A Multicenter, Randomized, Double-Blind, Comparative Trial of a Novel CCR5 Antagonist, Maraviroc Versus Efavirenz, both in Combination with Combivir (Zidovudine/Lamivudine),

A Multicenter, Randomized, Double-Blind, Comparative Trial of a Novel CCR5 Antagonist, Maraviroc Versus Efavirenz, both in Combination with Combivir (Zidovudine/Lamivudine), for the Treatment of Antiretroviral-Naive Subjects Infected with R5 HIV 1: Week 48 Results of the MERIT Study

Abstract Number WESS1044th IAS, Sydney, July 2007

Michael Saag1, Prudence Ive2, Jayvant Heera3, Margaret Tawadrous3, Edwin DeJesus4, Nathan Clumeck5, David Cooper6, Andrzej Horban7, Lerato Mohapi8, Horacio Mingrone9,

Gustavo Reyes-Teran10, Sharon Walmsley11, Frances Hackman12, Elna van der Ryst12, Howard Mayer3

1University of Alabama at Birmingham, Birmingham, USA2University of the Witwatersrand, Clinical HIV Research Unit, Johannesburg, South Africa

3Pfizer Global Research and Development, New London, USA4Orlando Immunology Center, Orlando, USA

5Saint-Pierre University Hospital, Infectious Diseases, Brussels, Belgium6University of New South Wales, National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia

7Hospital of Infectious Diseases, Warsaw, Poland8University of the Witwatersrand, Perinatal HIV Research Unit, Johannesburg, South Africa

9HIV Outpatient Care Unit, Muñiz Hospital, Buenos Aires City, Argentina10Instituto Nacional de Enfermedades Respiratorias, Center for Research in Infectious Diseases, Tlalpan, Mexico

11University of Toronto, Toronto, Canada12Pfizer Global Research and Development, Sandwich, UK

2

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 48 wk 96 wkScreening(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• R5 HIV-1 infection

First patient visit

Nov 2004

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

*Patients experiencing toxicity to ZDV or 3TC were permitted to substitute an alternative NRTI

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

3

Demographics and Baseline Characteristics

Randomized: N=740Treated: N=721

EFV + CBVN=361

MVC + CBV N=360

Mean age, yrs (range) 37.4 (18–77) 36.7 (20–69)

Male, n (%) 259 (71.7) 256 (71.1)

Race, n (%)WhiteBlackAsianOther

198 (54.8)133 (36.8)

5 (1.4)25 (6.9)

204 (56.7)123 (34.2)

6 (1.7)27 (7.5)

Median CD4+ count, cells/mm3 (range) 254 (8–1,053)

241 (5–1,422)

Mean HIV-1 RNA, log10 copies/mL (SD) 4.88 (0.699)

4.86 (0.640)

MERIT Study 48 weeks

4

Summary of Discontinuations Through 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)

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


5

Percentage of Patients with Undetectable HIV-1 RNA by VisitIncludes all patients who received at least one dose of study medication

MERIT Study 48 weeks Missing values classified as failures/non-responders

<400 copies/mL <50 copies/mL

EFV + CBV (N=361)MVC + CBV (N=360)

Patie

nts

(%)

Patie

nts

(%)

Time (weeks) Time (weeks)

0

10

20

30

40

50

60

70

80

90

100

2 4 8 16 24 32 40 48 2 4 8 16 24 32 40 48

70.0%

72.6% 69.0%

64.4%

0

10

20

30

40

50

60

70

80

90

100

6

Percentage of Patients with Undetectable HIV-1 RNA at Week 48 (Primary Endpoint)

0

10

20

30

40

50

60

70

80

90

100

361 360

361 360

73.1 70.6 69.365.3

Patie

nts

(%)

N=

MVC + CBV

EFV + CBVIncludes all patients who received at least one dose of study medication


<400 copies/mL <50 copies/mL

–3.0* (–9.5†) –4.2* (–10.9†)

*Difference (adjusted for randomization strata) †Lower bound of 1-sided 97.5% confidence interval; noninferiority margin = –10%Per-protocol analysis: <400 copies/mL difference = -4.1 (-10.5†), <50 copies/mL difference = -4.4 (-11.2†)

Intent-to-treat (ITT) analysis

7

Mean Change in CD4+ Count from Baseline by Visit

0

20

40

60

80

100

120

140

160

180

0 2 4 8 12 16 20 24 32 40 48Time (weeks)

EFV + CBVMVC + CBV

Mea

n ch

ange

in C

D4+

cou

nt fr

om b

asel

ine

(cel

ls/m

m3 )

MERIT Study 48 weeks LOCF

142 cells/mm3

169 cells/mm3

N = 331 346 348 348 348 348 348 348 348 348 N = 336 350 351 352 352 352 352 352 352 352


8

Mean Change in CD4+ Count from Baseline to Week 48M

ean

chan

ge in

CD

4+ c

ount

from

bas

elin

e (c

ells

/mm

3 )

LOCF

EFV + CBVN=348

MVC + CBV N=352

144

170

0

50

100

150


*Difference: +26(95% CI: +7, +46)

200


* Difference adjusted for randomization strata

9

Percentage of Patients with HIV-1 RNA <50 copies/mL by HIV-1 RNA at Screening

0

10

20

30

40

50

60

70

80

90

100

211 204

150 156

71.6 69.6 66.659.6

Patie

nts

(%)

N=



<100,000 copies/mL ≥100,000 copies/mL

Missing values classified as failures/non-responders

MVC + CBV

EFV + CBV

10

Percentage of Patients with HIV-1 RNA <50 copies/mL by Geographic Region

10

20

30

40

50

60

70

80

90

100

199 194

162 166

67.8 68.0 71.062.1

Patie

nts

(%)

N=



Northern Hemisphere* Southern Hemisphere†

Missing values classified as failures/non-responders

MVC + CBV

EFV + CBV

*Patients at study centers in North America and Europe†Patients at study centers in Argentina, South Africa and Australia

0

11

Safety Analyses

All causalities and severities EFV + CBVN=361

MVC + CBVN=360

Patients with adverse events 340 (94.2) 331 (91.9)

Patients with grade 3 AEs, n (%) 66 (18.3) 51 (14.2)

Patients with grade 4 AEs, n (%) 24 (6.6) 22 (6.1)

Patients with SAEs, n (%)† 46 (12.7) 41 (11.3)

Patients with Category C events, n (%) 12 (3.3) 6 (1.7)

Malignancies 16 (4.4) 10 (2.8)

Deaths†*, n (%) 1 1

AEs = adverse events; SAEs = serious adverse events†Based on all data through 21 June 2007

*Deaths reported up to 28 days after stopping study drug; one additional death on EFV within 28 days, date of death not captured in database



12

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 medication


MVC + CBV (N=360)

EFV + CBV (N=361)

Patie

nts

(%)

0

10

20

30

40

50

Headac

he

Cough

Bronch

itis

Vomiting

Nause

a

Fatigue

Abdominal pain

Upper res

p. trac

t infec

t.

Diarrh

ea

Abnormal

dreams

Nasophary

ngitisRas

h

Dizzines

s

13

Incidence of Category C AIDS-Defining Events

Number of patients EFV + CBVN=361

MVC + CBVN=360

Category C events 12 (3.3) 6 (1.7)

Infections 8 (2.2) 5 (1.4)

Tuberculosis 8 1Herpes simplex 1 1Lobar pneumonia/Lower respiratory tract infection 0 2

Pneumocystis jiroveci pneumonia 0 1

Malignancies 4 (1.1) 1 (0.3)

Hodgkin’s disease 2 0NHL/Diffuse large B-cell lymphoma 1 1Kaposi’s sarcoma 1 0



14

Median Maximum Change in Fasting Lipids

Total cholesterol

HDL cholesterol

LDL cholesterol

Triglycerides

1

27

4

9

-3

10

-4

10

-5

0

5

10

15

20

25

30

Med

ian

chan

ge (m

g/dL

)

MVC + CBVEFV + CBV

N= 332 321 327 319 318 311 332 321


15

Proportion of Patients with Grade 3 or 4 Liver Function Test Values Without Regard to Baseline

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

EFV + CBV MVC + CBV

AST: Grade 3 >5.0 to 10.0 ULN*

Grade 4 >10.0 x ULN*9/350 (2.6%)2/350 (0.6%)

7/353 (2.0%)5/353 (1.4%)

ALT: Grade 3 >5.0 to 10.0 ULN*

Grade 4 >10.0 x ULN*9/350 (2.6%)2/350 (0.6%)

9/353 (2.5%)2/353 (0.6%)

Total bilirubin: Grade 3 >2.5 to 5.0 x ULN* Grade 4 >5.0 x ULN*

0/3450/345

3/352 (0.9%)†

0/352

*Upper limit of normal†All three patients had hyperbilirubinemia not associated with transaminase elevations,

two associated with Gilbert’s syndrome. MERIT Study 48 weeks

16

Summary of 48-Week Primary Analyses (1)

● The percentage of subjects discontinuing from the study prior to Week 48 was similar in the MVC (26.9%) and EFV (25.2%) arms– The rate of discontinuation due to lack of efficacy was higher with MVC (11.9%) than

with EFV (4.2%)

– The rate of discontinuation due to adverse events was lower with MVC (4.2%) than with EFV (13.6%)

● Based on the pre-planned statistical analysis (noninferiority margin of –10%), MVC was:– Noninferior to EFV based on <400 copies/mL endpoint (70.6% vs 73.1%)

– But not the <50 copies/mL endpoint (65.3% vs 69.3%)

● CD4+ cell count increases were higher in patients receiving MVC compared to EFV (+170 vs +144 cells/mm3)


17

Summary of 48-Week Primary Analyses (2)

● Fewer patients experienced grade 3 or 4 adverse events in the MVC arm than in the EFV arm

● Fewer patients experienced Category C events in the MVC arm (n=6) than in the EFV arm (n=12)– The incidence of AIDS-defining malignancies and malignancies in general was lower

in the MVC arm than in the EFV arm

● Grade 3/4 transaminase elevations were infrequent and occurred at a similar rate in the two treatment arms

● Median lipid increases from baseline were greater in the EFV arm


18

Acknowledgements

● Patients participating in the MERIT study

● Investigators and study site staff

● Pfizer MERIT study team

● Monogram Biosciences

Documents

A Multicenter, Randomized, Double-Blind, Comparative Trial of a Novel CCR5 Antagonist, Maraviroc Versus Efavirenz, both in Combination with Combivir (Zidovudine/Lamivudine),