Overview of Phase 1 and 2aSafety and Efficacy Data

of Maraviroc (UK-427,857)Mary McHale, Sam Abel,

Deborah Russell, James Gallagher, Elna van der Ryst

Pfizer Global Research and Development, Sandwich Laboratories, Kent, UK

2

Maraviroc (MVC) Maraviroc (UK-427,857, MVC) is a CCR5 antagonist with potent anti-HIV activity in

vitro

An extensive Phase 1/2a program has been carried out

Here we present a summary of the data from the five double-blinded, placebo-controlled, multiple-dose studies with MVC alone, and one drug–drug interaction study with oral contraceptives (expected not to affect exposure to MVC in plasma)

Studies included a total of 259 healthy volunteers and HIV+ positive patients who received MVC at QD and BID doses ranging from 3 mg BID to 1200 mg QD or placebo

Some volunteers received more than one dose of MVC/placebo and are therefore included in more than one dose group in tables and figures.

• Total dosing events for MVC = 220 (154 healthy volunteers, 66 HIV+)• Total dosing events for placebo = 111 (95 healthy volunteers, 16 HIV+)

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Study Details

Study

(All double-blind, placebo-controlled)

Unit dose range* (mg)

Duration (days)

Dose-escalating multiple-dose study(with wash out periods)1

3–600 10

Oral contraceptive interaction study2 100 7

28–day safety study3 100–300 28

High dose-escalating multiple-dose study 300–1200 7 & 7

Monotherapy study in asymptomatic HIV+ subjects4

25–300 10

Monotherapy study in asymptomatic HIV+ subjects(investigating possible food effect)4

150–300 10

1. Abel S et al. 10th CROI 2003; Paper 547. 2. Russell D et al. 43rd ICAAC 2003; Paper 3080.

*Unit dose refers to actual dose taken at any time point and not total daily dose, several studies included BID doses

3. Abel S et al. 43rd ICAAC 2003; Paper 3066.4. Fätkenheuer G et al. 15th IAC 2004; Abstract TuPeB4489.

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Demographic Data

Dose

Placebo 150 mg 300 mg 600–1200 mg

N 111 109 50 61

Gender Male 76 90 37 41

Female 35 19 13 20

Age 18–44 104 99 48 61

45–64 7 10 2 0

Race White 104 102 48 60

Black 3 4 1 1

Asian 2 1 0 0

Other 2 2 1 0

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Most Frequent Adverse Events – Treatment Related

Dose

Adverse Event Placebo 150 mg 300 mg 600–1200 mg

N (%) 111 109 50 61

Headache 17 (15) 19 (17) 12 (24) 18 (30)

Dizziness 7 (6) 8 (7) 5 (10) 27 (44)

Nausea 6 (5) 1 (1) 6 (12) 16 (26)

Asthenia 8 (7) 5 (5) 3 (6) 16 (26)

Flatulence 6 (5) 3 (3) 7 (14) 8 (13)

Rhinitis 1 (1) 2 (2) 2 (4) 14 (23)

Postural hypotension 1 (1) 0 (0) 0 (0) 14 (23)

Abnormal vision 2 (2) 1 (1) 1 (2) 12 (20)

Conjunctivitis 0 (0) 0 (0) 0 (0) 14 (23)

Somnolence 3 (3) 0 (0) 0 (0) 12 (20)

Abdominal pain 3 (3) 1 (1) 2 (4) 7 (11)

6

Postural Hypotension

0

20

40

60

80

100

Placebo <100 mg 100 mg 150 mg 300 mg 600 mg 900 mg 1200 mg

Treatment group

Inci

den

ce o

fp

ost

ura

l hyp

ote

nsi

on

(%

)

Postural hypotension was the dose-limiting AE in phase 1 Occurred at rates in excess of placebo only at doses of 600 mg

3/35

5/17

6/9

2/111 0/36 0/57 0/16 0/50

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SAEs and Discontinuations

No SAEs reported

11 discontinuations on MVC

• 9 in 154 healthy volunteers in four Phase 1 studies(3 related)

• 2 in 66 HIV+ patients in two Phase 2a studies (not related)

– “no longer willing to participate” (25 mg QD)

– “headache” (100 mg QD fasted)

8 discontinuations on placebo

• 8 in 95 healthy volunteers in four Phase 1 studies (2 related)

• 0 in 16 HIV+ patients in two Phase 2a studies

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DiscontinuationsDose N Reason for discontinuation Treatment

related*

Severity*

3 mg 1 Transaminases elevated (1) Yes Severe

25 mg 2 Varicella infection (1)

No longer willing to participate (1)

No

-

Moderate

-

100 mg 3 Tooth abscess (1)

Headache (1)

No longer willing to participate (1)

No

No

-

Moderate

Moderate

-

300 mg 2 Protocol violation (1)

Infectious mononucleosis (1)

-

No

-

Moderate

600 mg 3 Postural hypotension (2)

No longer willing to participate (1)

Yes

-

Severe

-

Placebo 8 Postural hypotension(1)

Protocol violation (3)

Sore throat (1)

Laboratory abnormality (1)

Headache (1)

Itchy rash of thorax (1)

Yes

-

No

No

No

Yes

Severe

-

Moderate

Moderate

Mild

Mild

*Investigator assessment

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Laboratory Abnormalities

Changes in s-creatinine• Elevations in creatinine (<2ULN) in one study

at 1200 mg QD and placebo

• Not seen in other studies where similar exposures to MVC were achieved

Liver-enzyme abnormalities• Sporadic transaminase elevations with no dose relationship

• No associated bilirubin elevations

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Laboratory Abnormalities

ALT changesin patients with normal ALT at baseline, n

ULN >ULN to 2 ULN

>2ULN to 3ULN

>3ULN to 5ULN

>5ULN Total

Placebo 87 7 1 0 0 95

<100 mg 30 4 0 1 0 35

100 mg 34 6 1 0 0 41

150 mg 11 5 0 0 0 16

300 mg 43 5 0 1 1 50

600 mg 31 2 2 0 0 35

900 mg 14 3 0 0 0 17

1200 mg 7 2 0 0 0 9

ULN = Upper Limit of Normal

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Max Increase in QTcF From Baseline (msec)

No evidence of dose-related changes in QTcF at dosesof 1200 mg QD

Increase in QTcF from baseline (msec), n (%)

N <30 30–<60 60

Placebo 74 66 (89) 8 (11) 0 (0)

<100 mg 36 32 (89) 3 (8) 1 (3)

100 mg 57 55 (97) 2 (4) 0 (0)

150 mg 16 12 (75) 4 (25) 0 (0)

300 mg 50 47 (94) 3 (6) 0 (0)

600 mg 35 32 (91) 3 (9) 0 (0)

900 mg 17 16 (94) 0 (0) 1 (6)

1200 mg 9 9 (100) 0 (0) 0 (0)

QTcF, Fridericia’s correction

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MVC Safety Profile Summary

At doses of 300 mg BID, AE profile was similar to placebo

Postural hypotension was the dose-limiting AE – only seen at rates higher than placebo for doses of 600 mg

Clinically relevant elevations in transaminases occurred sporadically, with no dose relationship and no associated elevation in bilirubin

No evidence of clinically relevant prolongation of QTcF

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MVC Efficacy Results:Mean Reduction in Viral Load over Time

Ch

ang

e fr

om

bas

elin

e (

log

10 H

IV-1

co

pie

s/m

L)

Last day of dosing

Placebo 1015Placebo 100725 mg QD50 mg BID100 mg QD100 mg BID150 mg BID Fast150 mg BID Fed300 mg QD300 mg BID

Maraviroc dose4

1288878888

n

Time (day)5 10 15 20 25 30 35 40Baseline

–2.0

–1.5

–1.0

–0.5

0.0

0.5

Fätkenheuer G et al. 15th IAC 2004; Abstract TuPeB4489

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MVC Reduces Viral Load in All Patients Receiving Therapeutic Doses

Mean decrease in HIV RNAlog10 copies/mL (range)

HIV RNA decrease>1.0 log10 copies/mL

(no. patients)

Median time to nadir (days)

Dose n Day 11 Nadir Day 11 Nadir

25 mg QD 8 -0.43 (-1.08, 0.02) -0.59 (-1.10, 0.02) 1 1 10

50 mg BID 8 -0.66 (-1.37, 0.40) -0.86 (-1.37, -0.14) 4 5 13

100 mg QD 8 -1.13 (-1.70, -0.43) -1.25 (-1.70, -0.61) 5 6 10

100 mg BID 7 -1.42 (-1.84, -1.04) -1.68 (-2.10, -1.37) 7 7 12

150 mg BID 8 -1.45 (-1.71, -0.90) -1.77 (-2.16, -1.43) 7 8 12

150 mg BID fed 8 -1.34 (-1.79, -0.51) -1.74 (-2.09, -1.13) 7 8 15

300 mg QD 8 -1.35 (-1.62, -0.95) -1.60 (-2.08, -1.14) 7 8 12

300 mg BID 8 -1.60 (-2.42, -0.78) -1.84 (-2.42, -1.49) 7 8 11

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Emergence of CXCR4-Tropic Virus (1)

61/63 patients (97%) with CCR5-tropic virus at baseline remained CCR5-tropic after 10 days of MVC monotherapy

2 patients showed emergence of CXCR4-using variants during treatment with MVC 100 mg QDfor 10 days

R5 variants remained the predominant virus species post-treatment

Lewis M et al. 44th ICAAC 2004; Poster H-584b

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Emergence of CXCR4-Tropic Virus (2)

Patient 1

• HIV RNA decline: –0.71 log10 copies/mL

• Transient emergence of dual-/mixed-tropic virus at day 11

• Reverted to CCR5-tropic at day 40.

Patient 2

• HIV RNA decline: –1.26 log10 copies/mL

• Dual-/mixed-tropic virus detected from day 11 onwards

• R5 variants constituted ~80% of the circulating virus after one year’s follow-up.

Phylogenetic analysis suggested that R5/X4 variants which emerged post-treatment in each patient most likely expanded from a pre-treatment R5/X4 virus reservoir, rather thanco-receptor switching of an R5 clone

Lewis M et al. 44th ICAAC 2004; Poster H-584b

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Conclusions

MVC was safe and well tolerated in doses up toand including 300 mg BID in this population

Doses of 100 mg BID resulted in viral load reductions

of >1 log10 copies/mL

• Dosing with food had no significant effect onviral load reduction

• Dosing of 150 mg BID and 300 mg QD resulted in

similar viral load reductions Currently in Phase 2b/3 development in both naive and

treatment-experienced patients using doses equivalent to 300 mg QD and 300 mg BID

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Acknowledgements

The maraviroc development team

All the investigators and study-site staff

The patients and volunteers for their participation in these studies