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CANCIDAS  (caspofungin acetate) for intravenous injection. NDA 21-227 Merck & Co., Inc. 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.

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Cancidas caspofungin acetate for intravenous injection

CANCIDAS (caspofungin acetate)for intravenous injection

NDA 21-227

Merck & Co., Inc.


Safety and efficacy of cancidas caspofungin acetate in invasive aspergillosis
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


Fda review team for nda 21 227
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.


Outline
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


Proposed labeling
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.


Proposed dosage adjustments
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… CANCIDAS35 mg daily is recommended”

  • No dosage adjustment is necessary for patients with renal insufficiency.


Microbiology
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


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


Pharmacokinetics
Pharmacokinetics Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

  • Concentrations are more variable in patients

  • Trough levels >1 g/ml are immediately achieved with a 70 mg loading dose

  • CNS distribution low in rodents; unknown in humans


Pharmacokinetics1
Pharmacokinetics Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

  • 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…)


Outline1
Outline Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

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


Clinical studies invasive aspergillosis
Clinical Studies: Granulocytic Rabbits with Invasive Pulmonary AspergillosisInvasive Aspergillosis

  • Clinical trials

    Study 019 Open label N = 69

    Study 024 Compassionate use N = 3

  • Historical control

    Study 028/029 N = 229


Clinical studies mucosal candidiasis
Clinical Studies: Granulocytic Rabbits with Invasive Pulmonary AspergillosisMucosal Candidiasis


Protocol summary highlights for studies 019 and 028 029
Protocol Summary Highlights for Studies 019 and 028/029 Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

  • Procedures

  • Disease definition

  • Response to prior therapy

  • Timing of assessments

  • Outcome definitions

  • Study design and analysis


Study 019 study procedures
Study 019: Study Procedures Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Study 028 study procedures
Study 028: Study Procedures Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

  • 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


Exclusion criteria
Exclusion Criteria Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Study 019 and study 028 029 exclusion criteria

Severity of underlying disease: Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

a) Abnormal Lab values

Hemoglobin <8 gm/dL

Platelet count <25,000/L

INR > 1.6

Bilirubin >3 times the upper limit of normal

AST or ALT > 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)

Study 019 and Study 028/029:Exclusion Criteria


Disease definition
Disease Definition Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

DEFINITE

Pulmonary:histopathology OR tissue cultures

Extrapulmonary: histopathology (invasion of affected tissue)


Disease definition1
Disease Definition Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Response to prior therapy
Response to Prior Therapy Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

  • Refractory

    • progression or failure to improve despite AmB, lipid formulation AmB, itraconazole, or investigational azole

  • Intolerance

    • renal

      • baseline doubling or creatinine >2.5 mg/dL

    • other infusion toxicities

  • Study 028: intolerance (creatinine >2.5 mg/dL)


Study 019 and 028 029 timing of assessments
Study 019 and 028/029: Granulocytic Rabbits with Invasive Pulmonary AspergillosisTiming of Assessments

Response to prior therapy:

Refractory: 7 days

Intolerance: undefined

Study 019:

Response to caspofungin therapy: EOT

Relapse: 4 weeks post EOT


Study 019 and 028 029 outcome definitions
Study 019 and 028/029: Granulocytic Rabbits with Invasive Pulmonary AspergillosisOutcome Definitions

  • Favorable

    • Complete response: resolution of IA

    • Partial response: improvement

      • clinical, x-ray, bronchoscopic findings

  • Unfavorable

    • Stable: non-progressive disease

    • Failure: progression or death


Expert panel assessment
Expert Panel Assessment Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Expert panel assessment1
Expert Panel Assessment Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Study 019 study design
Study 019: Study Design Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

Efficacy: estimation study

response rate 30%

Population: Primary MITT 1 dose

Secondary CE > 7days

Expert Panel superceded MITT

Safety: 95% probability of detecting at least 1

DRAE if the incidence is  5.8%


Study 019 and 028 029 data analysis
Study 019 and 028/029: Granulocytic Rabbits with Invasive Pulmonary AspergillosisData Analysis

Primary: proportion of success at EOT

Secondary: logistic regression analysis

Adjusted for predictive/baseline risk

variables


Study 019 patient accounting may 1998 april 2000
Study 019: Patient Accounting Granulocytic Rabbits with Invasive Pulmonary Aspergillosis(May 1998- April 2000)

N

Enrolled 69

Excluded - 6

Evaluable 63

Reason for Exclusion:

protocol violation 1

another pathogen identified 3

unevaluable 2


Study 028 patient accounting 1995 1998
Study 028: Patient Accounting Granulocytic Rabbits with Invasive Pulmonary Aspergillosis1995-1998


Baseline characteristics
Baseline Characteristics Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Baseline characteristics cont
Baseline Characteristics (cont.) Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Baseline characteristics cont1
Baseline Characteristics (cont.) Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Baseline characteristics prior therapy in study 019 and 028 029
Baseline Characteristics: Prior Therapy Granulocytic Rabbits with Invasive Pulmonary Aspergillosisin Study 019 and 028/029


Duration of prior standard therapy
Duration of Prior/Standard Therapy Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Total treatment duration for current aspergillosis infection
Total Treatment Duration for Current Aspergillosis Infection Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Applicant clinical efficacy rates
Applicant Clinical Efficacy Rates Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

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)


Complete responses and relapse
Complete Responses and Relapse Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Complete response to caspofungin
Complete Response to Caspofungin Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

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


Clinical efficacy rates by baseline risk
Clinical Efficacy Rates by Baseline Risk Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Clinical efficacy rates by geographic region
Clinical Efficacy Rates by Geographic Region Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Clinical efficacy rates by total duration of treatment
Clinical Efficacy Rates by Total Duration of Treatment Granulocytic Rabbits with Invasive Pulmonary Aspergillosis


Central nervous system involvement in patients with ia
Central nervous system involvement in patients with IA Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

Success in CNS involvement 2/6

CNS aspergillosis emerging on treatment* 2

*Day 16 and 58 of therapy


Post caspofungin therapy
Post-Caspofungin Therapy Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

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


Comparability of the historical control 028 029 and the cancidas treated patients 019
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


Information bias
Information Bias Cancidas™-treated Patients (019)

  • 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


Bias from secular trends in diagnosis and or treatment
Bias from Secular Trends in Diagnosis and/or Treatment Cancidas™-treated Patients (019)

  • 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)


Selection bias
Selection Bias Cancidas™-treated Patients (019)

  • 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


Summary of comparability
Summary of Comparability Cancidas™-treated Patients (019)

  • 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


Outline2
Outline Cancidas™-treated Patients (019)

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


Safety database
Safety Database Cancidas™-treated Patients (019)

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


Drug exposure
Drug Exposure Cancidas™-treated Patients (019)


Overall caspofungin safety in clinical studies
Overall Caspofungin Safety in Clinical Studies Cancidas™-treated Patients (019)


Drug related adverse events
Drug-Related Adverse Events Cancidas™-treated Patients (019)


Lft elevations clinical studies relative elevation 3x uln
LFT Elevations : Clinical Studies Cancidas™-treated Patients (019)Relative Elevation > 3x ULN

Phase I

N = 257, excluding subjects with impaired hepatic function

4 subjects w/ ALT or AST >3x ULN

(these 4 patients had normal bilirubin levels)

Comparative Phase II and Phase III

Patients w/ ALT or AST >3x ULN and Bilirubin > ULN

Caspofungin vs. Fluconazole

6/263 2/93

(2.3%) (2.2%)


Potential safety issues
Potential Safety Issues Cancidas™-treated Patients (019)

  • 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


Summary
Summary Cancidas™-treated Patients (019)

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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