48-week results of once-daily maraviroc (MVC) 150 mg in combination with ritonavir-boosted atazanavir (ATV/r) compared to emtricitabine/tenofovir (FTC/TDF) + ATV/r in treatment-naïve patients infected with R5 HIV-1 (Study A4001078)

Simon Portsmouth,1 Charles Craig,2 Anthony Mills,3 Donna Mildvan,4 Daniel Podzamczer,5 Gerd Fätkenheuer,6 Manuel Leal,7 Hernan Valdez,1 Srinivas Rao Valluri,1 Jayvant Heera1

1Pfizer Inc., New York, NY, USA; 2Pfizer, Sandwich, Kent, UK; 3Anthony Mills MD, Los Angeles, CA, USA; 4Beth Israel Medical Center Division of Infectious Diseases, New York, NY, USA; 5HIV Unit, Infectious Disease Service, Hospital Universitari de Bellvitge, Barcelona, Spain; 6University Hospital of Cologne Köln, Germany; 7Laboratory of Immunovirology, Biomedicine Institute of Seville (IBIS), Infectious Disease Service, Virgen del Rocio University Hospital, Seville, Spain

Rationale for MVC + boosted PI regimen

• Potential for early use: prevalence of CCR5 tropic virus is greatest in treatment-naïve individuals1

• Nucleoside-sparing regimen• Good penetration of MVC in CSF and genital

secretions2-4

• MOTIVATE and PK studies support use of MVC 150 mg QD with selected ritonavir-boosted PIs

1. Hoffmann, Eur J Med Res, 2007. 2. Tiraboschi et al, J Acquir Immune Defic Syndr, 20103. Dumond et al, J Acquir Immune Defic Syndr, 2009. 4. Brown et al, J Infect Dis, 2011

Study A4001078: an exploratory pilot study of a low pill burden QD dual-therapy regimen, MVC + ATV/r

Study designOpen-label, 48-week Phase 2b pilot study

• Patient eligibility criteria – R5 HIV (ESTA) at screening– ≥16 years of age– HIV-1 RNA ≥1000 copies/mL– CD4 ≥100 cells/mm3

– No evidence of resistance to ATV/r, TDF, or FTC

– Study has iDMC– Ongoing study: USA, Spain,

Germany– Extended to 96 weeks– Study is not powered to show a

treatment difference and no formal comparative statistics will be performed

Randomization 1:1

N=121 MVC (150 mg QD) + ATV/r (300/100 mg QD)

FTC/TDF + ATV/r (300/100 mg QD)

0 24 wk 48 wkScreenin

g(6

weeks)

16 wk

Week 2First 15 US patients

Serial PK of MVC

Interim analyses Primary analysis

*Sparse PK sampling on all patients at Weeks 2 (non-PK substudy), 12 and 24 (Vourvahis. Abstract 37 IWCPHIV, 2010)

VL, HIV-1 RNA, viral load

Study disposition

MVC + ATV/rn=60

FTC/TDF + ATV/rn=61Discontinued

n=7• 2 AE (vomiting,

jaundice)

• 3 lost to follow-up

• 1 withdrew consent

• 1 insufficient clinical response (VL 934 copies/mL)

Enrolled into study n=121

Screening n=220

Discontinued n=7

• 2 lost to follow-up

• 1 withdrew consent

• 2 protocol violations

• 1 pregnancy

• 1 other: possible TDF-related kidney failure

Continuing in study n=53

Continuing in study n=54

• Two patients in each arm experienced protocol defined treatment failure

Summary of baseline characteristics

MVC + ATV/r n=60

FTC/TDF + ATV/r n=61

Mean age, years (range) 38.3 (21–61) 35.3 (18–68)

Male, n (%) 56 (93.3) 52 (85.2)

Race, n (%) White Black Asian Other

45 (75.0)13 (21.7)

02 (3.3)

46 (75.4)11 (18.0)3 (4.9)1 (1.6)

Median CD4+ count, cells/mm3 (range)

344 (160–744)

358(110–902)

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

4.6 (3.4–5.9) 4.7 (3.3–5.9)

HIV-1 RNA ≥100,000 copies/mL, n (%)

16 (27) 22 (36)

HIV-1 RNA <400 copies/mL at Week 48

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

Pati

en

ts w

ith

HIV

-1 R

NA

<

400 c

op

ies/m

L (

%)

MVC + ATV/r (N=59)

FTC/TDF + ATV/r (N=61)

89.8%

86.9%

Intent-to-treat. Missing=failure

Study week

HIV-1 RNA <50 copies/mL at Week 48

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

Study week

83.6%

74.6%

MVC + ATV/r (N=59)

FTC/TDF + ATV/r (N=61)

Intent-to-treat. Missing=failure

Pati

en

ts w

ith

HIV

-1 R

NA

<

50 c

op

ies/m

L (

%)

<100,000 copies/mL ≥100,000 copies/mLWeek 24 Week 48 Week 24 Week 48

Baseline HIV-1 RNA

Pat

ien

ts w

ith

HIV

-1 R

NA

<50

co

pie

s/m

L (

%)

0

10

60

70

80

90

100

50

40

30

20

HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline viral load

37/39

35/43 13/1617/22

81.4

94.9

81.377.3

Intent-to-treat. Missing=failure

MVC + ATV/r

FTC/TDF + ATV/r

HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline viral load

Week 24 Week 48 Week 24 Week 48

Pat

ien

ts w

ith

HIV

-1 R

NA

<50

co

pie

s/m

L (

%)

0

10

60

70

80

90

100

50

40

30

20

<100,000 copies/mL ≥100,000 copies/mL

Baseline HIV-1 RNA

34/39

33/43 17/22

11/16

76.7

87.2

68.8

77.3

37/39

35/43 13/1617/22

81.4

94.9

81.377.3

Intent-to-treat. Missing=failure

MVC + ATV/r

FTC/TDF + ATV/r

HIV-1 RNA <400 copies/mL at Week 24 and Week 48 according to baseline viral load

Week 24 Week 48 Week 24 Week 48Pat

ien

ts w

ith

HIV

-1 R

NA

<40

0 co

pie

s/m

L (

%)

0

10

60

70

80

90

100

50

40

30

20

<100,000 copies/mL ≥100,000 copies/mL

Baseline HIV-1 RNA

37/3939/43

15/1620/22

90.794.9 93.8

90.9

Intent-to-treat. Missing=failure

MVC + ATV/r

FTC/TDF + ATV/r

HIV-1 RNA <400 copies/mL at Week 24 and Week 48 according to baseline viral load

Week 24 Week 48 Week 24 Week 48Pat

ien

ts w

ith

HIV

-1 R

NA

<40

0 co

pie

s/m

L (

%)

0

10

60

70

80

90

100

50

40

30

20

<100,000 copies/mL ≥100,000 copies/mL

Baseline HIV-1 RNA

34/39

38/43 19/22

15/1688.4 87.2

93.8

86.4

MVC + ATV/r

FTC/TDF + ATV/r37/3939/43

15/1620/22

90.794.9 93.8

90.9

Intent-to-treat. Missing=failure

Outcomes for all patients with VL >50 copies/mL at Week 48

aPatient discontinued at Week 84 due to insufficient clinical responsebPatient discontinued at Week 96

MVC+ATV/rAa

BCDEFb

GHI

FTC/TDF+ATV/rJKL

691445781

16787615158

5278055

HIV-1 RNA, copies/mL

Week 48

497 (W84)<50

(W96)<50

(W72)<50

(W84)<50

(W96)274 (W96)

<50 (W72)<50

(W84)<50

(W84)

<50 (W84)<50

(W96)<50

(W84)

Post Week 48

Change in median CD4+ cell count over time (LOCF)

0

50

100

150

200

250

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48Med

ian

ch

an

ge f

rom

baselin

ein

CD

4 c

ell c

ou

nt

(cells/μ

L)

Study week

187

173

MVC + ATV/r (N=59)

FTC/TDF + ATV/r (N=61)

Intent-to-treat. LOCF, last observation carried forward

No genotypic or phenotypic resistance observed through Week 48

• 3 patients in the MVC arm and 3 patients in the FTC/TDF arm were identified for virologic analysesa

aPatients who discontinued from the study early with sufficient VL (≥500 copies/mL). Assays (ESTA, Monogram GenoSeq and/or PhenoSenseGT) performed at screening/baseline and at the last on-treatment time point were available

Change in tropism

0

Development of resistance mutations

MVC ATV TDF FTC

0 0 0 0

Susceptibility to drug retained

MVC FTC/TDF

3 3

Safety

MVC + ATV/r n=60

FTC/TDF + ATV/r n=61

Any AE, n (%) 58 (96.7) 60 (98.7)

Serious AE, n (%) 10 (16.7) 12 (19.7)

Grade 3 or 4 AE, n (%) 29 (48.3) 18 (29.5)

Discontinued due to AE, n (%) 2 (3.3) 0

Hyperbilirubinemia, n (%)AE relatedGrade 3 or 4 AE relatedGrade 3 or 4 laboratory*

27 (45.0)22 (36.7)39 (65.0)

21 (34.4)12 (19.7)32 (52.5)

*DAIDS grading

• 7 patients in the MVC + ATV/r group and 3 patients in the FTC/TDF group switched off of ATV/r therapy per protocol due to either tolerability or unconjugated hyperbilirubinemia

0 10 20 30 40 50 60 70 80 90 100

Modern dual-therapy studies: 48-week results No. of patients with

post-BL resistance mutations/no. of virologic failuresa

22/46

39/5616/78

0/03/3

HIV-1 RNA <50 copies/mL

COOL2

N=143 EFV +TDF

EFV + TDF/3TC

EFV + 2 NRTIEFV + LPV/r

ACTG 51421

N=500LPV/r + 2 NRTI

1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob Chemother, 2009.

% of patientsafrom evaluable samplesBL, baseline

0 10 20 30 40 50 60 70 80 90 100

Modern dual-therapy studies: 48-week results

% of patients

No. of patients with post-BL resistance mutations/no. of virologic failuresa

22/46

39/5616/78

0/03/3

HIV-1 RNA <50 copies/mL

COOL2

N=143 EFV +TDF

EFV + TDF/3TC

EFV + 2 NRTIEFV + LPV/r

ACTG 51421

N=500LPV/r + 2 NRTI

LPV/r BID + FTC/TDF

LPV/r BID + RAL BID

SPARTAN3

N=94 (2:1)

ACTG 52625

N=112

PROGRESS4

N=206

ATV BID + RAL BID

DRV/r QD + RALDRV/r QD + RAL BID

ATV/r QD + FTC/TDF 0/84/11

1/3 1/4

5/28

afrom evaluable samplesBL, baseline

1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob Chemother, 2009. 3. Kozal THLBB204, IAS 2010.

4. Reynes MOAB0101, IAS, 2010. 5. Taiwo Abstract 551, CROI, 2011.

0 10 20 30 40 50 60 70 80 90 100

Modern dual-therapy studies: 48-week results No. of patients with

post-BL resistance mutations/no. of virologic failuresa

22/46

39/5616/78

0/03/3

HIV-1 RNA <50 copies/mL

COOL2

N=143 EFV +TDF

EFV + TDF/3TC

EFV + 2 NRTIEFV + LPV/r

ACTG 51421

N=500LPV/r + 2 NRTI

LPV/r BID + FTC/TDF

LPV/r BID + RAL BID

SPARTAN3

N=94 (2:1)

ACTG 52625

N=112

PROGRESS4

N=206

ATV BID + RAL BID

DRV/r QD + RALDRV/r QD + RAL BID

ATV/r QD + FTC/TDF 0/8 4/11

1/3 1/4

5/28

0/0 0/0

0/2 0/2

LPV/r BID + MVC QD

LPV/r BID + FTC/TDF

ATV/r QD + MVC QD

ATV/r QD + FTC/TDF

VEMAN6

N=37

1078N=121

1. Riddler et al, N Engl J Med, 2008. 2. Girard et al, J Antimicrob Chemother, 2009. 3. Kozal THLBB204, IAS 2010.

4. Reynes MOAB0101, IAS, 2010. 5. Taiwo Abstract 551, CROI, 2011. 6. Nozza CDB325, IAS, 2011

% of patientsafrom evaluable samplesBL, baseline

Conclusions

• 48-week results of this pilot study of MVC + ATV/r support the antiviral activity of this once-daily, two-drug combination in treatment-naïve patients

• No resistance nor change in phenotypic tropism was observed

• No new unexpected safety events

• A Phase III study (A4001095; NCT01345630) will start in Q3/4 2011 – MVC + DRV/r QD vs FTC/TDF + DRV/r QD– Estimated enrollment of 804

Acknowledgments

• Thanks to the patients and investigators who participated in this study

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

Backups

Creatinine clearance

-14

-12

-10

-8

-6

-4

-2

0

0 4 8 12 16 20 24 28 32 36 40 44 48

Study week

Mean

ch

an

ge f

rom

baselin

e in

cre

ati

nin

e c

leara

nce (

mL/m

in)

MVC + ATV/r (N=60)

FTC/TDF + ATV/r (N=61)

Pharmacokinetics

Hours

0 4 8 12 16 20 24

*

7.65 ng/mL (in vivo IC50)1

1

10

100

1000

10,000

MV

C c

on

cen

trati

on

(n

g/m

L)

• All 15 patients had plasma MVC concentrations above the in vivo IC50 across the dosing Interval (150 mg QD + ATV/r)2

• There were 139 sparse PK samples with full dose and time data collected at the 2,12 and 24 week visits yielding concentrations from 13.7 to 933 ng/mL with samples taken from 0-32 hours after dose3

* One patient accidentally dosed with MVC prior to the 24-hour sample draw

1. Rosario et al, J Acquir Immune Defic Syndr, 2006.2. Vourvahis, Abstract 37 IWCPHIV, 2010.

3. Weatherley, Abstract P_05 IWCPHIV, 2011

Definition of Virologic Failure

• HIV-1 RNA <1.0 log10 decrease from Baseline at Week 4 or thereafter (confirmed by a second measurement taken no more than 14 days after the first measurement); or

• Failure to achieve HIV-1 RNA <400 copies/mL at Week 24, (confirmed by asecond measurement taken no more than 14 days after the first measurement);

• An increase in HIV-1 RNA to detectable levels (1,000 copies/mL on 2 consecutive measurements taken no more than 14 days apart) in subjects previously confirmed to have undetectable levels of <400 copies/mL on 2 consecutive visits.

Patients switching from ATV/r

• 10 patients switched from ATV/r (7 in the MVC arm and

3 in the FTC/TDF arm) due to either tolerability issues or unconjugated hyperbilirubinemia– 8 switched to DRV/r– 2 switched to LPV/r

• All 10 patients had reached HIV-1 RNA <50 copies/mL prior to switching

HIV-1 RNA <50 copies/mL at Week 24 and Week 48 according to baseline CD4 count

5/54/5 40/48n/N 46/49

Median CD4+ cell count over time (LOCF)

200

250

300

350

400

450

500

550

600

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

Med

ian

CD

4 c

ell c

ou

nt

(cells/m

m3)

Study week

Week 48

MVC + ATV/r = 580

FTC/TDF + ATV/r =

580

MVC + ATV/r (N=59)

FTC/TDF + ATV/r (N=61)

Intent-to-treat. LOCF, last observation carried forward

Week 24

MVC + ATV/r = 537

FTC/TDF + ATV/r =

536

Responders at Week 24 but not Week 48

HIV-1 RNA, copies/mL

Week 24 Week 32 Week 40 Week 48

MVC+ATV/r

ABCD

<50<50<50<50

<5056

<50<50

<5057

<50<50

144816158

FTC/TDF+ATV/r

Ea

FGHa

<50<50<50<50

<50<50<50<50

N/A<50<50<50

N/A780b

55N/A

N/A, not available; W, weekaPatient discontinued prior to Week 48bResult of repeat test 13 days later was <50 copies/mL

Responders at Week 24 but not Week 48

HIV-1 RNA, copies/mL

Week 24 Week 32 Week 40 Week 48Post Week

48

MVC+ATV/r

ABCD

<50<50<50<50

<5056

<50<50

<5057

<50<50

144816158

<50 (W96)<50 (W84)<50 (W72)<50 (W84)

FTC/TDF+ATV/r

Ea

FGHa

<50<50<50<50

<50<50<50<50

N/A<50<50<50

N/A780b

55N/A

N/A<50 (W96)<50 (W84)

N/AN/A, not available; W, weekaPatient discontinued prior to Week 48bResult of repeat test 13 days later was <50 copies/mL

• 7/9 (MVC + ATV/r) and 3/3 (FTC/TDF + ATV/r) patients with HIV-1 RNA ≥50 copies/mL at Week 48 had HIV-1 RNA <50 copies/mL at their latest visit. HIV-1 RNA levels for the remaining 2 patients were 274 copies/mL (W96), and 497 copies/mL (W84)