Antiviral Drug Products Advisory Committee Meeting

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
ProductsVoriconazole Review Team

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

3
Indications Requested in the NDA

• Treatment of invasive aspergillosis
• Empiric antifungal therapy of febrile neutropenic
  patients
• Treatment 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

6
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
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 lt5 days prior antifungal
  therapy
• Matched on certainty of diagnosis, underlying
  disease, and site of infection

14
Study 304/ Historical Control Study 1003

• Global Response
• Study 304 vori 26/50 52.0
• Historical Control 23/92 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

17
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