cancidas (caspofungin acetate) for intravenous injection nda 21-227 merck & co., inc
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CANCIDAS (caspofungin acetate)
for intravenous injection
NDA 21-227
Merck & Co., Inc.
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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
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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
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
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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
11
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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
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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 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
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