Transcript Antiviral Drug Products Advisory Committee Meeting NDA 21-266 voriconazole tablets

Antiviral Drug Products
Advisory Committee Meeting
NDA 21-266
NDA 21-267
voriconazole tablets
voriconazole for injection
Rosemary Tiernan, MD, MPH
1
Division of Special Pathogen and Immunologic Drug
Products
Voriconazole Review Team
Jouhayna Saliba, RPh
Gene W. Holbert, PhD
Owen G. McMaster, PhD
Linda L. Gosey, MS
Philip M.Colangelo, PharmD, PhD
Joette M. Meyer,PharmD
Cheryl A. Dixon, PhD
M. Regina Alivisatos, MD
Rosemary Johann-Liang, MD
John H. Powers III, MD
Marc Cavaillé-Coll, MD, PhD
Norman R. Schmuff, PhD
Kenneth L. Hastings, PhD
Shukal Bala, PhD
Funmi O. Ajayi, PhD
Wiley A. Chambers, MD
Karen M. Higgins, ScD
Edward M. Cox, MD, MPH
Rigoberto A. Roca, MD
Rosemary Tiernan, MD, MPH
2
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
3
FDA Presentation
Treatment of Invasive Aspergillosis
Empiric Antifungal Therapy of Febrile
Neutropenic Patients
Clinical Safety
Questions to the Advisory Committee
4
Treatment of Invasive
Aspergillosis
Study 307/602
Study 304 and
Historical Control Study 1003
5
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
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Study 307/602
• MITT
– voriconazole
– amphotericin B
(N = 144)
(N = 133)
• Patient Characteristics
– White male, hematologic malignancies, pulmonary
site
• Switch to OLAT
– voriconazole
– amphotericin B
36.1%
80.5%
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Study 307/602
Primary Efficacy Endpoint
• Satisfactory Response at Week 12
(MITT)
– voriconazole
– ampho B
76/144
42/133
52.8%
31.6%
• 95% CI stratified by protocol (9.6, 33.6)
8
Study 307/602
Additional 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%
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Study 307/602
Survival
Probability of Survival at
Day 84
vori
ampho B
0.708
0.579
AMPHOTERICIN B
VORICONAZOLE
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Study 304
• Expert Evaluable Population
– Overall
• Primary therapy
• Salvage therapy
N = 112
N = 58
N = 54
• Patient Characteristics
– White male, hematologic malignancies,
pulmonary site, European population
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Study 304
• Expert Global Response at EOT (expert
evaluable population)
– Overall
• Primary
• Salvage
55/112
49.1%
35/58
20/54
60.3%
37.0%
12
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
13
Study 304/ Historical
Control Study 1003
• Global Response
– Study 304 vori
26/50
– Historical Control 23/92
52.0%
25.0%
• Probability of Survival at Day 90
– Study 304 vori
– Historical Control
0.554
0.417
14
Historical Control Issues
• Patient populations
– Study 304
only in Europe
– Historical Control both in Europe and US
– Global Response
– US HC
– EU HC
– Study 304 vori
11/51
12/41
26/50
21.6%
29.3%
52.0%
– Probability of Survival at Day 90
– US HC
– EU HC
– Study 304 vori
0.290
0.573
0.554
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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
16
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
17
Clinical Safety
Rosemary Tiernan, MD, MPH
18
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
19
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
20
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
21
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
22
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
23
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
24
Cardiac Safety
• In vitro data
• In vivo data
• Clinical data
– One sudden death
25
Cardiac Safety
• Clinical data
– Adverse Events
• Cardiac arrhthymias, CHF, cardiac arrests
– Discontinuations
26
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
27
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.
28
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
29
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
30
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
31
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
32
Drug Interactions with Voriconazole
In 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
33
Drug Interactions with Voriconazole
In 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
34
Clinical Safety
Rosemary Tiernan, MD, MPH
35
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
36
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
37
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
38
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
39
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
40
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
41
Cardiac Safety
• In vitro data
• In vivo data
• Clinical data
– One sudden death
42
Cardiac Safety
• Clinical data
– Adverse Events
• Cardiac arrhthymias, CHF, cardiac arrests
– Discontinuations
43
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
44
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.
45
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
46
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
47
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
48
Clinical Safety
• Focus on 5 specific areas:
– Ocular safety
– Cardiac safety
– Hepatic safety
– Rash
– Drug interactions
49
Drug Interactions with Voriconazole
In 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
50
Drug Interactions with Voriconazole
In 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
51