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CANCIDAS caspofungin acetate for intravenous injection

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... and Amphotericin B in Granulocytic Rabbits with Invasive Pulmonary Aspergillosis ... retrospective review of medical records ... – PowerPoint PPT presentation

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Title: CANCIDAS caspofungin acetate for intravenous injection


1
CANCIDAS? (caspofungin acetate)for intravenous
injection
  • NDA 21-227
  • Merck Co., Inc.

2
Safety and Efficacy of CANCIDAS? (caspofungin
acetate) in Invasive Aspergillosis
  • Eileen Navarro, M.D., Medical Officer
  • Division of Special Pathogen and Immunologic Drug
    Products
  • CDER/FDA

3
FDA Review Team for NDA 21-227
  • Regulatory Project Manager L. Chan, R.Ph.
  • Chemistry G. Holbert, Ph.D. D.
    Matecka, Ph.D.
  • Microbiology S. Bala, Ph.D.
  • Pharmacokinetics/Biopharmaceutics H. Mahayni,
    Ph.D.
  • Pharmacotoxicologist O. McMaster, Ph.D.
  • Biostatistician C. Dixon, Ph.D.
  • Clinical E. Navarro, M.D. L. Sacks,
    M.D.
  • OPDRA consultant J. Staffa, Ph.D.

4
Outline
  • 1. CANCIDAS? proposed labeling, microbiology,
    pharmacokinetics
  • 2. Efficacy of CANCIDAS? as therapy for
    refractory or intolerant invasive aspergillosis
  • 3. Safety of CANCIDAS? in healthy subjects and in
    patients with fungal infections

5
Proposed Labeling
  • Indication
  • CANCIDAS? is indicated for the treatment of
    invasive aspergillosis in patients who are
    refractory to or intolerant of other therapies.
  • Dosage
  • A single 70-mg loading dose ... administered on
    Day 1, followed by 50 mg daily.

6
Proposed Dosage Adjustments
  • Increase
  • ...available safety data suggests an increase to
    70 mg daily ...in patients without evidence of
    clinical response
  • Decrease
  • In patients with moderate hepatic insufficiency
    CANCIDAS 35 mg daily is recommended
  • No dosage adjustment is necessary for patients
    with renal insufficiency.

7
Microbiology
  • Gene inhibition ? cell membrane enzyme modulation
    ? cell wall glucan reduction
  • Time kinetics studies slower kill rate for C.
    albicans
  • (7 hours caspofungin vs 1 hour Amphotericin B
    )
  • Activity specific for actively growing hyphae
  • Activity for Aspergillus spp not fungicidal
  • ? activity against Fusarium, Trichosporon, Mucor
    spp

8
Comparative Efficacy of Caspofungin and
Amphotericin B in Granulocytic Rabbits with
Invasive Pulmonary Aspergillosis
9
Pharmacokinetics
  • Concentrations are more variable in patients
  • Trough levels gt1 ?g/ml are immediately achieved
    with a 70 mg loading dose
  • CNS distribution low in rodents unknown in humans

10
Pharmacokinetics
  • No adjustment for itraconazole, amphotericin B,
    and mycophenolate mofetil
  • Reduces tacrolimus levels
  • Cyclosporine increases caspofungin AUC by 35
  • NOT an inhibitor or a substrate of CYP isoenzymes
  • Potential metabolic inducers nelfinavir, CYP
    3A4 inducers (rifampin, phenobarbital)

11
Outline
  • 1. CANCIDAS? proposed labeling, microbiology,
    pharmacokinetics
  • 2. Efficacy of CANCIDAS? as therapy for
    refractory or intolerant invasive aspergillosis
  • 3. Safety of CANCIDAS? in healthy subjects and in
    patients with fungal infections

12
Clinical StudiesInvasive Aspergillosis
  • Clinical trials
  • Study 019 Open label N 69
  • Study 024 Compassionate use N 3
  • Historical control
  • Study 028/029 N 229

13
Clinical StudiesMucosal Candidiasis
14
Protocol Summary Highlights for Studies 019 and
028/029
  • Procedures
  • Disease definition
  • Response to prior therapy
  • Timing of assessments
  • Outcome definitions
  • Study design and analysis

15
Study 019 Study Procedures
16
Study 028 Study Procedures
  • Case finding pathology/microbiology department,
    subspecialty consultation and hospital
    discharge registries
  • Sites 4/10 participated in Study 019
  • Data chart abstraction
  • Outcome assessment site investigator

17
Exclusion Criteria
18
Study 019 and Study 028/029Exclusion Criteria
  • Severity of underlying disease
  • a) Abnormal Lab values
  • Hemoglobin lt8 gm/dL
  • Platelet count lt25,000/?L
  • INR gt 1.6
  • Bilirubin gt3 times the upper limit of normal
  • AST or ALT gt 5 times the upper limit of normal
  • b) Patients who were not expected to survive
  • at least 5 days (after 7 days of prior
    therapy)

19
Disease Definition
  • DEFINITE
  • Pulmonary histopathology OR tissue cultures
  • Extrapulmonary histopathology (invasion of
    affected tissue)

20
Disease Definition
21
Response to Prior Therapy
  • Refractory
  • progression or failure to improve despite AmB,
    lipid formulation AmB, itraconazole, or
    investigational azole
  • Intolerance
  • renal
  • baseline doubling or creatinine gt2.5 mg/dL
  • other infusion toxicities
  • Study 028 intolerance (creatinine gt2.5 mg/dL)

22
Study 019 and 028/029Timing of Assessments
  • Response to prior therapy
  • Refractory ?7 days
  • Intolerance undefined
  • Study 019
  • Response to caspofungin therapy EOT
  • Relapse 4 weeks post EOT

23
Study 019 and 028/029Outcome Definitions
  • Favorable
  • Complete response resolution of IA
  • Partial response improvement
  • clinical, x-ray, bronchoscopic findings
  • Unfavorable
  • Stable non-progressive disease
  • Failure progression or death

24
Expert Panel Assessment
25
Expert Panel Assessment
26
Study 019 Study Design
  • Efficacy estimation study
  • response rate 30
  • Population Primary MITT 1 dose
  • Secondary CE gt 7days
  • Expert Panel superceded MITT
  • Safety 95 probability of detecting at least
    1
  • DRAE if the incidence is ? 5.8

27
Study 019 and 028/029Data Analysis
  • Primary proportion of success at EOT
  • Secondary logistic regression analysis
  • Adjusted for predictive/baseline risk
  • variables

28
Study 019 Patient Accounting(May 1998- April
2000)
  • N
  • Enrolled 69
  • Excluded - 6
  • Evaluable 63
  • Reason for Exclusion
  • protocol violation 1
  • another pathogen identified 3
  • unevaluable 2

29
Study 028 Patient Accounting1995-1998
30
Baseline Characteristics
31
Baseline Characteristics (cont.)
32
Baseline Characteristics (cont.)
33
Baseline Characteristics Prior Therapy in Study
019 and 028/029
34
Duration of Prior/Standard Therapy
35
Total Treatment Duration for Current
Aspergillosis Infection
36
Applicant Clinical Efficacy Rates
  • Study 019 Study 028/029
  • Expert Panel Investigator
  • Population n/N () n/N ()
  • All patients 26/63 (41.3) 35/206 (17.0)
  • Response to prior therapy
  • Refractory 19/53 (35.8) 27/188 (14.4)
  • Intolerant Only 7/10 (70.0) 3/5
    (60.0)
  • Site of infection
  • Pulmonary 21/45 (46.7) 32/154 (20.8)
  • All other sites 5/18 (27.8) 3/52 (5.8)

37
Complete Responses and Relapse
38
Complete Response to Caspofungin
  • Identifier 219 330 366 065
  • Extent of IA pulmonary pulmonary skull
    pulmonary
  • Underlying disease allo BMT lymphoma diabetes
    leukemia
  • Prior treatment AmB/ ABLC Itraconazole AmB
    ABLC, Itra
  • lobectomy resection
  • Caspofungin Rx (days) 8 28 27 90
  • Death yes no no no
  • Relapse N/A no no no
  • possible brain abscess
  • CT nodules without cavitation, (-) BAL cultures
    with suggestive direct
  • examination

39
Clinical Efficacy Rates by Baseline Risk
40
Clinical Efficacy Rates by Geographic Region
41
Clinical Efficacy Rates by Total Duration of
Treatment
42
Central nervous system involvement in patients
with IA
  • Success in CNS involvement 2/6
  • CNS aspergillosis emerging on treatment 2
  • Day 16 and 58 of therapy

43
Post-Caspofungin Therapy
  • Patient Initial RX Final treatment Outcome
  • 0002 AmB, ABCD AmBisome surgery died
  • 0056 AmBisome AmBisome failure
  • 0057 ABLC, azole lipid AmB failure
  • 0059 Itra, ABLC, AmBisome surgery failure
  • lipid AmB
  • 0186 ABLC ABLC failure
  • 0187 AmB, ABLC, ABLC died
  • 0246 Itra, AmB AmBisome died
  • 0296 AmB, Itra ABLC failed
  • 0412 azole, Itra AmB failed
  • 0446 lipid AmB, Itra Itraconazole surgery
    improved
  • 0507 AmB azole not known

44
Comparability of the Historical Control (028/029)
and the Cancidas-treated Patients (019)
  • Comparison is subject to several potential biases
  • Information bias
  • Bias from secular trends in diagnosis and/or
    treatment
  • Selection bias

45
Information Bias
  • Assessment of outcome was not as rigorous with
    the control group, due to lower quality of
    available information
  • retrospective review of medical records
  • incomplete information on concomitant medications
    and underlying disease
  • Expert assessment varied greatly between the two
    studies

46
Bias from Secular Trends in Diagnosis and/or
Treatment
  • Historical control success rate by year of
    enrollment increased from 1995 (12.0) to 1998
    (20.6)
  • Improved ability to manage the underlying disease
    from 1995 to 2000
  • Transplantation (new immunosuppressants)
  • Oncology (earlier diagnoses, improved therapy)

47
Selection Bias
  • Differences in distribution and success rates of
    US and foreign patients between studies
  • Differences in distribution of duration of
    therapy for current infection between studies
  • Differences in the exclusion criteria between
    studies

48
Summary of Comparability
  • All of these biases could act to predispose the
    historical control to have a lower success rate
    and the CANCIDASTM-treated group to have a higher
    success rate, independent of treatment with
    CANCIDASTM
  • Notable differences between 019 and 028/029 may
    provide alternative explanations for at least
    part of the treatment effects seen
  • Therefore, it is not clear that all the observed
    treatment effect is due to treatment with
    CANCIDASTM, and it is difficult to quantify the
    potential effect of these biases

49
Outline
  • 1. CANCIDAS? proposed labeling, microbiology,
    pharmacokinetics
  • 2. Efficacy of CANCIDAS? as therapy for
    refractory or intolerant invasive aspergillosis
  • 3. Safety of CANCIDAS? in healthy subjects and in
    patients with fungal infections

50
Safety Database
  • Clinical Pharmacology 12 Studies 274
  • Clinical Studies 338
  • 3 comparative Candida 263
  • 1 variable dose Candida 14
  • 1 Aspergillus study 58
  • 1 compassionate use 3
  • Total 612

51
Drug Exposure
52
Overall Caspofungin Safety in Clinical Studies
53
Drug-Related Adverse Events
54
LFT Elevations Clinical Studies Relative
Elevation gt 3x ULN
  • Phase I
  • N 257, excluding subjects with impaired
    hepatic function
  • 4 subjects w/ ALT or AST gt3x ULN
  • (these 4 patients had normal bilirubin levels)
  • Comparative Phase II and Phase III
  • Patients w/ ALT or AST gt3x ULN and Bilirubin gt
    ULN
  • Caspofungin vs. Fluconazole
  • 6/263 2/93
  • (2.3) (2.2)

55
Potential Safety Issues
  • Elevations in serum calcium / creatinine
  • 056 hypercalcemia
  • Respiratory adverse events
  • 186 pulmonary infiltrates
  • 220 pulmonary infiltrates
  • Possible histamine reactions
  • 1338 rash, pruritus, tachypnea
  • 0683 fever, wheeze, rash

56
Summary
  • 1. CANCIDAS? proposed labeling, microbiology,
    pharmacokinetics
  • 2. Efficacy of CANCIDAS? as therapy for
    refractory or intolerant invasive aspergillosis
  • 3. Safety of CANCIDAS? in healthy subjects and in
    patients with fungal infections

57
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