Virological Correlates Associated with Treatment Failure at Week 48 in the Phase 3 Study of Maraviroc in Treatment-Naive Patients Jayvant Heera 1, Mike

Virological Correlates Associated with Treatment Failure at Week 48 in the Phase 3 Study of Maraviroc in Treatment-Naive Patients

Jayvant Heera1, Mike Saag2, Prudence Ive3, Jeannette Whitcomb4, Marilyn Lewis5, Lynn McFadyen5, James Goodrich1, Howard Mayer1, Elna van der Ryst5, and Mike Westby5

1Pfizer Global Research and Development, New London, CT, USA2University of Alabama at Birmingham, Birmingham, AL, USA3University of the Witwatersrand, Johannesburg, South Africa4Monogram Biosciences Inc., South San Francisco, CA, USA5Pfizer Global Research and Development, Sandwich, UK

Presentation Number 40LB15th CROIBoston, USA, February 3–6, 2008

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Heera J, et al. 15th CROI 2008; Presentation 40LB

Randomization 1:1

MERIT Study: Phase 3 Trial Design

Maraviroc (MVC 300 mg BID) + Combivir (ZDV+3TC)*

Efavirenz (EFV 600 mg QD) + Combivir (ZDV+3TC)*

Primary analysis

0 Week 48 Week 96Screening(6 weeks)

Patients stratified by• HIV-1 RNA < and ≥100,000 copies/mL at screening• Geographic location: Northern Hemisphere and Southern Hemisphere

Patient eligibility criteria:• ≥16 years of age• Treatment naive• CCR5-tropic (R5) HIV-1 infection

• HIV-1 RNA ≥2,000 copies/mL• No evidence of resistance to EFV, zidovudine (ZDV), or lamivudine (3TC)

*Patients experiencing toxicity to ZDV or 3TC were permitted to substitute an alternative nucleoside reverse transcriptase inhibitor

MVC QD arm discontinued at end of Phase 2b (Week 16) for failure to meet protocol-defined criteria to continue (205 patients completed 16 weeks)

Saag M, et al. 4th IAS 2007. Abstract WESS104 MERIT Study

3


Week 48 Efficacy Results

Saag M, et al. 4th IAS 2007. Abstract WESS104 MERIT Study – 48 weeks

0

10

20

30

40

50

60

70

80

90

100

361 360

69.365.3

Patie

nts

(%)

N= MVC + CBVEFV + CBV

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

HIV-1 RNA <50 copies/mL (ITT)

–4.2* (–10.9†)

*Difference (adjusted for randomization strata) †Lower bound of 1-sided 97.5% confidence interval; non-inferiority margin = –10%CBV = Combivir

Time (weeks)

EFV + CBVMVC + CBV

0

20

40

60

80

100

120

140

160

180

0 8 16 24 32 40 48

Mea

n ch

ange

in fr

om b

asel

ine

in

CD

4+ c

ount

(ce

lls/m

m3 )

142 cells/mm3

169 cells/mm3

Change in CD4+ cell count (LOCF)

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Summary of Discontinuations Through 48 Weeks

Saag M, et al. 4th IAS 2007. Abstract WESS104 MERIT Study – 48 weeks

Reason for discontinuation EFV + CBVN=361

MVC + CBV N=360

All, n (%) 91 (25.2) 97 (26.9)

Adverse event, n (%) 49 (13.6) 15 (4.2)

Lack of efficacy, n (%) 15 (4.2) 43 (11.9)

Other reason, n (%) 9 (2.5) 14 (3.9)

Withdrew consent or lost to follow-up, n (%) 18 (5.0) 25 (6.9)


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Objectives

● To understand the virological correlates associated with treatment failure at Week 48

Methods● Tropism was measured throughout the study using the Trofile™ assay

● Resistance to NRTIs and EFV was evaluated by the PhenoSense GT™ assay

● Resistance to MVC was evaluated using the PhenoSense Entry™ assay, with plateaus in maximum percent inhibition (MPI) <95% as a marker of resistance

● MVC plasma concentrations were determined using sparse PK sampling and combined with adherence data

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Percentage of Patients with HIV-1 RNA <50 Copies/mL at Week 48 by Tropism Result at Baseline

10

20

30

40

50

60

70

80

90

100

339 331

11 14

69.3 68.0

54.6

7.1

Patie

nts

(%)

N=

R5 D/M

0


MVC + CBV

EFV + CBV

MERIT Study – 48 weeks

● 25 (3.5%) patients had D/M virus at baseline ● In both treatment groups the proportion of patients with D/M virus at baseline who

achieved undetectable HIV-1 RNA was reduced relative to patients with R5 virus

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Possible Correlates of Tropism Changes From Screening to Baseline: Combined Treatment Groups

Tropism change from screening to baseline, N=24

R5 at screening and baseline, N=697

Mean screening HIV-1 RNA, log10 copies/mL

4.79 4.84

Mean screening CD4+ count, cells/mm3 (min, max)

201 (23, 431)

271(3, 1,528)

Viral subtype

B

C

Other/undetermined

17 (4.2%)

4 (1.9%)

3 (4.2%)

390 (95.8%)

212 (98.1%)

68 (95.8%)

MERIT Study – 48 weeks

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Analysis of Virological Correlates Associated with Lack of Efficacy

● Virological analysis of patients who discontinued due to lack of efficacy

– 43 patients on MVC– 15 patients on EFV

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R5(32)

Missing(1)

NR/NP(2)

DM/X4(8)

TropismBaseline

TropismFailure

R5(13)

(7)

BLQ(9)

(2)

NR/NP(5)

(2)

D/M or X4(16)

(16)NRTI res

Tropism Shift and NRTI Resistance at Failure for Patients on MVC (n=43)

27*NR/NP = no result/non-phenotypableBLQ = HIV-1 RNA <500 copies/mL tropism tests were cancelled or censored for these samples*Excludes two patients with no resistance data at the last timepoint on treatment, but with resistance at earlier visits

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RTI Resistance Selected in Virus from Patients with Treatment Failure

Tropism at failure*

MVC (300 mg BID)

N n M184V 2NRTIres

R5

D/M or X4

Other

22

19

2

22

19

2

10 (45%)

19 (100%)

0

2 (9%)

5 (26%)

0Total 43 43 29 (67%) 7 (16%)

Tropism at failure*

EFV (600 mg QD)

N n EFVres +M184V +2NRTIresR5

Other

14

1

13

1

8

1

3

1

0

1Total 15 14 9 (64%) 4 (29%) 1 (7%)* Last valid tropism result while on treatmentN = total patients in group; n = total patients with a valid resistance test; 2NRTIres = genotypic resistance to 3TC and ZDV (or substituted NRTI); EFVres = genotypic resistance to EFV; Other = missing baseline tropism result (n=1) or no valid tropism data during failure (n=2)

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R5(32)

TropismBaseline

TropismFailure

R5(11)

(4*)

BLQ(6)

(5)

NR/NP(5)

(2)

D/M or X4(10)

(1)PK BLQ

Incomplete Adherence is a Significant Contributor to Treatment Failure in Patients with R5 Virus at Baseline

50%NR/NP = no result/non-phenotypableBLQ = HIV-1 RNA <500 copies/mL tropism tests were cancelled or censored for these samplesPK BLQ = MVC plasma concentrations below the limit of quantification corresponding to a rebound in viral load* Includes one patient with no BLQ PK but with documented interruption between visits corresponding to rebound in VL.

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Characteristics of Patients who Failed 300 mg BID MVC with R5 Virus

Country Race Sex Clade MVC resistance*

NRTI resistance** PK BLQ

Belgium Black M AG Yes M184V

Argentina White M BF Yes M184V, M41M/L

Poland White M B M184V

USA White M B M184V

South Africa Black M C M184V

Australia White M B Yes

Puerto Rico White M B (Note 1)

South Africa Black M C Yes

South Africa*** Black M C Yes

South Africa Black F C Yes

UK White M B

South Africa Other M C*By phenotype;**By genotype; *** Tropism was recorded as “BLQ” at last on-treatment timepoint, but ‘R5’ at all other timepoints PK BLQ = serum levels of MVC during periodic sampling were below limit of quantificationNote 1: documented non-adherence between visits coinciding with viral load rebound

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Example Patient Profile 1Treatment start

Treatment end

MPI 99

Time since first administration (day)

CD

4+ c

ount

(cel

ls/m

m3 )

R5 R5R5 R5 R5

MPI 92

1

2

3

4

5

6

0 100 300200

0

200

400

600

800

NR NR NR NR

M184V

FPV/r + TDF + 3TCMVC + CBV

R5

HIV

-1 R

NA

(log

10 c

opie

s/m

L)

FPV = fosamprenavir; TDF = tenofovir

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Mean Change from Baseline in CD4+ Count (cells/mm3) by Tropism Result at Baseline and Time of Failure

MVC + CBV

EFV + CBV

NR = not-reported, non-phenotypable, below limit of quantification, or missing

44

-18

86

101

80 83

111

128

-40

-20

0

20

40

60

80

100

120

140

N=0 N=0N=15

R5R5 R5D/M

or X4R5NR non-R5AnyTotal

N=6

N=9N=10 N=10N=42 N=11 N=11

Mea

n ch

ange

from

bas

elin

e in

CD

4+ c

ount

(cel

ls/m

m3 )

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Tropism Summary

● 13 patients (3.8%) receiving MVC had a change in tropism result from R5 to D/M between screening and baseline– The response to MVC was significantly reduced in this subgroup

– Tropism changes were 50% less frequent in patients with clade C HIV-1 than in patients with clade B or other clades

● For subjects with R5 virus at baseline, no appreciable difference in treatment response was seen between the MVC and EFV treatment groups

● A retrospective analysis will be performed to investigate the impact of an enhanced tropism assay on MERIT outcomes

● CXCR4-using virus was detected at failure in 10/32 (31.3%) MVC-treated (300 mg BID) subjects with R5 virus at baseline

● Patients failing MVC had higher CD4+ cell counts at failure than EFV, irrespective of tropism result at failure

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Resistance Summary

● Lamivudine resistance mutation (M184V/I) was most common in patients failing in the MVC arm– 19/19 patients failing with D/M or X4 virus

– 10/22 patients failing with R5 virus

● EFV-related resistance mutations were most common in patients failing in the EFV arm– 9/14 patients with resistance test data

● Resistance to MVC in patients failing with R5 virus was uncommon – 2/12 patients studied

● Viral load rebound in patients failing the MVC arm was more commonly associated with BLQ plasma levels of MVC at the time of failure

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Acknowledgements

● The patients participating in the MERIT study

● The investigators and study site staff

● The Pfizer MERIT study team

Documents

Virological Correlates Associated with Treatment Failure at Week 48 in the Phase 3 Study of Maraviroc in Treatment-Naive Patients Jayvant Heera 1, Mike