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

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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

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.

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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

Control

N = 12

Caspofungin1 mg/kgN =12

Ampho B1 mg/kgN = 16

Mean Survival(days)

6.90.7 10.4 0.5 8.80.5

Infarct score(# infarcted lobes/lung)

5.20.5 2.50.4 1.20.5

Lung weight(gm)

49.54.3 35.23.3 17.42.6

Lung Burden(cfu/g)

1.40.3 1.90.2 0.10.1

Drug concentration( g drug/gm lungtissue)

1.470.2

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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

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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

12

Clinical Studies:Invasive 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 Studies:Mucosal Candidiasis

Comparative studies

Study 003, 004 Caspofungin N = 268

Amphotericin N = 89

Study 020 Caspofungin N = 177

Fluconazole N = 93

Non-comparative

Study 007 Caspofungin N = 14

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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

Entry IV Rx EOT FUHistory/Physical

examinationX X X X

Laboratory safety X X X X

Noninvasive cultures X X X X

Radiographic studies X X X X

Adverse experiencemonitoring

X X X

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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 CriteriaStudy 019 Study 028/029

Disease limited to allergicbronchopulmonary aspergillosis,aspergilloma, or ocular disease

Disease limited to allergicbronchopulmonary aspergillosis,aspergilloma, or ocular disease

Disease limited to sinusitis or external otitisunless histopathological evidence of tissueinvastion with Aspergillus

Disease limited to sinusitis or external otitisunless histopathological evidence of tissueinvastion with Aspergillus

Abnormal Lab values Hemoglogin <8 gm/dl Platelet count < 25,000/ L INR > 1.6 Bilirubin >3 times the ULN AST or ALT >5 times the ULN Alkaline phosphatase >3 times the

ULNPatients who are not expected tosurvive at least 5 daysDiagnosis of acute hepatitis or cirrhosisAny condition or illness which mightconfuse the results of the study or poseadditional risk to the patientPatients who are taking rifampin, ritonavir,cycsloporin A or tacrolimus

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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)

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Disease Definition

DEFINITE

Pulmonary: histopathology OR tissue cultures

Extrapulmonary: histopathology (invasion of affected tissue)

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Disease Definition Probable Pulmonary

Culture Cytology Other

2 fromsputum

OR

CXR(nodules with cavities) PLUS

1 fromBAL

AND FromBAL

1 fromsputum or

1 fromBAL

OR Fromsputumor BAL

OR

CT scan(halo, crescentsign, orpleural-basedwedge-shapedinfiltrates) PLUS

2 (+)ELISAor PCR

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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 >2.5 mg/dL

– other infusion toxicities•Study 028: intolerance (creatinine >2.5 mg/dL)

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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

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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

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Expert Panel Assessment

Study 019 Study 028/029Composition 3 members (2 US)

Non-investigators for 019

1

Investigator for 028

Informationreviewed

Case summaries; casereport forms; caseradiographs and reports;culture, autopsy,pathology reports

20 data tablesabstracted fromcase report forms,no access to sourcedata /radiographs

Blinding Blinded to outcome Not blinded tooutcome; blinded tosite

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Expert Panel Assessment

Study 019 Study 028/029Procedures Independent application

of diagnostic/outcomecriteria on a case by casebasis, meetings toresolve discrepantevaluations, majorityassessment

Analysis of tabulardisplays of patientinformation, basisfor disagreement w/site assessmentcited

Submitted Results submitted at timeof filing

Submitted on12/22/00

Concordanceof outcomewith PI

54/69(78.3%)

200/214(93.5%)

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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%

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Study 019 and 028/029:Data 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

Study 019N = 63

Study 028/029N = 206

n (%) n (%)

Mean Age (yrs) 47 48

Sex = Male 42 (66.7) 108 (52.4)Study Site = US 29 (46.0) 183 (88.8)

Extent of InfectionPulmonary, probable 18 (28.6) 75 (36.4)

Definite Diagnosis Pulmonary, definite

4527

(71.4)(42.9)

131*

79(63.6)(38.3)

Extrapulmonary+ 18 (28.6) 52 (25.2)

+Includes single organ involvement outside of pulmonary*>50% confirmed at autopsy

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Baseline Characteristics (cont.)Study 019

N = 63Study 028/029

N = 206n (%) n (%)

Underlying disease:Hematologic malignancy+ 41 (65.1) 144 (69.9)

bone marrow transplant 20 (--) 85 (---)

Organ transplant 8 (12.7) 32 (15.5)

Solid tumor 3 (4.8) 10 (4.9)

Other risk factors 8 (12.7) 20 (9.7)

None 3 (4.8) 0 (0)

ANC < 500 cells/mm3

prednisone >20mg/day1423

(22.2)(36.5)

5774

(27.7)(35.9)

+ includes bone marrow transplant recipients

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Baseline Characteristics (cont.)Response to prior treatment

Study 019N = 63

Study 028/029N = 206

n (%) n (%)Refractory only 36 (57.1) 188 (91.3)

Refractory andintolerant

17 (27.0) N/A --

Intolerant only 10 (15.9) 5 (2.4)

Creatinine > 2.5 mg/dL 10 (15.9) 42 (20.4)

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

Prior treatment Study 019N = 63

Study 028/029 N = 206

n (%) n (%)Itraconazole 39 (61.9) 94 (45.6)

Amphotericin B 37 (58.7) 123 (59.7)

Abelcet 24 (38.1) 107 (51.9)

AmBisome 21 (33.3) 11 (5.3)

Investigational azole 3 (4.8) *

Amphotec 2 (3.2) 13 (6.3)

* 4 patients

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Duration of Prior/Standard Therapy

46

28.6

9.56.3

9.5

64.1

21.4

7.32.9 4.4

0

10

20

30

40

50

60

70

0-25 26-50 51-75 76-100 > 100Days on Therapy

Per

cent

age

of P

atie

nt

Study 019- Mean 49.8, Median 29

Study 028/029- Mean 29.2, Median 20

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Total Treatment Duration for Current Aspergillosis Infection

15.8

28.6

14.3 12.7

28.6

21.4

7.32.9 4.4

64.1

0

10

20

30

40

50

60

70

0-25 26-50 51-75 76-100 > 100Days on Therapy

Per

cent

age

of

Pat

ien

t

Study 019- Mean 86.1, Median 57

Study 028/029- Mean 29.2, Median 20

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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 Study 019

N = 63Study 028/029

N = 206

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

Successfuloutcome

26/63 (41.3) 35/206 (16.99)

Completeresponses

4/26 (15.4) 14/35 (40.0)

Relapses 2/20 (10.0)DocumentedSuspected

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Complete Response to Caspofungin

Identifier 219 330 366 065Extent of IA pulmonary pulmonary skull+ pulmonary*Underlying disease allo BMT lymphoma diabetes leukemiaPrior treatment AmB/ ABLC Itraconazole AmB ABLC, Itra

lobectomy resectionCaspofungin Rx (days) 8 28 27 90Death yes no no noRelapse 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

Study 019 Study 028/029Population n/N (%) n/N (%)Acute leukemia 8/17 (47.1) 9/69 (13.0)

Chronic leukemia 1/9 (11.1) 5/33 (15.2)

Lymphoma 4/8 (50.0) 1/22 (4.5)

Baseline prednisone >20 mg 8/23 (34.8) 8/74 (10.8)

Baseline neutropenia 2/14 (14.3) 4/57 (7.0)

Persistent neutropenia 0/8 (0) 0/38 (0)

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Clinical Efficacy Rates by Geographic Region

Study 019 Study 028/029n/N (%) n/N (%)

US 10/29 (34.5) 32/183 (17.5)

Europe 16/34 (47.1) 3/23 (13.0)

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Clinical Efficacy Rates by Total Duration of Treatment

Study 019N = 63

Study 028/029N = 206

Days

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

0-25 1/10 (10.0) 9/132 (6.8)26-50 5/18 (27.8) 10/44 (22.7)51-75 4/9 (44.4) 7/15 (46.7)

76-100 4/8 (50.0) 3/6 (50.0)

> 100 12/18 (66.7) 6/9 (66.7)

Overallefficacy

26/63 (41.3) 35/206 (17.0)

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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

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

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Drug ExposureDose

Duration(days)

35 mg 50 mg 70 mg Total

1 – 7 13 72 15 1008 – 14 21 116 54 19115– 28 0 21 1 22> 28 0 24 1 25

Total 34 233 71 338

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Overall Caspofungin Safety in Clinical Studies

HealthysubjectsN = 274

Mucosalcandidiasis

N = 263

Invasiveaspergillosis

N = 69n (%) n (%) n (%)

W/ an AE 127 (46.4) 235 (89.4) 64 (92.8)

W/ a DRAE 68 (24.8) 127 (48.3) 10 (14.5)

W/ a serious AE 7 (2.6) 49 (18.6) 54 (78.3)

W/ a serious DRAE 0 0 1 (1.4)

Deaths 0 15 (5.7) 38 (55.1)

D/C due to an AE 11 (4.0) 7 (2.7) 27 (39.1)

D/C due to a DRAE 5 (1.8) 3 (1.1) 1 (1.4)

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Drug-Related Adverse EventsCancidas™

N = 263Amphotericin B

N = 89Fluconazole

N = 93n (%) n (%) n (%)

Fever (DRAE) 44 (16.7) 62 (69.7) 1 (1.1)

IV site AEs 49 (18.6) 21 (23.6) 16 (17.2)

Respiratory 5 (1.9) 7 (7.8) 0 (0)

Skin 18 (6.8) 15 (16.9) 1 (1.1)

Hypersensitivity 3 (1.1) 4 (4.5) 1 (1.1)

Candidiasis 27 (10.2) 3 (3.4) 5 (5.4)

n/N n/N n/N

Hypokalemia 14/261 (5.4) 28/89 (31.5) 0/92 (0)

Elevated creatinine 1/261 (0.4) 25/89 (28) 2/92 (2.2)

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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 > ULNCaspofungin 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

57