1. 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
Randomization 1:2:2 MOTIVATE 1 N=601 MOTIVATE 2 N=474
OBT* + placebo
OBT* + maraviroc (150 mg† QD)
OBT* + maraviroc (150 mg† BID)
Screening (6 weeks)
Planned interim analysis
24w
48w
Patient eligibility criteria:
R5 HIV-1 infection
HIV-1 RNA ≥5,000 copies/mL
Stable pre-study ARV regimen, or no ARVs for ≥ 4 weeks
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
MVC QD + OBT (N=414)
MVC BID + OBT (N=426)
OBT alone (N=209)
P<0.001* Difference: +51 (95% CI: 33, 69)
P<0.001* Difference: +49 (95% CI: 31, 67)
P<0.0001*
P<0.0001*
Patients (%)
Mean change from baseline in CD4 count (cells/mm3)
HIV-1 RNA <50 copies/mL†
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
MOTIVATE 1 & 2-Week 24
van der Ryst, et al. 4th IAS 2007; Poster WEPEB116LB

4. Characterization of Maraviroc Resistance in MOTIVATE 1 and MOTIVATE 2: Study Overview
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

5. 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
Median screening CD4+ count (cells/mm3) R5 → R5 R5 → D/M or X4
MOTIVATE 1 & 2

6. 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
CD4+ Count Change
OBT alone
MVC QD + OBT
MVC BID + OBT
Mean change from baseline in CD4+ count at failure, cells/mm3
OBT alone
MVC QD + OBT
MVC BID + OBT
15 (n=5)
54 (n=8)
26 (n=19)
Tropism result at baseline:
D/M R5
Patients (%) N=
MOTIVATE 1 & 2-Week 24

7. CD4+ Count Increase in Patients Failing Maraviroc is Greater Even in Patients With D/M or X4 Virus at Failure
Tropism result, Baseline → Treatment Failure
Mean change from baseline in CD4+ count in patients with treatment failure (cells/mm3 )
OBT alone N=209
MVC QD + OBT
N=414
MVC BID + OBT N=426
All treatment failures*
+14 (n=97)
+49 (n=68)
+71 (n=77)
R5 → R5
+15 (n=80)
+61 (n=18)
+138 (n=17)
R5 → D/M or X4
+67 (n=4)
+37 (n=31)
+56 (n=32)
Data excludes patients who had no tropism result at time of failure * Includes patients with non-R5 tropism result at baseline
MOTIVATE 1 & 2
Lalezari J et al. CROI 2007; Abstract 104bLB; Nelson M et al. CROI 2007; Abstract 104aLB

8. Early failure (≤ day 70) (N=82) Late failure (> day 70) (N=59)
Patients Failing Maraviroc With D/M or X4 Virus Fail Earlier Than Those Failing with R5 Virus
Tropism result, Baseline → Treatment Failure:
R5 → D/M or X4
R5 → R5
Patients (%)
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

9. 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 treatment- emergent CXCR4-using virus
MOTIVATE 1 & 2
1. Lalezari J et al. CROI 2007; Abstract 104bLB; 2. Nelson M et al. CROI 2007; Abstract 104aLB

10. Reversion to R5 after Cessation of Maraviroc Treatment
Tropism result at last follow-up for patients with DM or X4 virus at treatment failure
D/M or X4 virus at last follow-up
R5 virus at last follow-up
# of Patients
Median Days
MVC All 44 14 16 30
203
OBT alone 3 2 22 1 20
For maraviroc patients with D/M or X4 virus at treatment failure and with in-study off-drug (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

11. Viral Populations That May Exist Within a Patient
A) Pure X4 R5
Dual/mixed (D/M) tropism R X D
B) Mixed R X D

12. Example of a Patient With Treatment-emergent D/M Virus
Treatment start
Failure
Treatment end
Patient T6 R5 R5 DM DM DM DM DM DM R5 R5
-100
100
200
300
400
500 6 5 4
HIV-1 RNA (log10 copies/mL) 3
CD4 Count (cells/mm3) 2 1
Time Since First Administration (Day)
Lewis M et al. XVI International HIV Drug Resistance Workshop, June 2007, Abstract 56

13. CXCR4-using env Clones Were Detected at Low Frequency in the Baseline Sample
Patient T6 R5 R5 DM DM DM DM DM DM R5 R5
-100
100
200
300
400
500 6 5 4
CXCR4-using clones detected at baseline (7%)
No CCR5-tropic clones on treatment
HIV-1 RNA (log10 copies/mL) 3
CD4 Count (cells/mm3) 2 1
Time Since First Administration (Day)
Lewis M et al. XVI International HIV Drug Resistance Workshop, June 2007, Abstract 56

14. 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 R D X D X D
MVC R5
D/M

15. 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, pre- existing 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:
2. Deeks et al. J Infect Dis 2007;195:

16. 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 treatment- emergent 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

17. 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