Efficacy and Safety of Maraviroc in Antiretroviral-Experienced Patients Infected With CCR5-Tropic HIV-1: 48-Week Results of MOTIVATE 1

J Lalezari1, J Goodrich2 , E DeJesus3, R Gulick4, H Lampiris5, M Saag6, N Bellos7, J Nadler8, P Tebas9, B Trottier10, M Wohlfeiler11, C Ridgeway12, M McHale12, E van der Ryst12, H Mayer2, on behalf of the MOTIVATE 1 Study Team

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

1Quest Clinical Research, UCSF, San Francisco, CA, USA2Pfizer Global Research and Development, New London, CT, USA3Orlando Immunology Center, Orlando, FL, USA4Weill Medical College of Cornell University, New York, NY, USA5San Francisco Veterans Affairs Medical Center, UCSF, San Francisco, CA, US6University of Alabama at Birmingham, Birmingham, AL, USA7Southwest Infectious Disease Associates, Dallas, TX, USA8University of South Florida, Tampa, FL, USA9University of Pennsylvania, Philadelphia, PA, USA10Clinique Medicale L'Actuel, Montreal, QC, CANADA11Wohlfeiler, Piperato & Associates, North Miami Beach, FL, USA12Pfizer Global Research and Development, Sandwich, UK

2

Background

● MOTIVATE 1 is one of two randomized, double-blind, placebo-controlled, Phase 3 studies investigating the safety and efficacy of the CCR5 antagonist maraviroc, in treatment-experienced patients with R5 HIV-1

● In a planned interim analysis at 24 weeks1, maraviroc (QD and BID) + OBT vs OBT alone demonstrated – significantly greater virologic suppression rates – significantly greater increases in CD4+ count – no clinically relevant differences in safety profile

● The MOTIVATE 1 primary efficacy endpoint is the change from baseline in HIV-1 RNA at 48 weeks

1. Lalezari J et al. 14th CROI 2007; Presentation 104bLB

3

Randomization 1:2:2

N=601

MOTIVATE 1 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)

4

Demographics and Baseline Characteristics

Treated N=585 § OBT aloneN=118

MVC QD + OBTN=232

MVC BID + OBT N=235

Mean age, yrs (range) 46 (31–71) 46 (19–75) 46 (25–69)Male, n (%) 106 (90) 210 (91) 212 (90)White, n (%) 99 (84) 187 (81) 197 (84)Median CD4+ count*,

cells/mm3 (range)160

(1675)168

(1812)150

(2678)Mean HIV-1 RNA*, log10 copies/mL (range)

4.84 (3.466.02)

4.85 (3.206.75)

4.86 (3.266.88)

Enfuvirtide in OBT, % 42 44 46≤2 active drugs in OBT†, % 65 69 75Tipranavir use in OBT, % 11 10 11Darunavir use in OBT Not Permitted

MOTIVATE 1-Week 48

Includes all patients who received at least one dose of study medication (full analysis set)

§ Two patients (1 MVC QD, 1 OBT alone) were assigned to the wrong treatment group due to a transcription error

* Calculated for each patient as the mean of up to three pre-dose assessments (screening, randomization, and baseline)

† According to overall susceptibility score

5

Mean Change from Baseline in HIV-1 RNA

-1.03-0.80

-1.82-1.66

-1.95-1.82

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Includes all patients who received at least one dose of study medication

HIV-1 RNA value imputed as baseline if patient discontinued before 48 weeks*Treatment difference vs OBT aloneMOTIVATE 1-Week 48

Mea

n ch

ange

in H

IV-1

RNA

fro

m b

asel

ine

(log 10

cop

ies/

mL)

Difference: -0.85* (97.5% CI: -1.22, -0.49) Difference: -1.02*

(97.5% CI: -1.39, -0.66)

MVC QD + OBT (N=232)MVC BID + OBT (N=235)

OBT alone (N=118)

Study week

Difference: -0.79* (97.5% CI: -1.14, -0.44)

Difference: -0.92* (97.5% CI: -1.28, -0.57)

24 48

6

<400 copies/mL

Percentage of Patients with Undetectable HIV-1 RNA

57.5%*

50.9%*

22.0%

0102030405060708090

100

Time (weeks)0 4 8 12 16 20 24 28 32 36 40 44 48

<50 copies/mL

46.8%*

41.8%*

16.1%0

102030405060708090

100

Time (weeks)0 4 8 12 16 20 24 28 32 36 40 44 48

OBT alone (N=118)MVC QD + OBT (N=232)MVC BID + OBT (N=235)

Patie

nts

(%)

24.6%

48.5%*

42.2%#

MOTIVATE 1-Week 48

HIV-1 RNA value imputed as baseline if missing or if patient discontinued before 48 weeks*P<0.0001 vs OBT alone#P<0.0006 vs OBT alone

Includes all patients who received at least one dose of study medication Number of patients remaining on study treatment at Week 48: OBT alone, 27 (30%); MVC QD + OBT, 109 (60%); MVC BID + OBT, 127 (66%)

60.4%*

54.7%*

31.4%

7

52 54

107 113111122

0

50

100

150

MOTIVATE 1-Week 48 Last observation carried forward

* P<0.0001 vs OBT alone

Mean Change from Baseline in CD4+ CountIncludes all patients who received at least one dose of study medication

Mea

n ch

ange

from

ba

selin

e in

CD4

+ co

unt (

cells

/mm

3 )

24 48

Difference: +59 *(95% CI: +34, +84)

Difference: +69 *(95% CI: +44, +93)

MVC QD + OBT (N=227)MVC BID + OBT (N=233)

OBT alone (N=116)

Difference: +55 *(95% CI: +30, +79)

Difference: +59 *(95% CI: +35, +83)

Study week

8

1927

7

4555

31

4960

32

0102030405060708090

100

Percentage of Patients With HIV-1 RNA <50 copies/mL at Week 48 According to Screening HIV-1 RNA*Includes all patients who received at least one dose of study medication and had a post-baseline observation

Patie

nts

(%)

MOTIVATE 1-Week 48

<100,000 copies/mL

≥100,000 copies/mL

Total population

N = 70 135 139 46 93 95 116 228 234

Last observation carried forward* Protocol-defined randomization stratum

MVC QD + OBT MVC BID + OBT

OBT alone

9

Patie

nts

(%)

N=

Maraviroc QD + OBT Maraviroc BID + OBT OBT alone

MOTIVATE 1 and 2: Proportion of Patients Receiving ENF With Undetectable HIV-1 RNA at Week 48 According to ENF First Use

<400 copies/mL <50 copies/mL

MOTIVATE 1 & 2-Week 48

3

2736

3

25

6471

35 32

6171

43

0102030405060708090

100

Last observation carried forward

ENF first use ENF experienced/resistance

91 10859 30 75 72ENF first use ENF experienced/

resistance

91 10859 30 75 72

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Safety Analyses Unadjusted for Duration of Exposure

All causalities and severities OBTaloneN=118

MVC QD + OBTN=232

MVC BID + OBTN=235

Total exposure, patient-years 64 168 169Patients with AEs 86% 90% 92%Patients discontinuing due to AEs 6% 6% 5%Patients with grade 3 AEs 25% 17% 23%Patients with grade 4 AEs 7% 9% 10%

Patients with SAEs 16% 14% 17%

Patients with Category C events 5% 5% 5%Deaths* 1% 1% 2%

AEs = adverse events; SAEs = serious adverse events*Includes deaths reported up to 28 days after stopping study drugNo deaths were related to study drug according to the investigatorMOTIVATE 1-Week 48

Includes all patients who received at least one dose of study medication

11

0

10

20

30

40

50

Diarrhea

Nausea

Fatigue

Headach

e

Upper RTI

Pyrexia ISR

Cough

Dizziness

Incidence of Adverse Events Occurring in ≥10% of Patients in Any Group, Unadjusted for ExposureIncludes all patients who received at least one dose of study medicationTotal exposure in patient-years: OBT alone 64, MVC QD + OBT 168, MVC BID + OBT 169

MOTIVATE 1-Week 48

MVC QD + OBT (N=232)MVC BID + OBT (N=235)

OBT alone (N=118)

Patie

nts

(%)

RTI = respiratory tract infection; ISR = injection site reaction

12

Number of Category C Events

Event, nOBTaloneN=118

MVC QD + OBTN=232

MVC BID + OBTN=235

Total exposure, patient-years 64 168 169Cryptosporidial gastroenteritis 0 1 0Cytomegalovirus infection* 0 1 1Herpes simplex 2 2 5Mycobacterium avium 0 0 1Esophageal candidiasis 0 6 1Pneumocystis jiroveci pneumonia 0 0 1Pneumonia 0 2 1Progressive multifocal leukoencephalopathy 0 0 1

Kaposi’s sarcoma 2 0 0Lymphoma* 2 1 1Total number of eventsTotal number of patients, n (% )

66 patients (5.1%)

1311 patients (4.7%)

12 12 patients (5.1%)

* Includes T-cell and diffuse large B-cell lymphomas MOTIVATE 1-Week 48

Includes all patients who received at least one dose of study medication

13

Maximum Liver Function Test Values Over 48 Weeks Without Regard to Baseline

All causalities, n (%)Unadjusted for duration of exposure

OBTalone

N=116*

MVC QD + OBTN=228*

MVC BID + OBTN=234*

AST:Grade 3 (5–10 x ULN†)Grade 4 (>10 x ULN†)

4 (3.4) 0

7 (3.1)3 (1.3)

7 (3.0) 4 (1.7)

ALT:Grade 3 (5–10 x ULN†)Grade 4 (>10 x ULN†)

2 (1.7) 0

11 (4.8) 1 (0.4)

5 (2.1) 3 (1.3)

Total bilirubin:Grade 3 (2.5–5 x ULN†) Grade 4 (>5 x ULN†)

4 (3.4) 2 (1.7)

17 (7.4) 2 (0.9)

10 (4.3)2 (0.9)

* Total patients evaluated for each laboratory parameter † Upper limit of normalMOTIVATE 1-Week 48

14

MOTIVATE 1 and 2: Change in CD4+ Cell Count from Baseline by Tropism Result at Time of Failure

MOTIVATE 1 & 2-Week 48

Tropism result, Baseline → Treatment Failure

Mean change from baseline in CD4+ count in patients with treatment failure (cells/mm3 )

OBT aloneN=271

MVC QD + OBTN=477

MVC BID + OBTN=487

All treatment failures* +24 (n=111)

+64 (n=92)

+74 (n=96)

R5 → R5 +25(n=89)

+77(n=33)

+133(n=24)

R5 → D/M or X4 +61(n=6)

+47(n=35)

+57(n=41)

* Includes patients with non-reportable/non-phenotypable tropism result at baseline and patients with non-reportable/non-phenotypable/missing tropism result at time of failure

15

MOTIVATE 1: Summary of 48-Week Primary Analysis

● Maraviroc (BID or QD) + OBT provided significantly greater virologic suppression rates and increases in CD4+ count compared to OBT alone at 48 weeks in this treatment-experienced population

● No new or unique safety findings emerged– Adverse events, serious adverse events, and lab abnormalities (including grade 3/4

transaminase elevations) occurred with similar frequency between treatment groups– Category C (AIDS-defining events) were balanced across treatment groups

● These results demonstrate that treatment with maraviroc + OBT provides sustained antiretroviral efficacy and tolerability in treatment-experienced patients

16

Acknowledgments

● Investigators and study site staff

● Patients who participated in the study

● Colleagues from Monogram Biosciences: J Whitcomb, E Coakley, C Petropoulos

● R Harrigan, BC Centre for Excellence in HIV

● Colleagues from Quintiles

● Colleagues from Pfizer: S Felstead, A Bullivant, I Oborska, K George, M Westby, K Turner, D Lindell, D Paige, S Nuttall, J Merson, L Kapili, M Dunne