Overview of Phase 1 and 2a Safety 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+)

3 Study Details Study (All double-blind, placebo-controlled) Unit dose range* (mg) Duration (days) Dose-escalating multiple-dose study (with wash out periods) 1 3–60010 Oral contraceptive interaction study –day safety study 3 100–30028 High dose-escalating multiple-dose study300–12007 & 7 Monotherapy study in asymptomatic HIV+ subjects 4 25–30010 Monotherapy study in asymptomatic HIV+ subjects (investigating possible food effect) 4 150– Abel S et al. 10 th CROI 2003; Paper Russell D et al. 43 rd ICAAC 2003; Paper *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. 43 rd ICAAC 2003; Paper Fätkenheuer G et al. 15 th IAC 2004; Abstract TuPeB4489.

4 Demographic Data Dose Placebo  150 mg 300 mg600–1200 mg N GenderMale Female Age18– – RaceWhite Black3411 Asian2100 Other2210

5 Most Frequent Adverse Events – Treatment Related Dose Adverse EventPlacebo  150 mg 300 mg600–1200 mg N (%) Headache17 (15)19 (17)12 (24)18 (30) Dizziness7 (6)8 (7)5 (10)27 (44) Nausea6 (5)1 (1)6 (12)16 (26) Asthenia8 (7)5 (5)3 (6)16 (26) Flatulence6 (5)3 (3)7 (14)8 (13) Rhinitis1 (1)2 (2)2 (4)14 (23) Postural hypotension1 (1)0 (0) 14 (23) Abnormal vision2 (2)1 (1)1 (2)12 (20) Conjunctivitis0 (0) 14 (23) Somnolence3 (3)0 (0) 12 (20) Abdominal pain3 (3)1 (1)2 (4)7 (11)

6 Postural Hypotension Incidence of postural hypotension (%)  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 2/1110/360/570/160/50

7 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

8 Discontinuations DoseNReason for discontinuationTreatment related* Severity* 3 mg1Transaminases elevated (1)YesSevere 25 mg2Varicella infection (1) No longer willing to participate (1) No - Moderate mg3Tooth abscess (1) Headache (1) No longer willing to participate (1) No - Moderate mg2Protocol violation (1) Infectious mononucleosis (1) - No - Moderate 600 mg3Postural hypotension (2) No longer willing to participate (1) Yes - Severe - Placebo8Postural hypotension(1) Protocol violation (3) Sore throat (1) Laboratory abnormality (1) Headache (1) Itchy rash of thorax (1) Yes - No Yes Severe - Moderate Mild *Investigator assessment

9 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

10 Laboratory Abnormalities ALT changes in patients with normal ALT at baseline, n  ULN >ULN to  2 ULN >2ULN to  3ULN >3ULN to  5ULN >5ULNTotal Placebo <100 mg mg mg mg mg mg mg ULN = Upper Limit of Normal

11 Max Increase in QTcF From Baseline (msec)  No evidence of dose-related changes in QTcF at doses of  1200 mg QD Increase in QTcF from baseline (msec), n (%) N<30  30–<60  60 Placebo7466 (89)8 (11)0 (0) <100 mg3632 (89)3 (8)1 (3) 100 mg5755 (97)2 (4)0 (0) 150 mg1612 (75)4 (25)0 (0) 300 mg5047 (94)3 (6)0 (0) 600 mg3532 (91)3 (9)0 (0) 900 mg1716 (94)0 (0)1 (6) 1200 mg99 (100)0 (0) QTcF, Fridericia’s correction

12 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

13 MVC Efficacy Results: Mean Reduction in Viral Load over Time Change from baseline (log 10 HIV-1 copies/mL) Last day of dosing Placebo 1015 Placebo mg QD 50 mg BID 100 mg QD 100 mg BID 150 mg BID Fast 150 mg BID Fed 300 mg QD 300 mg BID Maraviroc dose n Time (day) Baseline – 2.0 – 1.5 – 1.0 – Fätkenheuer G et al. 15 th IAC 2004; Abstract TuPeB4489

14 MVC Reduces Viral Load in All Patients Receiving Therapeutic Doses Mean decrease in HIV RNA log 10 copies/mL (range) HIV RNA decrease >1.0 log 10 copies/mL (no. patients) Median time to nadir (days) DosenDay 11NadirDay 11Nadir 25 mg QD (-1.08, 0.02)-0.59 (-1.10, 0.02) mg BID (-1.37, 0.40)-0.86 (-1.37, -0.14) mg QD (-1.70, -0.43)-1.25 (-1.70, -0.61) mg BID (-1.84, -1.04)-1.68 (-2.10, -1.37) mg BID (-1.71, -0.90)-1.77 (-2.16, -1.43) mg BID fed (-1.79, -0.51)-1.74 (-2.09, -1.13) mg QD (-1.62, -0.95)-1.60 (-2.08, -1.14) mg BID (-2.42, -0.78)-1.84 (-2.42, -1.49)7811

15 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 QD for 10 days  R5 variants remained the predominant virus species post-treatment Lewis M et al. 44th ICAAC 2004; Poster H-584b

16 Emergence of CXCR4-Tropic Virus (2)  Patient 1 HIV RNA decline: –0.71 log 10 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 log 10 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 than co-receptor switching of an R5 clone Lewis M et al. 44th ICAAC 2004; Poster H-584b

17 Conclusions  MVC was safe and well tolerated in doses up to and including 300 mg BID in this population  Doses of  100 mg BID resulted in viral load reductions of >1 log 10 copies/mL Dosing with food had no significant effect on viral 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

18 Acknowledgements  The maraviroc development team  All the investigators and study-site staff  The patients and volunteers for their participation in these studies