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

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

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

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

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

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= 17 33 33 187 362 377 MOTIVATE 1 & 2-Week 24

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

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

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

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

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

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

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

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

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; 192:1537-44. 2. Deeks et al. J Infect Dis 2007;195:387-91.

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

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