Helen Whamond Boucher, M.D.

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
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Global Comparative Aspergillosis Study
(307/602)Diagnosis - Patient 3181
Nodular lesion with halo sign at baseline
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Global Comparative Aspergillosis Study (307/602)
Results
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Global Comparative Aspergillosis Study
(307/602)Enrollment
95 of 199 sites enrolled 392 patients
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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
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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)
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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
Global Comparative Aspergillosis Study (307/602)
Disposition Over Time Amphotericin B Arm (MITT)
Day 84
56
7
11
Number of Patients
57
2
Day
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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

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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
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
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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 lt 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 Voriconazol
e 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)
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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
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)
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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
Aspergillosis Studies (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
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Success in Scedosporium By 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 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
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 Infections Salvage Therapy (N
43)
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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

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
Empirical Therapy Study (603/MSG42)
Results
53
Empirical Therapy Study (603/MSG42) Patient
Disposition
Voriconazole
Liposomal Amphotericin B
871Randomized
14
8
No Treatment
Safety Population Modified Intention to Treat
Population
One dose of randomized therapy
421
428
6
6
One dose of randomized therapy and sufficient
information to confirm investigators assessment
415
422
54
Empirical Therapy Study (603/MSG42)Demographic
and Clinical Characteristics (MITT)
55
Empirical Therapy Study (603/MSG42) Demographic
and Clinical Characteristics (MITT)
Includes both BMT and peripheral stem cell
transplants
One subject had both an autologous BMT and an
autologous peripheral stem cell transplant
56
Empirical Therapy Study (603/MSG42) Treatment
Duration (MITT)
57
Empirical Therapy Study (603/MSG42) Analysis of
Primary Endpoint (MITT)
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
Empirical Therapy Study (603/MSG42) Breakthrough
Fungal Infections (MITT)
Definite or probable according to the blinded
DRC
60
Empirical Therapy Study (603/MSG42) Documented
Breakthrough Fungal Infections
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
Empirical Therapy Study (603/MSG42) Deaths
Within 7 days of End Of Therapy (MITT)
63
Empirical Therapy Study (603/MSG42) Deaths
Within 7 days of End Of Therapy (MITT)
More than one cause possible, Includes one
fungal sepsis Includes one fungal pneumonia
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
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
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
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
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

Temperature less than 38o C for 48 hours prior
to recovery from neutropenia (ANC gt 250
cells/mm3)
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
Empirical Therapy Study (603/MSG42)
DRC-Assessment of Baseline Infection Outcome at
End of Therapy
71
Empirical Therapy Study (603/MSG42) Response to
Empirical Therapy (MITT)
Voriconazole L-AMB
108/415 129/422
-10
407/415 401/422
382/415 397/422
374/415 394/422
135/415 154/422
6/13 4/6
Difference (95 CI)
72
Empirical Therapy Study (603/MSG42) Breakthrough
Infections by Risk and Prophylaxis (MITT)
73
Empirical Therapy Study (603/MSG42)Overall
Response by Randomization Stratum (MITT)
C.I. 95 Confidence Interval
74
Empirical Therapy Study (603/MSG42) Response to
Empirical Therapy (MITT) High and Moderate Risk
-10
Difference (95 CI)
75
Empirical Therapy Study (603/MSG42) Infusion
Related Reactions (MITT) - All
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
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