Deeks et al. J Infect Dis 2007;195:387-91.
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Conclusions
● Tropism changes are associated with MVC treatment failure
● Patients failing MVC therapy had higher mean CD4+ count increases
even in the context of emergence of D/M or X4 virus
● Time to failure was shorter for patients failing with D/M or X4 virus vs
R5 virus
● Patients who failed MVC therapy with D/M or X4 virus reverted to an R5
virus tropism result after cessation of MVC therapy
● There was no association between Category C events and treatmentemergent D/M or X4 virus
● These data are consistent with the selective and reversible suppression
of R5 virus during MVC therapy, resulting in detection of D/M or X4 virus
at time of failure in two-thirds of failing patients
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Acknowledgments
● Investigators and study site staff
● Patients who participated in the study
● Colleagues from Pfizer: Howard Mayer, James Goodrich, Irina
Konourina, Margaret Tawadrous, Marilyn Lewis, Paul Simpson, Ayman
Ayoub, Andrew Bullivant and John Sullivan