9TH INTERNATIONAL CONGRESS ON DRUG THERAPY IN HIV INFECTION November 9–13, 2008 Glasgow, UK

Efficacy and Safety of Maraviroc in Treatment-Experienced (TE) Patients Infected with R5 HIV-1: 96-week Combined Analysis of the MOTIVATE 1 & 2 StudiesWD Hardy1, R Gulick2, H Mayer3, G Fätkenheuer4, M Nelson5, J Heera3, N Rajicic6, J Goodrich3 1 Cedars-Sinai Medical Center/Geffen School of Medicine, UCLA, Los Angeles, CA, USA; 2 Weill Medical College of Cornell University, New York, CA, USA; 3 Pfizer Global Research and Development, New London, CT, USA; 4 University of Cologne, Köln, Germany; 5 Chelsea & Westminster Hospital, London, UK; 6 Pfizer Inc., New York, NY, USA

9TH INTERNATIONAL CONGRESS 9TH INTERNATIONAL CONGRESS ON DRUG THERAPY IN HIV INFECTIONON DRUG THERAPY IN HIV INFECTION

November 9–13, 2008November 9–13, 2008Glasgow, UKGlasgow, UK

Randomization 1:2:2

MOTIVATE 1 N=601 MOTIVATE 2 N=474

MOTIVATE 1 & 2: Trial Design

OBT* + maraviroc (150 mg† BID)

OBT* + maraviroc (150 mg† QD)

OBT* + placebo

0 Week 48 Week 96

* OBT = optimized background therapy of 3–6 ARVs (PK boosting doses of ritonavir not counted as an ARV)† Patients receiving a PI (except tipranavir) and/or delavirdine in their OBT received 150 mg dose of MVC, all other patients

received 300 mg dose of MVC

Screening6 weeks

Patients were stratified by enfuvirtide use and HIV-1 RNA < and ≥100,000 copies/mL

Patient eligibility criteria: • R5 HIV-1 infection• HIV-1-RNA ≥5,000 copies/mL• Stable pre-study antiretroviral (ARV) regimen, or no ARVs for ≥4 weeks• Resistance to and/or ≥6 months’ experience with ≥one ARV from three classes (≥two for protease inhibitors[PIs])

MOTIVATE 1 and 2 Week 96

Adapted from Hardy et al. HIV-9 2008. Presentation 0425.

MOTIVATE 1 & 2: Percentage of Patients with HIV-1 RNA <50 copies/mL at Week 48

Adapted from Hardy et al. CROI 2008. Abstract 792.

0 4 20 28

Pat

ient

s (%

)

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)

MOTIVATE 1 & 2: Week-96 Analyses

Two analyses were conducted to characterize the Week-96 combined MOTIVATE 1 and 2 populations:

● Efficacy Analysis

This analysis includes patients receiving MVC QD and BID who had undetectable viral load (HIV-1 RNA <50 copies/mL ) at Week 48 and were followed until Week 96

● Safety Analysis

This analysis includes all blinded data for study participants according to their original randomization and includes data from patients who continued to receive blinded therapy beyond Week 48. It does not include any open-label treatment data. This results in a distribution of patients in the study with different exposures to blinded study drug. The study was unblinded when the last patient to be randomized reached Week 48

MOTIVATE 1 and 2 Week 96 Efficacy



OBT* + placebo

0 Week 48 Week 96

Efficacy data include all patients who reached

Week 48 with HIV-1RNA <50 copies/mL and

continued on blinded therapy or

open-label MVC BID



received 300 mg dose of MVC

Screening6 weeks


Patient eligibility criteria: • R5 HIV-1 infection• HIV-1-RNA ≥5,000 copies/mL• Stable pre-study antiretroviral (ARV) regimen, or no ARVs for ≥4 weeks• Resistance to and/or ≥6 months’ experience with ≥one ARV from three classes (≥two for protease inhibitors [PIs])

Randomization 1:2:2





Randomization 1:2:2




0 Week 48 Week 96

259/426 (60.8%) open-label MVC BID

239/414 (57.7%)open-label MVC BID




received 300 mg dose of MVC.

Screening6 weeks




MOTIVATE 1 & 2: Percentage of Patients with HIV-1 RNA <50 copies/mL at Week 96Includes all patients who received at least one dose of study medication




Pat

ient

s (%

)

Option to switch to open-label MVC BID

43.7%

45.1%

23.0%

43.5%

46.5%

16.7%

38.9%41.3%

7.2%

Time (weeks)


0

10

20

30

40

50

60

70

80

90

100

0 8 16 24 32 40 48 56 64 72 80 88 96

In this analysis, non-completers were categorized as failures


81.4%

10.5%

7.0%

MOTIVATE 1 & 2: Clinical Outcome At Week 96 of Patients with HIV-1 RNA <50 copies/mL at Week 48Maraviroc groups include patients on blinded therapy and open-label MVC BID

Does not include patients who discontinued for non-efficacy reasons: adverse events (n=4); withdrew/lost to follow up (n=8); other reasons (n=4); no discontinuation and no data at 96 weeks (N=4)

1.2% 2.8%0.6%

N=172 N=181

Lack of efficacy = HIV-1 RNA levels of at least three times the baseline HIV-1 RNA level

86.7%

9.9%

0

10

20

30

40

50

60

70

80

90

100

MVC QD + OBT MVC BID + OBT

Pa

tien

ts (

%)

Discontinuation due to lack of efficacy

On study, not failed

HIV-1 RNA 50 400 copies/mL

HIV-1 RNA <50 copies/mL

MOTIVATE 1 and 2 Week 96 EfficacyAdapted from Hardy et al. HIV-9 2008. Presentation 0425.

9

MOTIVATE 1 & 2: Week 96 Analyses

Two analyses were conducted to characterize the Week 96 combined MOTIVATE 1 and 2 populations:

● Efficacy Analysis

This analysis includes patients receiving MVC QD and BID, who had undetectable viral load (HIV-1 RNA <50 copies/mL ) at Week 48 and were followed until Week 96.

● Safety Analysis

This analysis includes all blinded data for study participants according to their original randomization and includes data from patients who continued to receive blinded therapy beyond Week 48. It does not include any open-label treatment data. This results in a distribution of patients in the study with different exposures to blinded study drug. The study was unblinded when the last patient to be randomized reached Week 48.

MOTIVATE 1 and 2 Week 96 SafetyAdapted from Hardy et al. HIV-9 2008. Presentation 0425.

Randomization 1:2:2





OBT* + placebo

0 Week 48 Week 96

259/426 (60.8%) open-label MVC BID



MOTIVATE 1 and 2 Week 96 Safety


received 300 mg dose of MVC.

Screening6 weeks




MOTIVATE 1 & 2: Duration of Exposure to Study Drug

Median (bars) and range (lines) of study treatment duration at indicated study time point

0

Wee

k 48

End

of B

linde

d T

hera

py

Time (weeks)

2062

4860

4856

20132

73134

73135

8 16 24 32 40 48 56 64 72 80 88 96 104 112120 128 136






MOTIVATE 1 & 2: Incidence of Malignancies at Week 48 and End of Blinded Therapy Includes all patients who received at least one dose of study medication




Total patient-years 111 300 309 60 522 5510R

ate

per

100

pa

tient

-yea

rs

9.3

4.1 4.6

7.1

3.5 3.6

2468

10

Week 48 End of blinded therapy

Adjusted incidence

0

Pat

ient

s (%

)

4.82.9 3.3

5.34.3 4.5

2468

10

Unadjusted incidence


N=209 414 426 209 414 426

If the same patient in a given treatment arm had more than one occurrence in the same event category, only the most severe occurrence was taken



MOTIVATE 1 & 2: Incidence of Category C (AIDS-defining) Events at Week 48 and End of Blinded TherapyIncludes all patients who received at least one dose of study medication

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


Total patient-years 111 300 309 160 522 5510

Rat

e p

er 1

00

patie

nt-y

ears

10.0


N= 209 414 426 209 414 426

0

Pat

ient

s (%

) 7.77.0

5.2

8.1 7.55.9

2468

10

Unadjusted incidence

Adjusted incidence

2468

1012141618 14.9

7.6

11.0

6.25.3




MOTIVATE 1 & 2: Incidence of LFT Abnormalities (Without Regard to Baseline) at Week 48 and End of Blinded Therapy

ULN, upper limit of normalTotal patient-years of exposure to study drug at Week 48: Placebo + OBT 111; MVC QD + OBT 300; MVC BID + OBT 309 Total patient-years of exposure to study drug at at end of blinded therapy: Placebo + OBT 160; MVC QD + OBT 522; MVC BID + OBT 551

Incidence (unadjusted)

n (%)

Incidence (adjusted)

Event counts adjusted to 100 years of patient exposure

Placebo + OBT

MVC QD

+ OBT

MVC BID + OBT

Placebo + OBT

MVC QD + OBT

MVC BID + OBT

Week 48

AST: >3.0 x ULN 17 (8) 39 (10) 45 (11) 16.2 13.8 15.7

ALT: >3.0 x ULN 13 (6) 29 (7) 37 (9) 12.4 10.1 12.7

Total bilirubin: >1.5 x ULN

30 (14) 66 (16) 51 (12) 31.9 25.3 18.5

End of blinded therapy

AST: >3.0 x ULN 19 (9) 45 (11) 46 (11) 13.3 9.4 9.5

ALT: >3.0 x ULN 15 (7) 37 (9) 39 (9) 10.0 7.8 7.8

Total bilirubin: >1.5 x ULN

31 (15) 68 (17) 54 (13) 23.8 16.0 11.3



MOTIVATE 1 & 2: Adverse Events Occurring in ≥5% Patients at End of Blinded Therapy

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


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

Pa

tien

ts

(%) Unadjusted incidence

RTI, respiratory tract infectionIf the same patient in a given treatment had more than one occurrence in the same preferred term event category, only the most severe occurrence is taken. Event counts are adjusted to 100 years of patient exposure. Includes data up to 7 days after last dose of study drug.

Ra

te p

er

10

0

pa

tien

t-ye

ars

0

10

20

30

40

50

Nausea Vomiting Fatigue Naso-pharyngitis

Upper RTI Dizziness Headache Rash

Exposure adjusted incidence

0

10

20

30

40

50

Nausea Vomiting Fatigue Naso-pharyngitis

Upper RTI Dizziness Headache Rash

MOTIVATE 1 and 2 Week 96 SafetyAdapted from Hardy et al. HIV-9 2008. Presentation 0425.

MOTIVATE 1 & 2 Week 96: Summary

Efficacy Analysis

● Maraviroc + OBT results in durable viral suppression through 96 weeks in treatment-experienced patients with R5 HIV-1.

– 87% of patients in the BID arm who were fully suppressed at Week 48 remained suppressed at Week 96.

Safety Analysis

● Pooled analyses revealed no new or unique safety signals between Week 48 and end of blinded therapy.

– Category C events, malignancies, and LFT abnormalities occurred with similar frequency among treatment groups when not adjusted for the longer duration of exposure in the maraviroc groups.

– The incidence of these events decreased between Week 48 and end of blinded therapy.

– After adjusting for exposure, the incidence of Category C events and malignancies was lower in the maraviroc groups compared to placebo.



Documents

9TH INTERNATIONAL CONGRESS ON DRUG THERAPY IN HIV INFECTION November 9–13, 2008 Glasgow, UK