1

Antiviral Drug Products Advisory Committee Meeting

NDA 21-266 voriconazole tablets

NDA 21-267 voriconazole for injection

Rosemary Tiernan, MD, MPH

2

Division of Special Pathogen and Immunologic Drug Products

Voriconazole Review Team

Jouhayna Saliba, RPh Marc Cavaillé-Coll, MD, PhD Gene W. Holbert, PhD Norman R. Schmuff, PhDOwen G. McMaster, PhD Kenneth L. Hastings, PhDLinda L. Gosey, MS Shukal Bala, PhD Philip M.Colangelo, PharmD, PhD Funmi O. Ajayi, PhDJoette M. Meyer,PharmD Wiley A. Chambers, MDCheryl A. Dixon, PhD Karen M. Higgins, ScDM. Regina Alivisatos, MD Edward M. Cox, MD, MPH Rosemary Johann-Liang, MD Rigoberto A. Roca, MDJohn H. Powers III, MD Rosemary Tiernan, MD, MPH

3

Indications Requested in the NDA

Treatment of invasive aspergillosisEmpiric antifungal therapy of febrile neutropenic

patientsTreatment of: -candida esophagitis

-serious candida infections-serious fungal infections due to Fusarium and Scedosporium spp.-serious fungal infections in patients refractory or intolerant to other therapy

4

FDA Presentation

Treatment of Invasive Aspergillosis

Empiric Antifungal Therapy of Febrile Neutropenic Patients

Clinical Safety

Questions to the Advisory Committee

5

Treatment of Invasive Aspergillosis

Study 307/602

Study 304 and

Historical Control Study 1003

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Treatment of Invasive Aspergillosis

• Study 307/602– Randomized, controlled, open-label, initial therapy– Blinded Data Review Committee– voriconazole vs. amphotericin B followed by “other

licensed antifungal therapy” (OLAT)

• Study 304– Uncontrolled study of primary and salvage cases– Expert Panel– Retrospectively designed historical control

7

Study 307/602• MITT

– voriconazole (N = 144)– amphotericin B (N = 133)

• Patient Characteristics– White male, hematologic malignancies, pulmonary

site

• Switch to OLAT– voriconazole 36.1% – amphotericin B 80.5%

8

Study 307/602Primary Efficacy Endpoint

• Satisfactory Response at Week 12 (MITT)– voriconazole 76/144 52.8%– ampho B 42/133 31.6%

• 95% CI stratified by protocol (9.6, 33.6)

9

Study 307/602Additional Efficacy Analyses

• Not allowing DRC to upgrade investigator assessment– vori 46.5% vs. ampho B 29.3%

• “Modified Week 12”– vori 45.1% vs. ampho B 31.6%

• Week 16 follow-up– vori 45.8% vs ampho B 33.1%

10

Study 307/602Survival

AMPHOTERICIN B

VORICONAZOLE

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 10 20 30 40 50 60 70 80 90

SURVDAY

Probability of Survival at Day 84

vori 0.708 ampho B 0.579

11

Study 304• Expert Evaluable Population

– Overall N = 112• Primary therapy N = 58• Salvage therapy N = 54

• Patient Characteristics– White male, hematologic malignancies,

pulmonary site, European population

12

Study 304

• Expert Global Response at EOT (expert evaluable population)– Overall 55/112 49.1%

• Primary 35/58 60.3%• Salvage 20/54 37.0%

13

Historical Control (HC)Study 1003

• Substantial effort to provide the most comparable population to primary therapy patients in Study 304– primary therapy was <5 days prior

antifungal therapy

• Matched on certainty of diagnosis, underlying disease, and site of infection

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Study 304/ Historical Control Study 1003

• Global Response– Study 304 vori 26/50 52.0%– Historical Control23/92 25.0%

• Probability of Survival at Day 90– Study 304 vori 0.554– Historical Control 0.417

15

Historical Control Issues• Patient populations

– Study 304 only in Europe– Historical Control both in Europe and US– Global Response

– US HC 11/51 21.6%– EU HC 12/41 29.3%– Study 304 vori 26/50 52.0%

– Probability of Survival at Day 90 – US HC 0.290– EU HC 0.573– Study 304 vori 0.554

16

Historical Control Issues (cont.)

• Duration of treatment– longer for voriconazole treated patients

• Difference in inclusion/exclusion criteria– which could possibly allow for sicker

patients in the HC

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Aspergillosis Summary

• HC good effort but still concerns about comparability of the study populations

• Study 304 results are used to support the randomized controlled study

• Study 307/602 showed– Non-inferior Global Response

• Statistically superior

– Survival Benefit

18

Clinical Safety

Rosemary Tiernan, MD, MPH

19

Clinical Safety

• Focus on 5 specific areas:– Ocular safety – Cardiac safety– Hepatic safety– Rash– Drug interactions

20

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash – Drug interactions

21

Ocular Safety

• Pre-clinical studies• Incidence in clinical studies is 1 out of every 3

subjects• Symptoms

Decreased vision, photophobia, altered color perception and ocular discomfort

• Unknown Mechanism• No human histopathology• Ocular biomicroscopy has not detected ocular

lesions

22

Ocular safety

Results from study 150-1004– Effects noted in

• ERG• Farnsworth-Munsell 100 hue test (color vision)• Humphrey Perimetry (visual field)

– Drug effect on both rod and cone function– Decreased vision on day 1 and continued

through 28 days of therapy– Testing 2 weeks after the end of treatment

demonstrated return to normal function

23

Ocular Safety

Additional issues regarding use of this drug

-re-challenge or re-treatments

-ocular development in pediatric patients

-patients with underlying eye disease

-treatment beyond 28 days

24

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash– Drug interactions

25

Cardiac Safety

• In vitro data

• In vivo data • Clinical data

– One sudden death

26

Cardiac Safety

• Clinical data

– Adverse Events• Cardiac arrhthymias, CHF, cardiac arrests

– Discontinuations

27

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash– Drug interactions

28

Hepatic Safety Summary

• Phase I/II Studies– Positive dose (exposure) response with ALT and AST

• Phase III Comparative Studies– Hepatic adverse events and ALT & AST abnormalities

were more frequent with voriconazole than fluconazole

– Frequency of hepatic adverse effects similar between voriconazole and amphotericin B formulations studied

– Serious hepatic adverse events reported more frequently in voriconazole treated patients.

29

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash– Drug interactions

30

Rash

• Difficulties in assessment of rash include:– Concomitant medications that can also

cause rash– Concomitant medications can affect the

type or severity of skin exanthem observed– Underlying conditions such as GVHD

31

Rash Observed in 18.6% of patients on

voriconazole in therapeutic studies program

• Most rashes mild to moderate• No major differences in discontinuations for

rash• 4 non-fatal cases of Stevens-Johnson

32

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash – Drug interactions

33

Drug Interactions with VoriconazoleIn Vitro Metabolism

• Voriconazole is a substrate and inhibitor of CYP2C19, CYP2C9, CYP3A4

• Substrate affinity and inhibition potency of voriconazole is greater for CYP2C19 and CYP2C9 compared to CYP3A4

– CYP3A4 inhibition potency of voriconazole weaker than ketoconazole and itraconazole

• Potency of voriconazole to inhibit CYP3A4 metabolism varies among several CYP3A4 substrates (and vice-versa)

– HIV-PI, NNRTI, and Immunosuppressant Drugs

34

Drug Interactions with VoriconazoleIn Vivo Metabolism

• Representative substrates / inhibitors / inducers of the three CYP enzymes were studied, since it is not possible to evaluate every potential drug interaction – Example: HIV-PI and NNRTI drugs not studied in vivo

• CYP3A4 inhibitors and/or inducers• Exception: Indinavir no significant interaction

• The potential for drug interactions with voriconazole presents a therapeutic challenge for the prescriber

35

Clinical Safety

Rosemary Tiernan, MD, MPH

36

Clinical Safety

• Focus on 5 specific areas:– Ocular safety – Cardiac safety– Hepatic safety– Rash– Drug interactions

37

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash – Drug interactions

38

Ocular Safety

• Pre-clinical studies• Incidence in clinical studies is 1 out of every 3

subjects• Symptoms

Decreased vision, photophobia, altered color perception and ocular discomfort

• Unknown Mechanism• No human histopathology• Ocular biomicroscopy has not detected ocular

lesions

39

Ocular safety

Results from study 150-1004– Effects noted in

• ERG• Farnsworth-Munsell 100 hue test (color vision)• Humphrey Perimetry (visual field)

– Drug effect on both rod and cone function– Decreased vision on day 1 and continued

through 28 days of therapy– Testing 2 weeks after the end of treatment

demonstrated return to normal function

40

Ocular Safety

Additional issues regarding use of this drug

-re-challenge or re-treatments

-ocular development in pediatric patients

-patients with underlying eye disease

-treatment beyond 28 days

41

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash– Drug interactions

42

Cardiac Safety

• In vitro data

• In vivo data • Clinical data

– One sudden death

43

Cardiac Safety

• Clinical data

– Adverse Events• Cardiac arrhthymias, CHF, cardiac arrests

– Discontinuations

44

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash– Drug interactions

45

Hepatic Safety Summary

• Phase I/II Studies– Positive dose (exposure) response with ALT and AST

• Phase III Comparative Studies– Hepatic adverse events and ALT & AST abnormalities

were more frequent with voriconazole than fluconazole

– Frequency of hepatic adverse effects similar between voriconazole and amphotericin B formulations studied

– Serious hepatic adverse events reported more frequently in voriconazole treated patients.

46

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash– Drug interactions

47

Rash

• Difficulties in assessment of rash include:– Concomitant medications that can also

cause rash– Concomitant medications can affect the

type or severity of skin exanthem observed– Underlying conditions such as GVHD

48

Rash Observed in 18.6% of patients on

voriconazole in therapeutic studies program

• Most rashes mild to moderate• No major differences in discontinuations for

rash• 4 non-fatal cases of Stevens-Johnson

49

Clinical Safety

• Focus on 5 specific areas:– Ocular safety– Cardiac safety– Hepatic safety– Rash – Drug interactions

50

Drug Interactions with VoriconazoleIn Vitro Metabolism

• Voriconazole is a substrate and inhibitor of CYP2C19, CYP2C9, CYP3A4

• Substrate affinity and inhibition potency of voriconazole is greater for CYP2C19 and CYP2C9 compared to CYP3A4

– CYP3A4 inhibition potency of voriconazole weaker than ketoconazole and itraconazole

• Potency of voriconazole to inhibit CYP3A4 metabolism varies among several CYP3A4 substrates (and vice-versa)

– HIV-PI, NNRTI, and Immunosuppressant Drugs

51

Drug Interactions with VoriconazoleIn Vivo Metabolism

• Representative substrates / inhibitors / inducers of the three CYP enzymes were studied, since it is not possible to evaluate every potential drug interaction – Example: HIV-PI and NNRTI drugs not studied in vivo

• CYP3A4 inhibitors and/or inducers• Exception: Indinavir no significant interaction

• The potential for drug interactions with voriconazole presents a therapeutic challenge for the prescriber