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.

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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

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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.

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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.

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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

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Comparative Efficacy of Caspofungin and
Amphotericin B in Granulocytic Rabbits with
Invasive Pulmonary Aspergillosis
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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

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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)

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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

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Clinical StudiesInvasive Aspergillosis

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

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Clinical StudiesMucosal Candidiasis
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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

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Study 019 Study Procedures
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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

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Exclusion Criteria
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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)

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Disease Definition

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

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Disease Definition
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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)

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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

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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

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Expert Panel Assessment
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Expert Panel Assessment
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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

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Study 019 and 028/029Data Analysis

• Primary proportion of success at EOT
• Secondary logistic regression analysis
• Adjusted for predictive/baseline risk
• variables

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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

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Study 028 Patient Accounting1995-1998
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Baseline Characteristics
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Baseline Characteristics (cont.)
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Baseline Characteristics (cont.)
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Baseline Characteristics Prior Therapy in Study
019 and 028/029
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Duration of Prior/Standard Therapy
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Total Treatment Duration for Current
Aspergillosis Infection
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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)

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Complete Responses and Relapse
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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

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Clinical Efficacy Rates by Baseline Risk
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Clinical Efficacy Rates by Geographic Region
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Clinical Efficacy Rates by Total Duration of
Treatment
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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

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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

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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

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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

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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)

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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

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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

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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

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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

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Drug Exposure
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Overall Caspofungin Safety in Clinical Studies
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Drug-Related Adverse Events
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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)

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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

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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

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