1. FDA Analyses of Maraviroc Safety Data Scott Proestel, M.D. Division of Antiviral Products Food and Drug Administration April 24, 2007

2. Presentation Outline Overall Summary of AEs Mortality Malignancies Hepatic AEs Infections Additional AEs Selected Laboratory Data

3. Summary of AEs During Double-Blind Phase Studies 1027 and 1028

4. Duration of Therapy During Double-Blind Period Studies 1027 and 1028 Median Treatment Days MVC QD236 MVC BID239 Placebo145

5. Days to Individual AEs During Double-Blind Period Placebo Arms, Studies 1027 and 1028 Study Day

6. Days to Subject Discontinuation From the Double-Blind Period Placebo Arms, Studies 1027 and 1028 Study Day

7. Mortality Data

8. 1026 1027 1028 1029

9. Mortality Data Numerical increase in mortality in MVC arms overall, however: –Imbalance occurred in only 1 of 4 trials –Degree of imbalance extremely small (for double-blind phase, p-value 0.60, Barnard's unconditional exact test) –No clustering of death causes –Types of deaths were consistent with the population studied –Sick population at baseline (there were 11 additional deaths between screening and randomization)

10. Malignancies

11. All Lymphomas by Treatment Arm Studies 1027 and 1028 1 Received placebo during double-blind period, but subsequently received MVC during open-label period prior to malignancy diagnosis 2 Presumed diagnosis as no biopsy was performed

12. Non-Hematologic Malignancies During Double-Blind Phase* Studies 1027 and 1028 Malignancy Numbers of Subjects with an AE MVC QD (n=414) MVC BID (n=426) Placebo (n=209) Anal cancer333 Kaposi’s sarcoma123 Squamous cell carcinoma311 Basal cell carcinoma110 Oesophageal carcinoma100 Liver metastases100 Skin cancer010 Bowen’s disease010 TOTAL1097 * A subject could have more than one type of adverse event.

13. Hepatic Adverse Events

14. Hepatic AEs

15. Hy’s Law Summary Hy’s Law –AST or ALT >= 3x ULN –TB >= 2x ULN –No marked increase in alkaline phosphatase –No evidence of another cause –Predicts a 10-50% likelihood of death or liver transplant No Hy’s Law cases were observed

16. Case History The subject is a 43 year-old woman with history of injection drug use, alcoholism, and hepatitis C who received MVC for 203 days. On enrollment, she was HBsAg negative, HBcAb negative, HCV RNA positive, and reported drinking 5 alcoholic beverages per week. Her baseline AST and ALT were elevated at 101 and 43 IU/L. There were no substantive increases from these baseline LFT values through Day 169. Her baseline total bilirubin was normal at 1.1 mg/dL, but peaked at 5.2 mg/dL on Day 15. The bilirubin subsequently decreased from the peak level and was normal at the last measurement on Day 169. Of note, her total bilirubin was 2.3 mg/dL 41 days prior to starting MVC (peak direct and indirect bilirubin levels were abnormal at 3.3 and 1.9 mg/dL, respectively). She started atazanavir 537 days prior to MVC, and stopped on the day that MVC was started. She had 3 reported liver AEs during her study participation (grade 3 increase in bilirubin on two occasions, and grade 1 hepatosplenomegaly once).

17. AST and/or ALT Elevation During Double-Blind Period Studies 1027 and 1028 AST and/or ALT MVC QD (n=414) MVC BID (n=426) Placebo (n=209) > ULN249 (60%)269 (63%)139 (67%) > 3 x ULN43 (10%)56 (13%)21 (10%) > 5 x ULN21 (5%) 10 (5%) > 10 x ULN3 (1%)6 (1%)1 (<1%)

18. Total Bilirubin During Double-Blind Period Studies 1027 and 1028

19. Infectious Adverse Events

20. Most Common Infection-Related AEs During Double- Blind Period (Studies 1027 and 1028)

21. Category C AEs During Double-Blind Period Studies 1027 and 1028

22. Herpes Virus Infections During Double-Blind Period Studies 1027 and 1028 65 Herpes AEs –MVC QD25 AEs in 18 (4.3%) subjects –MVC BID32 AEs in 29 (6.8%) subjects –Placebo8 AEs in 8 (3.8%) subjects 19 Category C Herpes-related AEs –MVC QD11 AEs in 10 (2.4%) subjects –MVC BID6 AEs in 6 (1.4%) subjects –Placebo2 AEs in 2 (1.0%) subjects

23. Herpes Virus Infections During Double-Blind Period* Studies 1027 and 1028 Adverse Event Numbers of Subjects with an AE MVC QD (n=414) MVC BID (n=426) Placebo (n=209) Time-Adjusted Placebo (Placebo x 2.6) Herpes simplex10825 Herpes virus3225 Anal/rectal herpes 3813 Labial herpes3800 Oral herpes0300 Genital herpes1238 TOTAL2031821 * A subject could have more than one type of adverse event.

24. Candidiasis Infections During Double-Blind Period Studies 1027 and 1028 70 Candidiasis AEs –MVC QD41 AEs in 26 (6.2%) subjects –MVC BID18 AEs in 17 (4.0%) subjects –Placebo11 AEs in 11 (5.3%) subjects 19 Category C Candidiasis AEs –MVC QD14 AEs in 12 (2.9%) subjects –MVC BID3 AEs in 3 (0.7%) subjects –Placebo2 AEs in 2 (1.0%) subjects

25. Candidiasis Infections During Double-Blind Period* Studies 1027 and 1028 Adverse Event Numbers of Subjects with an AE MVC QD (n=414) MVC BID (n=426) Placebo (n=209) Time-Adjusted Placebo (Placebo x 2.6) Oral candidiasis1613821 Oesophageal candidiasis 12225 Oropharyngeal candidiasis 2013 Pharyngeal candidiasis1000 Vaginal candidiasis2000 Worsening candidiasis1000 Candidiasis1200 Balanitis candida1000 Nail candida0100 TOTAL36181129 * A subject could have more than one type of adverse event.

26. Additional Adverse Events

27. Cardiovascular AEs During Double-Blind Period Studies 1027 and 1028

28. Cardiovascular Disorders at Baseline 95 patients with any cardiovascular disorder –MVC QD40 (10%) –MVC BID40 (9%) –Placebo15 (7%) 45 patients with any ischemic cardiac disorder –MVC QD21 (5%) –MVC BID17 (4%) –Placebo7 (3%)

29. Thrombotic AEs During Double-Blind Period* Studies 1027 and 1028 Adverse Event Numbers of Subjects with an AE MVC QD (n=414) MVC BID (n=426) Placebo (n=209) Transient ischemic attack003 Angina pectoris210 Unstable angina110 Myocardial ischemia020 Myocardial infarction200 Coronary artery disease310 Antiphospholipid syndrome100 Mesenteric artery thrombosis001 Peripheral embolism010 Portal vein thrombosis010 Pulmonary embolism010 Venous thrombosis010 Thrombophlebitis001 Cavernous sinus thrombosis100 Iliac artery stenosis001 Intermittent claudication100 TOTAL1196 * A subject could have more than one type of adverse event.

30. Postural Hypotension During Double-Blind Period Studies 1027 and 1028 Dose-limiting AE during phase 1 at doses of 600-1200 mg MedDRA terms: Hypotension, orthostatic hypotension, dizziness, syncope 109 Patients: –MVC QD 51 (12%) –MVC BID 39 (9%) –Placebo 19 (9%)

31. AEs Potentially Associated with QT Prolongation During Double-Blind Period (Studies 1027 and 1028) Preclinical testing revealed potential for QT prolongation A previous CCR5 antagonist (“Schering C”) found to cause QT prolongation Thorough QT study for MVC determined to be inadequate –No significant prolongation with MVC, but control arm was not interpretable –Attempts to resolve this issue are underway MedDRA terms: Arrhythmia, Palpitations, Syncope, Tachycardia 14 patients with potential ventricular events: –MVC QD4 (1.0%) –MVC BID 7 (1.6%) –Placebo 3 (1.4%)

32. CPK Elevation AEs During Double-Blind Period Studies 1027 and 1028 MedDRA terms: Blood creatine phosphokinase increased, myositis, rhabdomyolysis 19 Subjects with AEs –MVC QD7 (1.7%) –MVC BID11 (2.6%) –Placebo1 (0.5%)

33. CPK Elevation by Treatment Group During Double- Blind Period (Studies 1027 and 1028)

34. Fasting Total Cholesterol During Double-Blind Period Studies 1027 and 1028

35. Fasting Total Cholesterol at Week 24 (+/- 2 Weeks) Studies 1027 and 1028

36. Fasting Total Cholesterol During Double-Blind Period Studies 1027 and 1028

37. LDL Cholesterol During Double-Blind Phase Studies 1027 and 1028

39. Summary No increase in mortality or malignancy observed No clear evidence of hepatotoxicity, but this was a complicated patient population with a high rate of liver abnormalities at baseline. Infections –No evidence of increase overall –Possible increase in Candida, Herpes, and influenza infections Possible increase in cardiac ischemic events Possible increase in myositis Mild increase in total cholesterol and LDL levels

40. FDA Analyses of Maraviroc Efficacy Data Susan Zhou, Ph.D. Division of Biometrics IV, FDA Scott Proestel, M.D. Division of Antiviral Products, FDA April 24, 2007

41. Summary of Change from Baseline in HIV-1 RNA to Week 24 Sensitivity Analysis for All Missing Data (Treatment Failure Classification, No Change) Treatment Group Change from Baseline to Week 24Treatment Difference Maraviroc - Placebo NRaw Mean (se) Raw Median Adjusted Mean (se) Estimate (se) -0.872 (0.119) -0.988 (0.118) N/A Maraviroc QD414-1.825 (0.070)-2.229-1.833 (0.069) Maraviroc BID426-1.946 (0.069)-2.409-1.950 (0.068) Placebo209-0.960 (0.091)0.000-0.962 (0.097) Primary Efficacy Endpoint (Studies 1027 and 1028) Mean Change from Baseline to Week 24 in HIV-1 RNA (log 10 copies/mL) Mean Treatment Difference & 99.95% CI for (Adjusted Data) Maraviroc QD-Placebo-0.872 (-1.335, -0.409) Maraviroc BID-Placebo-0.988 (-1.447, -0.529)

42. Primary Efficacy Endpoint (Week 24) Sensitivity Analyses Analysis 1: Using both on- and off- treatment HIV-1 VL data –MVC-QD -Placebo: -0.50 (-0.90,-0.10) –MVC-BID-Placebo: -0.49 (-0.90,-0.09) Analysis 2: Completers through Week 24 –MVC-QD-Placebo: -0.48 (-0.93,-0.02) –MVC-BID-Placebo: -0.54 (-0.99,-0.09) Analysis 3: Imputing a single value (-0.4 to 0.3 by 0.1) to missing –Results are similar to the sponsor’s sensitivity analyses –The imputed value is the median for the placebo –MVC-QD-Placebo: -0.79~0.97 –MVC-BID-Placebo: -0.88~1.06 –All 99.95% CIs support the superiority of MVC

43. Efficacy at Week 24 by Baseline Demographics Studies 1027 and 1028

44. Efficacy at Week 24 by Disease Characteristics Studies 1027 and 1028

45. Change in CD4+ Cell Counts (Studies 1027 and 1028) Completers through Week 24 (n=672) n Mean (se) Treatment Effect (99.95% CI) –MVC QD 283137.8 (7.7) 41.1 (-5.0,87.3) –MVC BID 296123.6 (6.2) 26.9 (-18.9,66.3) –Placebo 9396.7 (10.8) LOCF through Week 24 (n=1033) n Mean (se) Treatment Effect (99.95% CI) –MVC QD408113.5 (6.1) 58.8 (26.5,91.1) –MVC BID418105.9 (5.1) 51.2 (21.0,81.4) –Placebo20754.7 (7.0) Treatment effects are robust

46. Conclusions Evidence of Superiority Over Placebo Convincing –Efficacy reduced by the most conservative analyses –At least of 0.5 log 10 copies/mL –Increase in CD4+ cell count observed Patients with OSS >= 3 without apparent benefit