Efficacy of maraviroc (MVC) administered once-daily or twice-daily with boosted protease inhibitors to treatment-experienced patients

S Taylor,1 J Arribas,2 C-F Perno,3 R Burnside,4 L McFadyen,5 D Hardy,6 H-J Stellbrink,7 DA Cooper,8 J-M Molina,9 E van der Ryst,5 J Heera,4 H Valdez10

1Birmingham Heartlands Hospital, Birmingham, UK; 2Hospital La Paz, Madrid, Spain; 3University of Rome, Tor Vergata, Italy; 4Pfizer Inc., Groton, CT, USA; 5Pfizer Global Research and Development, Sandwich, Kent, UK; 6Cedars-Sinai Medical Center/Geffen School of Medicine-UCLA, Los Angeles, CA, USA; 7ICH Study Center, Hamburg, Germany; 8University of New South Wales and St Vincent’s Hospital, Sydney, Australia; 9Assistance Publique-Hopitaux de Paris, Paris, France; 10Pfizer Inc., New York, NY, USA

Percentage of patients with HIV-1 RNA <50 copies/mL in the MOTIVATE studies through 48 weeks

Hardy et al, Abstract 792 , CROI, 2008.

0 4 20 28

Pati

en

ts (

%)

40

30

20

0

16.7%

43.2%*45.5%*

100

90

80

70

60

50

10

8 12 16 24 32 36 40 44 48

*P <0.0001 vs placebo

Time (weeks)

Placebo + OBT (N=209)

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

Option to switch to open-label MVC BID

In this analysis, non-completers and missing data were categorized as failures

OBT, optimized background therapy

MOTIVATE: Effect of boosted PIs on MVC Cavg

1Weatherly et al, Poster 17a, IWCPHIV, 2008. 2Kakuda et al, Antimicrob Agents Chemother, 2011; 55(5) 2290-6.

Phase 2b/3 MVC 150 mg QD vs Phase 2a 300 mg BID monotherapy1

Horizontal line = median Phase 2a 300 mg BID in asymptomatic HIV-1 infected subjects as target exposure (133 ng/mL)

DRV/r boosts MVC exposures comparable to LPV/r and ATV/r in formal drug interaction studies in healthy volunteers2

800

600

400

200

0

MV

C C

avg (

ng

/mL)

FPV/rQD7872

n =Median =

ATV/rQD56

109

IDV/rQD6

134

LPV/rQD107149

SQV/rQD35

174

Rationale for once-daily MVC with a boosted PI in treatment-experienced patients

• MVC monotherapy data show comparable antiviral responses with both 300 mg QD and BID1

• MVC 150 mg QD with boosted PIs achieved similar or greater concentrations compared to 300 mg BID without inhibitors/inducers2

• MVC when dosed QD with select boosted PIs may offer treating physicians and patients the option of simplified dosing of MVC

1. Fätkenheuer et al, Nat Med, 2005. 2. Weatherley et al, Poster 17a, IWCPHIV, 2008.

Objective

• To determine in a post-hoc analysis, whether the efficacy of QD MVC in combination with select boosted PIs (excluding TPV/r and FPV/r) is comparable to MVC BID at week 48

Analysis population

MOTIVATE patients n=1049

CCR5+ patients by enhanced sensitivity Trofile assay (ESTA) n=841

Boosted PI patients n=448

MVC QD n=187

MVC BID n=176

Placebo n=85

Boosted PI patients: patients whose baseline regimen included ATV/r, IDV/r, LPV/r, or SQV/r

FPV/r patients n=149

MVC QD n=50

MVC BID n=56

Placebo n=43

Remainder patients n=244

( TPV/r , unboosted or no PI)

MVC QD n=98

MVC BID n=96

Placebo n=50

Baseline characteristics

BID, twice daily; bPI, boosted PI; ESTA, enhanced sensitivity Trofile assay; MVC, maraviroc; QD, once daily

In a post-hoc analysis, a comparable percentage of patients treated with MVC QD or BID with a boosted PI achieved VL <50 copies/mL at Week 48

Pati

en

ts w

ith

HIV

-1 R

NA

<50 c

op

ies/m

L

at

Week 4

8 (

%)

40

20

100

80

60

0

n/N= 85/187 84/176 14/85

45.547.7

16.5

Difference (97.5% CI)QD vs PBO 27.8% (16.2,

39.4)BID vs PBO 30.6% (18.5,

42.7)

BID, twice daily; CI, confidence interval; MVC, maraviroc; PBO, placebo; QD, once daily; VL, viral blood

Placebo

MVC 150 mg QDMVC 150 mg BID

Patient subgroup analyses: Screening VL < or ≥ 100,000 copies/mL

Pati

en

ts w

ith

HIV

-1 R

NA

<50 c

op

ies/m

L

at

Week 4

8 (

%)

40

20

100

80

60

0

61.0

23.8

14.3

Placebo

MVC 150 mg QDMVC 150 mg BID

BID, twice daily; MVC, maraviroc; PBO, placebo; QD, once daily; VL, viral blood

39.038.5

60.4

Baseline HIV-1 RNA<100,000 copies/mL

n/N= 64/105 58/96 10/42 30/78 30/77 6/42

≥100,000 copies/mL

Patient subgroup analyses: Baseline CD4 cell count < or ≥ 50 cells/mm3

Pati

en

ts w

ith

HIV

-1 R

NA

<50 c

op

ies/m

L

at

Week 4

8 (

%)

40

20

100

80

60

0

17.2

5.0

22.2

Placebo

MVC 150 mg QDMVC 150 mg BID

56.857.8

18.5

Baseline CD4 count<50 cells/mm3

n/N= 5/29 5/27 1/20 89/154 83/146 14/63

≥50 cells/mm3

BID, twice daily; MVC, maraviroc; PBO, placebo; QD, once daily

Patient subgroup analyses: Number of active drugs in background regimen at baseline (wOBTss < or ≥ 1)

Pati

en

ts w

ith

HIV

-1 R

NA

<50 c

op

ies/m

L

at

Week 4

8 (

%)

40

20

100

80

60

0

35.9

3.7

26.3

Placebo

MVC 150 mg QDMVC 150 mg BID

58.159.7

35.7

wOBTss<1

n/N= 23/64 20/56 1/27 71/119 68/117 15/57

≥1

BID, twice daily; MVC, maraviroc; PBO, placebo; QD, once daily; wOBTss, weighed optimized background therapy susceptibility score

Patient subgroup analyses: First-time use of a selected boosted PI

Pati

en

ts w

ith

HIV

-1 R

NA

<50 c

op

ies/m

L

at

Week 4

8 (

%)

40

20

100

80

60

0

59.0

Placebo

MVC 150 mg QDMVC 150 mg BID

56.3

All boosted PIfirst use

n/N= 49/83 8/39

BID, twice daily; MVC, maraviroc; PBO, placebo; QD, once daily

Atazanavir/rfirst use

Lopinavir/rfirst use

20.5

59.4 57.1

22.2

69.0

58.1

16.7

40/71 19/32 4/1816/28 20/29 2/1218/31

Patient subgroup analyses: Use of a selected boosted PI to which virus is susceptible

Pati

en

ts w

ith

HIV

-1 R

NA

<50 c

op

ies/m

L

at

Week 4

8 (

%)

40

20

100

80

60

0

59.0

Placebo

MVC 150 mg QDMVC 150 mg BID

56.5

All boosted PI susceptible

n/N= 36/61 9/29

BID, twice daily; MVC, maraviroc; PBO, placebo; QD, once daily

Atazanavir susceptible Lopinavir susceptible

31.0

58.365.0

23.1

63.355.3

33.3

35/62 14/24 3/1313/20 19/30 5/1521/38

Conclusions

• Comparable efficacy was demonstrated in subjects treated with MVC 150 mg QD or BID compared to placebo in combination with a boosted PI (except TPV/r and FPV/r)

• Efficacy was maintained with MVC QD or BID with a boosted PI compared to placebo in patients:– with high screening VL or low baseline CD4+ cells– receiving >1 other fully active drug (wOBTss >1)– receiving selected boosted PI for the first time or with

documented viral susceptibility to the selected boosted PI

• MVC administered QD in combination with select boosted PIs may be a potential option for treatment-experienced patients seeking a simplified treatment regimen

Acknowledgments

• Thank you to all study participants and investigators who participated in the MOTIVATE 1 and MOTIVATE 2 studies.

• Editorial support was provided by Dr Clemence Hindley at Complete Medical Communications and funded by ViiV Healthcare

BACK UPS

Maraviroc 150 mg QD + Darunavir/r 800/100 mg QD

• Ongoing study evaluating intensive PK in HIV-infected patients receiving MVC 150 mg QD + DRV/r 800/100 mg QD

MVC 150 mg QD + DRV/r

(n=15)

MVC 300 mg BID + TDF/FTC (n=12)

MVC trough

Median 50 ng/mL 48 ng/mL

Mean 65 ng/mL 48 ng/mL

Taylor et al, CROI, 2011

In a post-hoc analysis a comparable percentage of patients on MVC QD or BID with a boosted PI achieved a VL <50 copies/mL at Week 48

Pati

en

ts w

ith

HIV

-1 R

NA

<50 c

op

ies/m

L

at

Week 4

8 (

%)

40

20

100

80

60

0

n/N= 85/187 84/176 14/85

45.547.7

16.5

Difference (97.5% CI)QD vs PBO 27.8% (16.2,

39.4)BID vs PBO 30.6% (18.5,

42.7)Difference (95% CI)

QD vs BID -2.4% (-12.5, 7.7)

Placebo

MVC 150 mg QDMVC 150 mg BID

BID, twice daily; CI, confidence interval; MVC, maraviroc; PBO, placebo; QD, once daily; VL, viral blood