1. 1 Helen Whamond Boucher, M.D. Senior Associate Director Clinical Development Pfizer Global Research & Development

2. 2 Voriconazole Clinical Program Invasive Aspergillosis  Global Comparative Aspergillosis Study (307/602)  Non-Comparative Aspergillosis Study (304)  Contemporaneous Historical Control Study (1003) Emerging Pathogens  Scedosporium Infections  Fusarium Infections Candida Infections  Esophageal Candidiasis Study (305)  Pooled Efficacy Data Empirical Therapy Study (603/MSG42)

3. 3 The Global Comparative Aspergillosis Study (307/602) A prospective, randomized, open-label multicenter controlled study

4. 4 Global Comparative Aspergillosis Study (307/602)  Two protocols 1997 (US 602, EORTC 307)  Identical patient populations, treatments and assessments  Prospectively planned analysis of the combined interim data: the Umbrella analysis  In agreement with participants, recruitment into studies was discontinued  Final report on Global Comparative Aspergillosis Study (307/602)

5. 5 Global Comparative Aspergillosis Study (307/602) Key Inclusion Criteria  Immunocompromised  Definite or probable invasive aspergillosis (radiological, clinical, mycological)  Modified National Institute of Allergy and Infectious Diseases Mycoses Study Group/EORTC criteria*  Less than 96 hours of systemic antifungal treatment at therapeutic doses *Ascioglu et al, CID, in press

6. 6 Global Comparative Aspergillosis Study (307/602) Umbrella Analysis: Sample Size and Statistical Considerations  Assumed overall response rate of 50%  At least 90% power to exclude a difference in DRC- assessed success at Week 12 of -20% (non-inferiority)  Sample size estimate: assumed 25% exclusion, total sample size 368 patients to enroll 276 patients in the Modified Intention to Treat (MITT) population  Stratification at randomization:  Site of infection  Underlying disease  Neutrophil count

7. 7 Global Comparative Aspergillosis Study (307/602) Study Design - Background  Conventional amphotericin B  Historically the standard  Approved for primary treatment of Invasive Aspergillosis  Lipid formulations, itraconazole  Approved for salvage therapy in Aspergillosis  Used more frequently  Less toxicity  Other Licensed Antifungal Therapy (OLAT)

8. 8 Global Comparative Aspergillosis Study (307/602) Study Procedures: End of Randomized Therapy Randomized Therapy Withdraw from Randomized Therapy Switch to Other Licensed Antifungal Therapy Voriconazole Standard loading doses, then 4 mg/kg IV q 12 h, oral option 200 mg BID p 7 days IV Amphotericin B 1 mg/kg/d IV x 14 days

9. 9 Global Comparative Aspergillosis Study (307/602) Study Procedures: Week 12 Week 12 DRC Assessment of Outcome at End of Randomized Therapy = DRC Assessment at Week 12 DRC Assessment at Week 12 Survival through Day 84 Randomized Therapy Withdraw from Randomized Therapy Switch to Other Licensed Antifungal Therapy DRC Assessment of Outcome at End of Randomized Therapy DRC Assessment of Outcome at End of Randomized Therapy

10. 10 Global Comparative Aspergillosis Study (307/602) Endpoints  Outcome at Week 12  Test for non-inferiority (DRC-assessed success)  Primary Efficacy Endpoint  Outcome at End Of Randomized Therapy  Test for superiority (DRC-assessed success)  Secondary Efficacy Endpoint  Survival through Day 84  Secondary Efficacy Endpoint

11. 11 Global Comparative Aspergillosis Study (307/602) Blinded Data Review Committee Composition  12 physicians, including 4 radiologists  Expertise in assessment and treatment of invasive fungal infections in immunocompromised patients  Two sub-groups:  European members (elected by the EORTC)  US members (Sponsor-selected)  A standard operating procedure was followed when assessing cases

12. 12 Global Comparative Aspergillosis Study (307/602) Blinded Data Review Committee Process*  Blinded review of all patients  Mycology reports, clinical assessments, investigator response  Digitized radiology studies  Assessed  Certainty of infection at baseline  Outcome at End of Randomized Therapy  Outcome at Week 12  Cause of death *Patterson et al, ICAAC 2000, Toronto; Denning et al, ICAAC 2000, Toronto

13. 13 Global Comparative Aspergillosis Study (307/602) Diagnosis - Patient 3181 Nodular lesion with “halo sign” at baseline

14. 14 Global Comparative Aspergillosis Study (307/602) Results

15. 15 Global Comparative Aspergillosis Study (307/602) Enrollment *95 of 199 sites enrolled 392 patients

16. 16 Global Comparative Aspergillosis Study (307/602) Patient Disposition No Treatment Incorrect Randomization No Definite or Probable Aspergillosis per Blinded Data Review Committee 196 194 144 VoriconazoleAmphotericin B 392 Enrolled 185 133 Safety Population Intention to Treat Population Modified Intention to Treat Population 38 20 5052

17. 17 Global Comparative Aspergillosis Study (307/602) Demographic and Clinical Characteristics (MITT)

18. 18 Global Comparative Aspergillosis Study (307/602) Demographics by Stratification Factors as Assessed by the DRC (MITT)

19. 19 Global Comparative Aspergillosis Study (307/602) DRC-Assessed Certainty of Infection by Study (MITT)

20. 20 Global Comparative Aspergillosis Study (307/602) Study Procedures: Progress Over Time Randomized Therapy Withdraw from Randomized Therapy Switch to Other Licensed Antifungal Therapy DRC Assessment of Outcome at End of Randomized Therapy DRC Assessment of Outcome at End of Randomized Therapy Week 12 DRC Assessment of Outcome at End of Randomized Therapy = DRC Assessment at Week 12 DRC Assessment at Week 12 Survival through Day 84

21. 21 Global Comparative Aspergillosis Study (307/602) Disposition Over Time: Voriconazole Arm (MITT) Day 42 5 13 22 62 Day 84 Voriconazole Randomized TherapyOLAT Died Post Treatment Follow upDiscontinued Number of Patients

22. 22 Global Comparative Aspergillosis Study (307/602) Disposition Over Time: Amphotericin B Arm (MITT) Number of Patients Day 84 56 7 11 57 2 Amphotericin B Randomized TherapyOLAT Died Post Treatment Follow upDiscontinued Day

23. 23 Global Comparative Aspergillosis Study (307/602) Endpoints  Outcome at Week 12  Test for non-inferiority (DRC-assessed success)  Primary Efficacy Endpoint  Outcome at End Of Randomized Therapy  Test for superiority (DRC-assessed success)  Secondary Efficacy Endpoint  Survival through Day 84  Secondary Efficacy Endpoint

24. 24 Global Comparative Aspergillosis Study (307/602) DRC-Assessed Success at Week 12 (MITT) Difference (raw) = 21.2%, 95 % CI (9.9, 32.6) Difference (adjusted) = 21.8%, 95% CI (10.5, 33.0) 76/144 42/133 * OLAT = Other licensed antifungal therapy

25. 25 Global Comparative Aspergillosis Study (307/602) DRC-Assessed Success at Week 12 (MITT) 27/58 11/49 49/86 31/84 Study 602  (raw) = 24.1%, 95% CI (6.8, 41.5) Study 307  (raw) = 20.1%, 95% CI (5.4, 34.8)  (raw) = 21.2% 76/144 42/133

26. 26 Global Comparative Aspergillosis Study (307/602) DRC-Assessed Success at Week 12 (MITT) Difference in Success Rates (%, 95% CI) Probable Non-Neutropenic (ANC  500) Definite Neutropenic (ANC < 500) Allogeneic BMT Extrapulmonary Pulmonary Overall Other immunosuppressed state (eg solid organ transplant, HIV/AIDS) Autologous BMT or other hematological condition (eg leukemia) -20

27. 27 Global Comparative Aspergillosis Study (307/602) Endpoints  Outcome at Week 12  Test for non-inferiority (DRC-assessed success)  Primary Efficacy Endpoint  Outcome at End Of Randomized Therapy  Test for superiority (DRC-assessed success)  Secondary Efficacy Endpoint  Survival through Day 84  Secondary Efficacy Endpoint

28. 28 Global Comparative Aspergillosis Study (307/602) DRC-Assessed Success at End of Randomized Therapy (MITT) Difference (raw) = 31.7%, 95% CI (20.9, 42.4) Difference (adjusted) = 31.9%, 95% CI (21.2, 42.6) Median Duration of Randomized Therapy Voriconazole = 77 days Amphotericin B = 11 days 77/144 29/133

29. 29 Global Comparative Aspergillosis Study (307/602) Endpoints  Outcome at Week 12  Test for non-inferiority (DRC-assessed success)  Primary Efficacy Endpoint  Outcome at End Of Randomized Therapy  Test for superiority (DRC-assessed success)  Secondary Efficacy Endpoint  Survival through Day 84  Secondary Efficacy Endpoint

30. 30 At Risk (Censored) Vori144 (0)131 (0)125 (0)117 (0) 111 (0) 107 (0) 102 (0) AMB133 (0)117 (0) 99 (0) 87 (0) 84 (0) 80 (0) 77 (0) Global Comparative Aspergillosis Study (307/602) Time to Death (MITT) Number of days of Therapy Probability of Survival Amphotericin B +/- OLAT Voriconazole +/- OLAT Hazard ratio = 0.60 95% CI (0.40, 0.89)

31. 31 Global Comparative Aspergillosis Study (307/602) DRC-Assessed Cause of Death at Day 84 (MITT)

32. 32 Global Comparative Aspergillosis Study (307/602) Conclusions  Voriconazole (+/- OLAT) led to greater DRC- assessed success than did amphotericin B (+/- OLAT)  Success  12 Weeks  End of Randomized Therapy  Survival Benefit  Robust treatment benefit across relevant subpopulations including component studies

33. 33 Non-Comparative Aspergillosis Study (304)* Outcome * Denning et al, CID in press

34. 34 Non-Comparative Aspergillosis Study (304) Historical Control Study (1003) 26/50 23/92 % Success (95% Confidence Interval) Non-Comparative and Historical Control Aspergillosis Studies (304,1003) Success Success

35. 35 Invasive Aspergillosis Summary  Superiority in Global Comparative Aspergillosis Study (307/602)  Efficacy in Non-Comparative Aspergillosis Study (304)  Consistent data in contemporaneous Historical Control Study (1003)  In a large pooled efficacy population, success in  Central nervous system infections  Other poor prognostic risk factors  Total of 476 patients with documented Invasive Aspergillosis treated with voriconazole

36. 36 Voriconazole Clinical Efficacy Data Invasive Aspergillosis  Global Comparative Aspergillosis Study (307/602)  Non-Comparative Aspergillosis Study (304)  Contemporaneous Historical Control Study (1003) Emerging Pathogens  Scedosporium Infections  Fusarium Infections Candida Infections  Esophageal Candidiasis Study (305)  Pooled Efficacy Data Empirical Therapy Study (603/MSG42)

37. 37 Voriconazole Efficacy Database Emerging Pathogens  Infections due to rare pathogens more frequently recognized and more patients at risk 1  Refractory to available agents 2  Overall mortality 76 – 87% for Scedosporium 3 Fusarium carries 50 – 80% attributable mortality 4 1 Perfect, Schell, CID 1996; 2 Hennequin et al, AAC 1997; Espinel-Ingroff et al, Mycologica 2001 3 Nesky et al, CID 2000; Berenguer et al, Medicine 1997; 4 Boutai et al, Blood 1997; Martino et al, J Infect 1994; Gamis et al, Rev Infect Dis 1991

38. 38 ** Jabado et al, CID 1998; Munoz et al, CID 2000; Nesky et al, CID 2000; Poza et al, CID 2000 Success in Scedosporium By Site of Infection * One patient relapsed; in four patients multiple sites were involved

39. 39 Success in Fusarium By Site of Infection * Reis et al, British J Ophtalmol 2000 ** One patient relapsed † Four patients had Fusarium as part of a mixed fungal infection

40. 40 Voriconazole Clinical Efficacy Data Invasive Aspergillosis  Global Comparative Aspergillosis Study (307/602)  Non-Comparative Aspergillosis Study (304)  Contemporaneous Historical Control Study (1003) Emerging Pathogens  Scedosporium Infections  Fusarium Infections Candida Infections  Esophageal Candidiasis Study (305)  Pooled Efficacy Data Empirical Therapy Study (603/MSG42)

41. 41 Voriconazole Efficacy Database Candida Infections Esophageal candidiasis was selected as the proof of concept for efficacy in treating invasive infection Systemic Candida Infections  Experience in 91 patients from across the program  Primary therapy (n = 48)  Salvage therapy (n = 43)  Comparative Candidemia Study (Study 608) ongoing

42. 42 Esophageal Candidiasis Study (305)* Outcome (Per Protocol) 113/115 134/141 Success (cured + improved): 98.3% Voriconazole, 95.0% Fluconazole Difference 3.23%, 95% CI (-1.08, 7.53) * Ally et al, CID 2001 VoriconazoleFluconazole

43. 43 Systemic Candida Infections Salvage Therapy (N = 43)

44. 44 Candida Infections Conclusions  Success in esophageal candidiasis proven in a double-blind, double dummy trial vs fluconazole  Experience in treating 91 systemic Candida infections  43 patients received voriconazole as salvage therapy  Candidemia Study (608) in non-neutropenic patients ongoing (n = 256, target N = 426)

45. 45 Voriconazole Clinical Efficacy Data Invasive Aspergillosis  Global Comparative Aspergillosis Study (307/602)  Non-Comparative Aspergillosis Study (304)  Contemporaneous Historical Control Study (1003) Emerging Pathogens  Scedosporium Infections  Fusarium Infections Candida Infections  Esophageal Candidiasis Study (305)  Pooled Efficacy Data Empirical Therapy Study (603/MSG42)

46. 46 Empirical Therapy  Significant chance of developing fungal infection among patients with neutropenia and persistent fever despite several days of broad-spectrum antibiotics *  Approved Agents  Liposomal amphotericin B (MSG32)**  Itraconazole † * Pizzo et al Am J Med 1982, EORTC Am J Med 1989 ** Walsh et al N Engl J Med 1999 † Boogaerts et al Ann Int Med 2001

47. 47 Empirical Therapy Study (603/MSG42) Objectives Primary:  To evaluate the efficacy of voriconazole compared with liposomal amphotericin B by composite endpoint Components:  Breakthrough fungal infections*  Survival*  Premature discontinuation from study medication  Defervescence during neutropenia*  Response in baseline invasive fungal infections * Secondary efficacy endpoint

48. 48 Empirical Therapy Study (603/MSG42) Key Inclusion Criteria  Neutropenia  500/mm 3 for at least 96 hours and  250/mm 3 within 24 hours prior to randomization  At least 96 hours of parenteral systemic antibiotic therapy  Temperature  38º C within 24 hours of randomization

49. 49 Empirical Therapy Study (603/MSG42) Sample Size and Statistical Considerations  Assumed overall response rate of 50%*  At least 80% power to exclude a difference in success in composite endpoint of -10% (non-inferiority)  Sample size estimate: assume 10% exclusion, total sample size 866 patients to enroll 786 patients in the Modified Intention to Treat (MITT) population * Based on MSG32

50. 50 Empirical Therapy Study (603/MSG42)  Stratification at randomization:  Risk of developing invasive fungal infection  High risk: allogeneic transplant or relapsed leukemia  Moderate risk: newly diagnosed leukemia, autologous transplant or other neoplasm  Systemic antifungal prophylaxis: yes vs no

51. 51 Empirical Therapy Study (603/MSG42) Blinded Data Review Committee  Eight physicians, including infectious disease specialists and oncologists  Blinded review of all potential infections  Mycology reports, clinical assessments, and global response  Radiology studies (films) and reports  Assessed  Presence of infection  Type of infection (baseline or breakthrough)  Certainty of infection  Global response at the End of Therapy  A standard operating procedure was followed when assessing cases

52. 52 Empirical Therapy Study (603/MSG42) Results

53. 53 Empirical Therapy Study (603/MSG42) Patient Disposition No Treatment One dose of randomized therapy One dose of randomized therapy and sufficient information to confirm investigator’s assessment 421 415 428 422 VoriconazoleLiposomal Amphotericin B 871 Randomized Safety Population Modified Intention to Treat Population 148 66

54. 54 Empirical Therapy Study (603/MSG42) Demographic and Clinical Characteristics (MITT)

55. 55 † One subject had both an autologous BMT and an autologous peripheral stem cell transplant * Includes both BMT and peripheral stem cell transplants Empirical Therapy Study (603/MSG42) Demographic and Clinical Characteristics (MITT)

56. 56 Empirical Therapy Study (603/MSG42) Treatment Duration (MITT)

57. 57 Empirical Therapy Study (603/MSG42) Analysis of Primary Endpoint (MITT)

58. 58 Empirical Therapy Study (603/MSG42) Composite Endpoint Success, all of the following:  No breakthrough fungal infection during neutropenia and for at least 7 days after end of therapy  Survival for at least 7 days after end of therapy  No discontinuation from study medication due to toxicity or lack of efficacy prior to recovery from neutropenia  Defervescence during neutropenia  Baseline infections: global response assessed as complete or partial at end of therapy

59. 59 Empirical Therapy Study (603/MSG42) Breakthrough Fungal Infections (MITT)* * Definite or probable according to the blinded DRC

60. 60 Empirical Therapy Study (603/MSG42) Documented Breakthrough Fungal Infections

61. 61 Empirical Therapy Study (603/MSG42) Composite Endpoint Success, all of the following:  No breakthrough fungal infection during neutropenia and for at least 7 days after end of therapy  Survival for at least 7 days after end of therapy  No discontinuation from study medication due to toxicity or lack of efficacy prior to recovery from neutropenia  Defervescence during neutropenia  Baseline infections: global response assessed as complete or partial at end of therapy

62. 62 Empirical Therapy Study (603/MSG42) Deaths Within 7 days of End Of Therapy (MITT)

63. 63 *More than one cause possible, ** Includes one fungal sepsis † Includes one fungal pneumonia Empirical Therapy Study (603/MSG42) Deaths Within 7 days of End Of Therapy (MITT)

64. 64 Empirical Therapy Study (603/MSG42) Composite Endpoint Success, all of the following:  No breakthrough fungal infection during neutropenia and for at least 7 days after end of therapy  Survival for at least 7 days after end of therapy  No discontinuation from study medication due to toxicity or lack of efficacy prior to recovery from neutropenia  Defervescence during neutropenia  Baseline infections: global response assessed as complete or partial at end of therapy

65. 65 Empirical Therapy Study (603/MSG42) Discontinuation Due to Toxicity or Lack of Efficacy Prior to Recovery from Neutropenia (MITT)* * Included only permanent discontinuation. 7 voriconazole and 52 liposomal amphotericin B patients temporarily discontinued study drug or had dose reductions during study

66. 66 Empirical Therapy Study (603/MSG42) Discontinuation Due to Lack of Efficacy Prior to Recovery from Neutropenia (MITT) * Six of the 22 patients who discontinued prematurely due to lack of efficacy were from one site

67. 67 Empirical Therapy Study (603/MSG42) Composite Endpoint Success, all of the following:  No breakthrough fungal infection during neutropenia and for at least 7 days after end of therapy  Survival for at least 7 days after end of therapy  No discontinuation from study medication due to toxicity or lack of efficacy prior to recovery from neutropenia  Defervescence during neutropenia  Baseline infections: global response assessed as complete or partial at end of therapy

68. 68 *Temperature less than 38 o C for 48 hours prior to recovery from neutropenia (ANC > 250 cells/mm 3 ) Empirical Therapy Study (603/MSG42) Defervescence*  Number of patients who met defervescence criteria  Voriconazole: 135/415 (33.0%)  Liposomal amphotericin B: 154/422 (36.0%)  Median time to recovery from neutropenia  Voriconazole: 4.8 days  Liposomal amphotericin B: 5.4 days

69. 69 Empirical Therapy Study (603/MSG42) Composite Endpoint Success, all of the following:  No breakthrough fungal infection during neutropenia and for at least 7 days after end of therapy  Survival for at least 7 days after end of therapy  No discontinuation from study medication due to toxicity or lack of efficacy prior to recovery from neutropenia  Defervescence during neutropenia  Baseline infections: global response assessed as complete or partial at end of therapy

70. 70 Empirical Therapy Study (603/MSG42) DRC-Assessment of Baseline Infection Outcome at End of Therapy

71. 71 Voriconazole L-AMB % Difference (95% CI) -10 108/415 129/422 407/415 401/422 382/415 397/422 374/415 394/422 135/415 154/422 6/13 4/6 Empirical Therapy Study (603/MSG42) Response to Empirical Therapy (MITT)

72. 72 Empirical Therapy Study (603/MSG42) Breakthrough Infections by Risk and Prophylaxis (MITT)

73. 73 Empirical Therapy Study (603/MSG42) Overall Response by Randomization Stratum (MITT) C.I. = 95% Confidence Interval

74. 74 -10 High Risk Moderate Risk Empirical Therapy Study (603/MSG42) Response to Empirical Therapy (MITT) High and Moderate Risk % Difference (95% CI)

75. 75 * 10,398 infusions monitored in 837 patients ** Syndrome of sporadic acute infusion related reactions due to liposomal amphotericin B; Roden et al, ICAAC, Chicago 2001 Empirical Therapy Study (603/MSG42) Infusion Related Reactions (MITT) - All*

76. 76 Voriconazole  Superior outcome and survival benefit in primary therapy of acute invasive aspergillosis  Efficacy in patients with Scedosporium and Fusarium infections  Efficacy in Candida infections  Appropriate option for empirical therapy  Better tolerated than amphotericin B formulations  Acceptable overall safety profile  Manageable drug-drug interactions