CANCIDAS ? (caspofungin acetate) for intravenou

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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




                                                    2
    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.


                                                            3
               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
                                          4
        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.
                                                 5
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.
                                                     6
                 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
                                                            7
Comparative Efficacy of Caspofungin and Amphotericin B in
Granulocytic Rabbits with Invasive Pulmonary Aspergillosis

                              Control Caspofungin   Ampho B
                                        1 mg/kg     1 mg/kg
                              N = 12     N =12       N = 16
 Mean Survival                6.90.7  10.4 0.5     8.80.5
   (days)
 Infarct score                5.20.5    2.50.4    1.20.5
   (# infarcted lobes/lung)
 Lung weight                  49.54.3   35.23.3   17.42.6
   (gm)
 Lung Burden                  1.40.3    1.90.2    0.10.1
    (cfu/g)
 Drug concentration                      1.470.2
    ( g drug/gm lung
    tissue)

                                                               8
        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
                                        9
           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…)
                                            10
               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
                                       11
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

                                        12
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



                                                13
    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
                                  14
 Study 019: Study Procedures
                       Entry   IV Rx   EOT   FU
History/Physical        X        X      X     X
 examination
Laboratory safety       X       X       X    X

Noninvasive cultures    X       X       X    X

Radiographic studies    X       X       X    X

Adverse experience              X       X    X
 monitoring


                                                  15
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

                                    16
                     Exclusion Criteria
                  Study 019                                      Study 028/029
Disease limited to allergic                       Disease limited to allergic
bronchopulmonary aspergillosis,                   bronchopulmonary aspergillosis,
aspergilloma, or ocular disease                   aspergilloma, or ocular disease
Disease limited to sinusitis or external otitis   Disease limited to sinusitis or external otitis
unless histopathological evidence of tissue       unless histopathological evidence of tissue
invastion with Aspergillus                        invastion 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
   ULN
Patients who are not expected to
survive at least 5 days
Diagnosis of acute hepatitis or cirrhosis
Any condition or illness which might
confuse the results of the study or pose
additional risk to the patient
Patients who are taking rifampin, ritonavir,
cycsloporin A or tacrolimus
                                                                                                17
  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)
                                                       18
       Disease Definition
              DEFINITE
Pulmonary: histopathology OR tissue
cultures

Extrapulmonary: histopathology
(invasion of affected tissue)

                                 19
           Disease Definition
                    Probable Pulmonary
                      Culture            Cytology   Other
CXR                   2 from
(nodules with         sputum
 cavities)
           PLUS                        OR
                       1 from    AND      From
                        BAL               BAL
CT scan                1 from    OR       From
(halo, crescent      sputum or           sputum
sign, or               1 from            or BAL
pleural-based           BAL
wedge-shaped                           OR
infiltrates)                                         2 (+)
             PLUS                                   ELISA
                                                    or PCR
                                                            20
     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)
                                                    21
    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
                                   22
     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
                                           23
           Expert Panel Assessment
            Study 019                    Study 028/029
Composition 3 members (2 US)             1

              Non-investigators for 019 Investigator for 028

Information   Case summaries; case       20 data tables
reviewed      report forms; case         abstracted from
              radiographs and reports;   case report forms,
              culture, autopsy,          no access to source
              pathology reports          data /radiographs

Blinding      Blinded to outcome         Not blinded to
                                         outcome; blinded to
                                         site

                                                           24
       Expert Panel Assessment

             Study 019                    Study 028/029
Procedures   Independent application      Analysis of tabular
             of diagnostic/outcome        displays of patient
             criteria on a case by case   information, basis
             basis, meetings to           for disagreement w/
             resolve discrepant           site assessment
             evaluations, majority        cited
             assessment

Submitted    Results submitted at time Submitted on
             of filing                 12/22/00

Concordance 54/69                         200/214
of outcome  (78.3%)                       (93.5%)
with PI
                                                           25
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%
                                                      26
   Study 019 and 028/029:
       Data Analysis
Primary: proportion of success at EOT

Secondary: logistic regression analysis
  Adjusted for predictive/baseline risk
  variables


                                   27
 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

                                     28
Study 028: Patient Accounting
         1995-1998




                                29
      Baseline Characteristics
                                 Study 019          Study 028/029
                                   N = 63              N = 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 Infection
  Pulmonary, probable            18        (28.6)     75         (36.4)
    Definite Diagnosis           45        (71.4)    131*        (63.6)
      Pulmonary, definite        27        (42.9)     79         (38.3)
      Extrapulmonary+            18        (28.6)     52         (25.2)

+
 Includes single organ involvement outside of pulmonary
*>50% confirmed at autopsy
                                                                      30
     Baseline Characteristics (cont.)
                                        Study 019       Study 028/029
                                          N = 63            N = 206
                                        n      (%)        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                   14     (22.2)    57     (27.7)
  prednisone >20mg/day                  23     (36.5)    74     (35.9)
+ includes bone marrow transplant recipients
                                                                          31
   Baseline Characteristics (cont.)
              Response to prior treatment

                         Study 019       Study 028/029
                            N = 63          N = 206
                         n       (%)       n       (%)
Refractory only          36     (57.1)    188     (91.3)

Refractory and           17     (27.0)      N/A     --
   intolerant
Intolerant only          10     (15.9)       5    (2.4)

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

                                                    32
Baseline Characteristics: Prior Therapy
      in Study 019 and 028/029
   Prior treatment           Study 019      Study 028/029
                               N = 63           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


                                                             33
                             Duration of Prior/Standard Therapy
                        70        64.1
                                                   Study 019- Mean 49.8, Median 29
                        60
                                                   Study 028/029- Mean 29.2, Median 20
                        50   46
Percentage of Patient




                        40
                                         28.6
                        30
                                            21.4
                        20
                                                       9.5 7.3                       9.5
                        10                                           6.3                   4.4
                                                                           2.9
                         0
                              0-25        26-50         51-75
                                                   Days on Therapy
                                                                     76-100          > 100
                                                                                            34
                             Total Treatment Duration for Current
                                    Aspergillosis Infection
                        70        64.1
                                                  Study 019- Mean 86.1, Median 57
                        60
                                                  Study 028/029- Mean 29.2, Median 20
                        50
Percentage of Patient




                        40
                                         28.6                                       28.6
                        30
                                            21.4
                        20     15.8                     14.3           12.7
                        10                                     7.3
                                                                              2.9          4.4
                        0
                                0-25      26-50          51-75
                                                     Days on Therapy
                                                                       76-100        > 100

                                                                                                 35
  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)
                                                            36
Complete Responses and Relapse
                Study 019       Study 028/029
                  N = 63           N = 206
              n/N      (%)      n/N      (%)
Successful    26/63   (41.3)   35/206   (16.99)
outcome
Complete      4/26    (15.4)   14/35    (40.0)
responses
Relapses      2/20    (10.0)
 Documented     1
 Suspected      1



                                                  37
            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


                                                                           38
Clinical Efficacy Rates by Baseline Risk

                              Study 019      Study 028/029
Population                   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)


                                                             39
Clinical Efficacy Rates by Geographic Region


            Study 019      Study 028/029
           n/N     (%)      n/N     (%)
US        10/29   (34.5)   32/183   (17.5)
Europe    16/34   (47.1)    3/23    (13.0)




                                             40
Clinical Efficacy Rates by Total Duration of
Treatment

   Days        Study 019      Study 028/029
                 N = 63          N = 206
              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)

  Overall    26/63   (41.3)   35/206   (17.0)
  efficacy
                                                41
   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




                                                 42
            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


                                                                     43
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


                                            44
          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
                                            45
 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)                                46
            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
                                               47
   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                        48
               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
                                          49
           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
                                        50
           Drug Exposure
                    Dose
Duration    35 mg   50 mg   70 mg   Total
 (days)
  1–7        13       72     15     100
 8 – 14      21      116     54     191
 15– 28      0        21     1       22
  > 28       0        24     1       25

 Total       34      233     71     338


                                            51
Overall Caspofungin Safety in Clinical Studies
                       Healthy         Mucosal      Invasive
                       subjects       candidiasis aspergillosis
                       N = 274          N = 263      N = 69
                       n     (%)       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)


                                                             52
   Drug-Related Adverse Events
                    Cancidas™ Amphotericin B Fluconazole
                      N = 263       N = 89         N = 93
                     n       (%)  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)
                                                                53
    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%)
                                                     54
            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




                                             55
             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
                                          56
57

				
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