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Helen Whamond Boucher, M.D.

Helen Whamond Boucher, M.D. Senior Associate Director Clinical Development Pfizer Global Research & Development. Voriconazole Clinical Program. Invasive Aspergillosis Global Comparative Aspergillosis Study (307/602) Non-Comparative Aspergillosis Study (304)

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Helen Whamond Boucher, M.D.

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

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

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

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

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

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

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

  16. Global Comparative Aspergillosis Study (307/602)Patient Disposition 392Enrolled Voriconazole Amphotericin B 3 8 No Treatment 196 185 Safety Population Intention to Treat Population Modified Intention to Treat Population IncorrectRandomization 2 0 194 185 No Definite or Probable Aspergillosisper Blinded Data Review Committee 50 52 144 133

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

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

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

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

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

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

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

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

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

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

  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. Voriconazole +/- OLAT Amphotericin B +/- OLAT Global Comparative Aspergillosis Study (307/602)Time to Death (MITT) Probability of Survival Hazard ratio = 0.60 95% CI (0.40, 0.89) Number of days of Therapy At Risk (Censored) Vori 144 (0) 131 (0) 125 (0) 117 (0) 111 (0) 107 (0) 102 (0) AMB 133 (0) 117 (0) 99 (0) 87 (0) 84 (0) 80 (0) 77 (0)

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

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

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

  35. Invasive AspergillosisSummary • 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. 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. Voriconazole Efficacy Database Emerging Pathogens • Infections due to rare pathogens more frequently recognized and more patients at risk1 • Refractory to available agents2 • Overall mortality 76 – 87% for Scedosporium3 Fusarium carries 50 – 80% attributable mortality4 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. Success in ScedosporiumBy Site of Infection * One patient relapsed; in four patients multiple sites were involved ** Jabado et al, CID 1998; Munoz et al, CID 2000; Nesky et al, CID 2000; Poza et al, CID 2000

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

  43. Systemic Candida InfectionsSalvage Therapy (N = 43)

  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. 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. 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. 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. Empirical Therapy Study (603/MSG42) Key Inclusion Criteria • Neutropenia  500/mm3 for at least 96 hours and  250/mm3 within 24 hours prior to randomization • At least 96 hours of parenteral systemic antibiotic therapy • Temperature  38º C within 24 hours of randomization

  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. 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

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