helen whamond boucher, m.d

1

Helen Whamond Boucher, M.D.

Senior Associate Director

Clinical Development

Pfizer Global Research & Development

2

Voriconazole Clinical ProgramInvasive 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


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


Study Procedures: End of Randomized Therapy

Randomized Therapy

Withdraw from Randomized

Therapy

Switch to Other LicensedAntifungal Therapy

VoriconazoleStandard loading doses, then4 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


Study Procedures: Week 12

Week 12

DRC Assessmentof Outcome at End ofRandomized Therapy=DRC Assessment at

Week 12

DRC Assessment at

Week 12

Survival through Day 84

Randomized Therapy


Therapy


DRC Assessmentof Outcome at End ofRandomized 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


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


Results

15

Global Comparative Aspergillosis Study (307/602)Enrollment

Number of Centers

Approved

Number of Patients Enrolled

US-Led Study 602 United States 55 112

Canada 16 19 Mexico, Argentina, Brazil, India 16 8

EORTC-Led Study 307 Germany 24 126

France 16 65 Belgium 8 27

Europe, Australia, Israel 64 35

Total 199* 392

*95 of 199 sites enrolled 392 patients

16


Patient Disposition

No Treatment

IncorrectRandomization

No Definite or Probable

Aspergillosisper

Blinded Data Review

Committee

196

194

144

Voriconazole Amphotericin B392

Enrolled

185

185

133

Safety Population

Intention to Treat Population

Modified Intention to Treat Population

3 8

2 0

50 52

17

Characteristics

Voriconazole

N = 144

Amphotericin B

N = 133

Age – years Mean 48.5 50.5 Range 13 - 79 12 - 75 Sex – N (%) Male 98 (68.1) 89 (66.9) Female 46 (31.9) 44 (33.1) Race – N (%) White 130 (90.3) 126 (94.7) Black 7 (4.9) 1 (0.8) Other 7 (4.9) 6 (4.5)

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)

Voriconazole N = 144

Amphotericin B N = 133

Site of Infection n (%) Pulmonary 119 (82.6) 112 (84.2)

Extrapulmonary 25 (17.4) 21 (15.8)

Underlying Disease Allogeneic BMT/PSCT 37 (25.7) 30 (22.5)

Autologous BMT/PSCT or other hematological condition (eg leukemia)

81 (56.3)

84 (63.2)

Other immunosuppression (eg solid organ transplant, HIV/AIDS)

26 (18.0)

19 (14.3)

Neutrophil Status at Baseline ANC < 500 cells/mm3 63 (43.8) 60 (45.1) ANC 500 cells/mm3 81 (56.3) 73 (54.9)

19

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

Certainty of Infection



n (%)

Definite 67 (46.5) 41 (30.8)

Probable 77 (53.5) 92 (69.2)

20


Study Procedures: Progress Over Time

Randomized Therapy


Therapy




Week 12

DRC Assessmentof Outcome at End ofRandomized Therapy=DRC Assessment at

Week 12

DRC Assessment at

Week 12

Survival through Day 84

21

Global Comparative Aspergillosis Study (307/602) Disposition Over Time: Voriconazole Arm (MITT)

0

20

40

60

80

100

120

140

160

1 8 15 22 29 36 43 50 57 64 71 78

Day

42

51322

62

Day 84

Voriconazole Randomized Therapy OLAT Died

Post Treatment Follow up Discontinued

Nu

mb

er o

f P

atie

nts

22

Global Comparative Aspergillosis Study (307/602) Disposition Over Time: Amphotericin B Arm (MITT)

0

20

40

60

80

100

120

140

1 8 15 22 29 36 43 50 57 64 71 78

Nu

mb

er o

f P

atie

nts

Day 84

56

711

57

2

Amphotericin B Randomized Therapy OLAT Died

Post Treatment Follow up Discontinued

Day

23


Endpoints Outcome at Week 12

Test for non-inferiority (DRC-assessed success)

Primary Efficacy Endpoint



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)

0

10

20

30

40

50

60

% S

ucc

ess

Voriconazole +/- OLAT*

Amphotericin B +/- OLAT*

76/144

42/133

* OLAT = Other licensed antifungal therapy

25

Global Comparative Aspergillosis Study (307/602)DRC-Assessed Success at Week 12 (MITT)

0

10

20

30

40

50

60

Study 602 Study 307

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%

0

10

20

30

40

50

60

% S

ucc

ess

Voriconazole +/- OLAT

Amphotericin B +/- OLAT

76/144

42/133

26-20 -10 0 10 20 30 40 50 60


DRC-Assessed Success at Week 12 (MITT) Success Voriconazole Ampho B

52.8% 31.6%

55.5% 34.8%

40.0% 14.3%

32.4% 13.3%

63.0% 38.1%

50.0% 31.6%

50.8% 31.7%

54.3% 31.5%

44.8% 19.5%

59.7% 37.0%

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







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 ofRandomized Therapy

Voriconazole = 77 days

Amphotericin B = 11 days

0

10

20

30

40

50

60

% S

uc

ce

ss

Voriconazole Amphotericin B

77/144

29/133

29







30

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)

0 14 28 42 56 70 840.0

0.2

0.4

0.6

0.8

1.0

Global Comparative Aspergillosis Study (307/602) Time to Death (MITT)

Number of days of Therapy

Pro

bab

ilit

y o

f S

urv

ival

Amphotericin B +/- OLAT

Voriconazole +/- OLAT

Hazard ratio = 0.6095% CI (0.40, 0.89)

31

Voriconazole +/- OLAT N = 144 n (%)

Amphotericin B +/- OLAT N = 133

n (%)

Mortality 42 (29.2) 56 (42.1)

Death caused by aspergillosis 18 (12.5) 38 (28.6)

Death unrelated to aspergillosis but evidence of active Aspergillus infection

10 (6.9) 8 (6.0)

Death unrelated to aspergillosis and no evidence of residual Aspergillus

infection

7 (4.9) 3 (2.3)

Indeterminate 7 (4.9) 4 (3.0)

Not assessed by DRC 0 3 (2.3)


DRC-Assessed Cause of Death at Day 84 (MITT)

32


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

Success n (%)

ITT

N = 137

Expert Evaluable

N = 112

Per Protocol Primary

Subgroup

5 Days Prior Therapy

N = 50

Success 74 (54.0) 55 (49.1) 26 (52.0)

Failure 61 (44.5) 56 (50.0) 24 (48.0)

No Evaluable Data 2 (1.5) 1 (0.9) 0

Non-Comparative Aspergillosis Study (304)* Outcome

* Denning et al, CID in press

34

0 20 40 60 80 100

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

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 DataInvasive Aspergillosis





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 20013 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

Fungus

Antifungal Agent

MIC Range

g/ml

MIC50 g/ml

MIC90 g/ml

S. apiospermum (n = 13) Amphotericin B 1 - 8 4 8 Itraconazole 0.125 – 8 0.5 0.5 Miconazole 0.06 - 1 0.12 0.12

S. prolificans (n = 5) Amphotericin B 2 – 16 Itraconazole 2 – 16 Miconazole 0.5 - >16

F. solani (n = 65) Amphotericin B 0.5 - > 16 1 - 4 Itraconazole 1 - > 16 > 16

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

Success n/N

S. apiospermum N = 27

S. prolificans N = 8

Central Nervous System 7/11* 0/2

Disseminated 3/4 1/3

Blood 0 0/1

Pulmonary 5/7 0/1

Cutaneous 0/2 -

Bone/Joint 1/3 1/1

Total 16/27** 2/8

* One patient relapsed; in four patients multiple sites were involved

39

Success in Fusarium By Site of Infection

Success n/N

Eye 2/4*

Sinus 2/3**

Skin 1/2

Disseminated 1/6

Total 6/15 (40%)†

* 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)




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)

0

20

40

60

80

100

% S

ucc

ess

113/115134/141

Success (cured + improved): 98.3% Voriconazole, 95.0% Fluconazole Difference 3.23%, 95% CI (-1.08, 7.53)

* Ally et al, CID 2001

Voriconazole Fluconazole

43

Systemic Candida Infections Salvage Therapy (N = 43)

Voriconazole Success n/N (%)

Clinical Trial

Patients

Compassionate

Use Patients

Total

Prior Efficacy Failure

10/20 (50) 6/16 (38) 16/36 (44)

Intolerance 2/3 1/1 3/4

Unknown 2/2 1/1 3/3

Total 14/25 (56) 8/18 (44) 22/43 (51)

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 DataInvasive Aspergillosis





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


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


Results

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

Voriconazole Liposomal

Amphotericin B871

Randomized

Safety Population

Modified Intention to Treat Population

14 8

6 6

54

Characteristics


Liposomal


Age – years Mean 46.3 45.0 Range 12 – 82 12 - 80

Sex – N (%) Male 233 (56.1) 216 (51.2) Female 182 (43.9) 206 (48.8)

Race – N (%) White 325 (78.3) 333 (78.9) Black 35 (8.4) 32 (7.6) Other 55 (13.3) 57 (13.5)

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

55

Characteristics

Voriconazole N = 415 n (%)

Liposomal

Amphotericin B N = 422 n (%)

Risk Category High 143 (34.5) 141 (33.4) Moderate 272 (65.5) 281 (66.6)

Systemic Antifungal Prophylaxis 222 (53.5) 250 (59.2)

Bone Marrow Transplant (BMT)* Allogeneic BMT 76 (18.3) 79 (18.7) Autologous BMT 122 (29.4) 139 (32.9)

Total BMTs 198 (47.7) 217 (51.4)

†

† 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

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

Voriconazole Liposomal Amphotericin B

Number of Patients

Median Duration Days

(range)

Number of

Patients

Median Duration Days

(range)

IV 415 6 (1 - 46) 422 7 (1 - 81)

Oral + IV 91 6 (1 - 95) N/A N/A

Total 415 7 (1 - 113) 422 7 (1 - 81)

57

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

Voriconazole

Liposomal Amphotericin B

Number of Patients 415 422

Success (Raw) 108 (26.0%) 129 (30.6%)

Difference between arms - 4.5 (-10.6%, 1.6%)

Primary Analysis

Success (Stratified) 23.7% 30.1%

Difference between arms (Stratified)

- 6.1% (-12.0%, -0.1%)

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)*

Voriconazole

n/N (%)

LiposomalAmphotericin B

n/N (%)

BreakthroughInvasive FungalInfection 8/415 (1.9) 21/422 (5.0)

* Definite or probable according to the blinded DRC

60

Organism and Site

Voriconazole


Aspergillus 4 13 Lung 4 9 Sinuses 0 2 CNS/Skin 0 1 Disseminated 0 1

Candida 2 6 Disseminated 1 0 Blood 1 6

Zygomycetes 2 0 Lung 1 0 Nasal 1 0

Dematiaceous moulds 0 2 Blood 0 1 Lungs 0 1

Total 8 21

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

61








62

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

Voriconazole

N = 415 n (%)


N = 422 n (%)

Deaths

33 (8.0)

25 (5.9)

63

Investigator-Assessed Cause of Death* Voriconazole L-AMB

Total Number of Deaths 33 25 Progression of malignancy 13 5

Sepsis 13 9**

Cardiac/respiratory arrest/failure 9 5

Other 8 5

Pneumonia 6

† 0

Multi-organ failure 5 5

Disseminated fungal Infection 2 2

Renal failure 2 1

Ventricular fibrillation 1 0

Hemorrhage 1 6

*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








65

Empirical Therapy Study (603/MSG42) Discontinuation Due to Toxicity or Lack of Efficacy Prior to Recovery from Neutropenia (MITT)*

Voriconazole

N = 415 n


N = 422 n

Toxicity 19 23

Lack of efficacy 22 5

Total 41 28

* Included only permanent discontinuation. 7 voriconazole and 52 liposomal amphotericin B patients temporarily discontinued study drug or had dose reductions during study

66

Voriconazole N = 22*

n

Liposomal


n

Confirmed fungal infection 5 3

Suspected fungal infection 1 0

Pulmonary infiltrates only 2 0

Fever only 14 2

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








68*Temperature less than 38o C for 48 hours prior to recovery from neutropenia (ANC > 250 cells/mm3)

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








70

Voriconazole Success n/N (%)


Success n/N (%)

Baseline Infections 6/13 (46) 4/6 (67)

Candida infection 5/10 2/3

Aspergillus infection 1/2 1/2

Other organisms 0/1 1/1

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

71-70 -60 -50 -40 -30 -20 -10 0 10 20 30

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)

Overall response to empirical therapy (raw)

(stratified)

No breakthrough fungal infections within 7 days of End

of Therapy

Survival through 7 days of End of Therapy

No discontinuation due to toxicity or lack of efficacy before

recovery from neutropenia

Resolution of fever during neutropenia

Global response of baseline fungal infections at End of

Therapy (complete or partial response)

72

Prior Antifungal

Prophylaxis n/N (%)

No Prophylaxis n/N (%)

Total n/N (%)

High Risk Voriconazole 1/83 (1.2) 1/60 (1.7) 2/143 (1.4) L-AMB 9/99 (9.1) 4/42 (9.5) 13/141 (9.2)

Moderate Risk Voriconazole 1/139 (0.7) 5/133 (3.8) 6/272 (2.2) L-AMB 4/151 (2.6) 4/130 (3.1) 8/281 (2.8) Total Voriconazole 2/222 (0.9) 6/193 (3.1) 8/415 (1.9) L-AMB 13/250 (5.2) 8/172 (4.7) 21/422 (5.0)

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

73

Voriconazole

n/N (%)


n/N (%)

Raw Estimate (C.I.)

High Risk 45/143 (32%) 42/141 (30%) + 1.7% (- 9.0%, 12.4%)

Moderate Risk 63/272 (23%) 87/281 (31%) - 7.8% (- 15.2%, - 0.4%)

Empirical Therapy Study (603/MSG42)Overall Response by Randomization Stratum (MITT)

C.I. = 95% Confidence Interval

74

-10

High RiskModerate Risk

-100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 70 80

Empirical Therapy Study (603/MSG42) Response to Empirical Therapy (MITT) High and Moderate Risk

% Difference (95% CI)

Overall response to empirical therapy (raw data)

No breakthrough fungal infections within 7 days of End

of Therapy

Survival through 7 days of End of Therapy

No discontinuation due to toxicity or lack of efficacy before

recovery from neutropenia

Resolution of fever during neutropenia

Global response of baseline fungal infections at End of

Therapy (complete or partial response)

75

VoriconazoleN = 415n (%)

LiposomalAmphotericinB

N = 422n (%)

Abnormal Vision 91 (21.9) 3 (0.7)

Chills 57 (13.7) 126 (29.9)

Flushing** 14 (3.4) 46 (10.9)

Dyspnea/Wheezing/Cough/Tachypnea/Hypoxia** 8 (1.9) 50 (11.9)

Chest Pain** 1 (0.2) 17 (4.0)

Abdominal Pain** 1 (0.2) 12 (2.8)

Flank Pain** 1 (0.2) 8 (1.9)

Urticaria** 1 (0.2) 3 (0.7)

Back Pain** 0 14 (3.3)

Anaphylactoid Reaction** 0 7 (1.7)

* 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


Infusion Related Reactions (MITT) - All*

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

helen whamond boucher, m.d

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