Changes in HIV-1 Co-receptor Tropism for Patients Participating in the Maraviroc MOTIVATE 1 and 2 Clinical TrialsE van der Ryst and M Westby Pfizer Global Research and Development, Sandwich, UK

47th ICAACChicago, USA, September 17–20, 2007

2

Randomization 1:2:2

MOTIVATE 1 N=601MOTIVATE 2 N=474

MOTIVATE 1 and 2: Trial Design

OBT* + maraviroc (150 mg† BID)

OBT* + maraviroc (150 mg† QD)

OBT* + placebo

0 24w

* 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

Screening(6 weeks) 48w

Patients stratified by:• Enfuvirtide use in OBT •HIV-1 RNA < and ≥100,000 copies/mL at screening

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 ARVfrom three classes (≥ two for PIs)

Plannedinterim analysis

3

23

44 45

0102030405060708090

100

MOTIVATE 1 & 2-Week 24

* 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 and 2: Summary of Week 24 Efficacy ResultsIncludes all patients who received at least one dose of study medication

Mea

n ch

ange

from

ba

selin

e in

CD4

cou

nt (c

ells

/mm

3 )

MVC QD + OBT (N=414)MVC BID + OBT (N=426)

OBT alone (N=209)

P<0.0001* P<0.0001*57

109 106

0

20

40

60

80

100

120

Patie

nts

(%)

P<0.001* Difference: +51(95% CI: 33, 69)

P<0.001* Difference: +49(95% CI: 31, 67)

HIV-1 RNA <50 copies/mL†

Mean Change from Baseline in CD4 Count‡

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)

Assessment of CD4 count at failure, time of failure, and occurrence of Category C events

by tropism result

NR/NPNon-reportable/

non-phenotypable

D/M*†

Dual/mixed tropic virus population

R5*Only CCR5-tropic

virus detected

X4†

Only CXCR4-tropic virus detected

Tropism determined for all patients at screening, baseline, and all visits where VL>500 c/mL (Trofile™

assay, Monogram Biosciences)

* 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 +

OBTMVC BID +

OBTMean screening HIV-1 RNA (copies/mL)R5 → R5R5 → D/M or X4

4.825.09

4.845.16

4.865.07

Median screening CD4+ count (cells/mm3)R5 → R5R5 → D/M or X4

18092

18259

17057

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

182627

50

18

50

0

10

20

30

40

50

60

70

80

90

100

N= 17 33 33 187 362 377

MVC QD + OBT MVC BID + OBTOBT alone

MOTIVATE 1 & 2-Week 24

D/M R5

Patie

nts

(%)

Tropism result at baseline: 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)

HIV-1 RNA <50 c/mL CD4+ Count Change

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 aloneN=209

MVC QD + OBTN=414

MVC BID + OBTN=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

Patients Failing Maraviroc With D/M or X4 Virus Fail Earlier Than Those Failing with R5 Virus

● Time to maraviroc treatment failure with a D/M or X4 virus was approximately 30 days shorter than for failure with R5 virus

R5 → R5R5 → D/M or X4

Early failure (≤ day 70) (N=82)

Late failure (> day 70) (N=59)

Tropism result, Baseline → Treatment Failure:

Patie

nts

(%)

MOTIVATE 1 & 2

62

4237

53

0

10

20

30

40

50

60

70

80

90

100

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

1. Lalezari J et al. CROI 2007; Abstract 104bLB; 2. Nelson M et al. CROI 2007; Abstract 104aLBMOTIVATE 1 & 2

10

Reversion to R5 after Cessation of Maraviroc Treatment

Treatment N

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 # of Patients Median DaysMVC All 44 14 16 30 203OBT 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

Dual/mixed (D/M) tropism

R5X4A) Pure

B) Mixed

Viral Populations That May Exist Within a Patient

R

X

XX

X

XX

XXX

XX

XX

XX X

XX

RR

RR

RR R

RRRR R

RR

R RR

RRR

DDDD

DDD D D DDDD D

D D D DDD

R

XX X X X XX X X X X

XX X XXXXX

XX

X X XX X

XX X

X X X

XX

R R RRR RR R RRR

R RRR

RR R

RR

RR R

R

R

RR

D D

DD

DD

12

Example of a Patient With Treatment-emergent D/M Virus

Patient T6

CD

4 C

ount

(ce

lls/m

m3 )

1

2

3

4

5

6

Time Since First Administration (Day)

HIV

-1 R

NA

(log

10 c

opie

s/m

L)

R5 R5 DM DM DM DM DM DM R5 R5

Treatment start

Treatment endFailure

-100 0 100 200 3000

100

200

300

400

500

Lewis M et al. XVI International HIV Drug Resistance Workshop, June 2007, Abstract 56

13

-100 0 100 200 3000

100

200

300

400

500

CXCR4-using env Clones Were Detected at Low Frequency in the Baseline Sample

Time Since First Administration (Day)

• CXCR4-using clones detected at baseline (7%)

• No CCR5-tropic clones on treatment

R5 R5 DM DM DM DM DM DM R5 R5

1

2

3

4

5

6

HIV

-1 R

NA

(log

10 c

opie

s/m

L)

CD

4 C

ount

(ce

lls/m

m3 )

Patient T6

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

R R RRR R RR

R R RRR R DR

R R RRR R RR

R R RRR R DR

R R RRR R RR

R R RRR R DR

R R RRR R RR

R R RRR R DR

R R RRR R RR

R R RRR R DR

R R RRR R RR

R R RRR R XR

R R RRR R RR

R R RRR R DR

R R RRR R RR

R R RRR R DR

D

X

D

D

D

D

D

D

R5 D/M

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

MVC

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; 192:1537-44.2. Deeks et al. J Infect Dis 2007;195:387-91.

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