Cancidas caspofungin acetate for intravenous injection
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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

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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


Cancidas caspofungin acetate for intravenous injection

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


Pharmacokinetics

Pharmacokinetics

  • 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

  • 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

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:Invasive Aspergillosis

  • Clinical trials

    Study 019 Open labelN = 69

    Study 024 Compassionate useN = 3

  • Historical control

    Study 028/029 N = 229


Clinical studies mucosal candidiasis

Clinical Studies:Mucosal Candidiasis


Protocol summary highlights for studies 019 and 028 029

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


Study 019 study procedures

Study 019: Study Procedures


Study 028 study procedures

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


Exclusion criteria

Exclusion Criteria


Study 019 and study 028 029 exclusion criteria

Severity of underlying disease:

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

DEFINITE

Pulmonary:histopathology OR tissue cultures

Extrapulmonary: histopathology (invasion of affected tissue)


Disease definition1

Disease Definition


Response to prior therapy

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 >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:Timing 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:Outcome 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


Expert panel assessment1

Expert Panel Assessment


Study 019 study design

Study 019: Study Design

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:Data 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(May 1998- April 2000)

N

Enrolled 69

Excluded- 6

Evaluable63

Reason for Exclusion:

protocol violation 1

another pathogen identified 3

unevaluable2


Study 028 patient accounting 1995 1998

Study 028: Patient Accounting1995-1998


Baseline characteristics

Baseline Characteristics


Baseline characteristics cont

Baseline Characteristics (cont.)


Baseline characteristics cont1

Baseline Characteristics (cont.)


Baseline characteristics prior therapy in study 019 and 028 029

Baseline Characteristics: Prior Therapy in Study 019 and 028/029


Duration of prior standard therapy

Duration of Prior/Standard Therapy


Total treatment duration for current aspergillosis infection

Total Treatment Duration for Current Aspergillosis Infection


Applicant clinical efficacy rates

Applicant Clinical Efficacy Rates

Study 019Study 028/029

Expert Panel Investigator

Populationn/N (%)n/N (%)

All patients26/63 (41.3)35/206 (17.0)

Response to prior therapy

Refractory19/53 (35.8) 27/188 (14.4)

Intolerant Only 7/10 (70.0) 3/5 (60.0)

Site of infection

Pulmonary21/45 (46.7)32/154(20.8)

All other sites5/18 (27.8) 3/52(5.8)


Complete responses and relapse

Complete Responses and Relapse


Complete response to caspofungin

Complete Response to Caspofungin

Identifier 219330 366 065

Extent of IApulmonarypulmonaryskull+ pulmonary*

Underlying disease allo BMTlymphomadiabetes leukemia

Prior treatmentAmB/ ABLCItraconazoleAmB ABLC, Itra

lobectomyresection

Caspofungin Rx (days)8 2827 90

Deathyesnono no

RelapseN/Anono 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


Clinical efficacy rates by geographic region

Clinical Efficacy Rates by Geographic Region


Clinical efficacy rates by total duration of treatment

Clinical Efficacy Rates by Total Duration of Treatment


Central nervous system involvement in patients with ia

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


Post caspofungin therapy

Post-Caspofungin Therapy

Patient #Initial RXFinal treatment Outcome

0002 AmB, ABCD AmBisome + surgery died

0056AmBisome AmBisomefailure

0057ABLC, azolelipid AmB failure

0059Itra, ABLC, AmBisome + surgery failure

lipid AmB

0186ABLC ABLC failure

0187AmB, ABLC, ABLC died

0246Itra, AmB AmBisome died

0296AmB, Itra ABLC failed

0412azole, Itra AmB failed

0446lipid AmB, Itra Itraconazole + surgery improved

0507AmB 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

  • 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

  • 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

  • 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

  • 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

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

Clinical Pharmacology12 Studies274

Clinical Studies338

3 comparative Candida263

1 variable dose Candida 14

1 Aspergillus study 58

1 compassionate use 3

Total612


Drug exposure

Drug Exposure


Overall caspofungin safety in clinical studies

Overall Caspofungin Safety in Clinical Studies


Drug related adverse events

Drug-Related Adverse Events


Lft elevations clinical studies relative elevation 3x uln

LFT Elevations : Clinical Studies 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

  • Elevations in serum calcium / creatinine

    • 056hypercalcemia

  • Respiratory adverse events

    • 186pulmonary infiltrates

    • 220pulmonary infiltrates

  • Possible histamine reactions

    • 1338rash, pruritus, tachypnea

    • 0683fever, wheeze, rash


Summary

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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