Zyvox _linezolid_ tablets_ injection_ suspension.ppt by handongqp

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									    Zyvox™ (linezolid)
Tablets, injection, suspension
      NDAs 21-130, 21-131, 21-132
            FDA presentation
Anti-Infective Drugs Advisory Committee
             March 24, 2000
                                          1
                  Overview
•   Clinical pharmacology
•   Clinical/statistical analyses of efficacy
•   Clinical/statistical analyses of safety
•   Development of resistance




                                                2
 Clinical pharmacology:
    Pharmacokinetics
               IV    PO
Tmax (h)       0.5   1.0
Cmax (g/mL)   15    21
Cmin (g/mL)   3.7   6.2
T1/2 (h)       4.8   5.4

                           3
    Clinical pharmacology:
       Pharmacokinetics
• With 600 mg bid dosing:
  – AUC (PO) = 68 - 209 µg·h/mL
  – After normalization for body weight,
     AUC = 11.2 - 23.8 µg·h/mL




                                           4
      Clinical pharmacology:
     Metabolism and excretion
• Metabolism
  – two major metabolites; toxicity not characterized
• Excretion
     • 35% in urine as parent drug
     • 50% in urine as metabolites
     • 10% in feces as metabolites
     • Metabolites accumulate in patients with renal
       impairment
                                                  5
Efficacy Analyses




                    6
            Clinical studies
• Community-acquired pneumonia
  – Study 33 (CAP in inpatients)
  – Study 51 (CAP in outpatients)
• Hospital-acquired pneumonia (Study 48A)
• Skin/skin structure infections
  – Studies 39A/39 (uncomplicated SSSI)
  – Study 55 (complicated SSSI)
• MRSS infections (Study 31)
• VRE infections (Studies 54A/54)           7
         Differences in outcome
               assessment
                                         Sponsor      FDA
Alive at TOC but no post-baseline          Failure   Missing*
assessment
Alive at EOT but died before TOC Missing*            Failure

D/C’d for lack of efficacy                Generally Failure
                                           failure

*failure under certain pre-specified circumstances
                                                          8
        Analytic populations

Randomized patients            ITT (all treated patients)



ITT (all treated patients)   CE (meet baseline and post-
                                     baseline criteria)



MITT (pathogen isolated)                 ME
                             (susceptible pathogen isolated
                                 within baseline window)  9   13
Community-acquired
   pneumonia



                     10
         Community-acquired
         pneumonia (Study 33)
• Population: 747 inpatients with CAP
• Design: Multi-center, multi-national,
  randomized, comparative, open-label
• Treatment arms (7-14 d treatment duration)
  – Linezolid 600 mg IV q12h /600 mg po q12h
  – Ceftriaxone 1 g IV q12h /Cefpodoxime 200 mg po bid
  Aztreonam allowed for Gram-negative infections
• 1º endpoint: Microbiologic outcome
                                                  11
       Study 33 (Inpatient CAP)
            Demographics
                           Linezolid         Ceftriaxone
                           N          %       N            %
Age (years)
          <18               8          2.1    5             1.4
         18-44             120        31.5   112           30.6
         45-64             110        28.9   113           30.9
          >65              143        37.5   136           37.2
       Mean  SD              54.6  20.1          54.7  19.2
Gender
          Male             228        59.8   209           57.1
         Female            153        40.2   157           42.9
Race
         White             246        64.6   241           65.8
         Black              46        12.1    44           12.0
  Asian/Pacific Islander    34        8.9     37           10.1
         Mixed              55        14.4    44           12.0
                                                                  12
      Study 33 (inpatient CAP)
         Patient populations
        Total Linezolid Ceftriaxone
ITT      747     381        366
MITT     254     128        126
CE       559     285        274
ME       191     92         99

                                      13
                         Study 33 (inpatient CAP)
                          Clinical efficacy results
                       100
                        90              84        86        87
                              81                       82        82
                        80         77        77
    Success rate (%)




                        70
                        60
                                                                      Linezolid
                        50
                                                                      Ceftriaxone
                        40
                        30
                        20
                        10
                         0
                               ITT      MITT       CE        ME
                         N=   330 313   109 117   285 274   92 99
                                                                                14
Excludes patients with missing outcomes
           Study 33 (inpatient CAP)
           95% confidence intervals
ITT


MITT


CE                                  `


ME


 -20     -15    -10     -5      0       5     10      15     20
Difference in response rate between linezolid and ceftriaxone/cefpodoxime
                             FDA                   Sponsor
    Study 33 (inpatient CAP)
Results by pathogen (ME patients)
                        Linezolid          Ceftriaxone
                            N    % cured   N    % cured
 S. pneumoniae              73    86.3     73    84.9
 S. pneumoniae bacteremia   30    90.0     24    62.5
 PRSP (PCN MIC  2)         5     60.0     2     100.0
 S. aureus                  21    85.7     19    68.4
 S. aureus bacteremia       1     100.0    2     50.0
 MRSA                       1     100.0    0      -
 H. influenzae              8     62.5     12    83.3
     no aztreonam           7     57.1     10    90.0
                                                         16
    Study 33 (inpatient CAP)
 Subgroup analyses (CE patients)
                         Linezolid   Ceftriaxone
                    N      % cured   N     % cured
Bacteremia          31       90.3    26      61.5
Age > 50 y          171      85.4    160     80.0
> 1 lobe involved   15       93.3    7       71.4
> 1 lung involved   10       90.0     7      71.4
RR > 30             29       79.3    31      74.2
Hypotensive         22       77.3    35      71.4
[BUN] > 7 mM        75       80.0    63      69.8
HIV+                 7       100.0   6       83.3
                                                    17
                         Study 33 (inpatient CAP)
                           Effect of missing data
                   100
                    90    81                     84
                               77                     77
                    80               70                     71 71
Success rate (%)




                    70                    66
                    60
                                                                      Linezolid
                    50
                                                                      Ceftriaxone
                    40
                    30
                    20
                    10
                     0
                           ITT       ITT*       MITT        MITT*
                     N=   330 313    381 366    109 117     128 126

                     *Missing outcomes scored as failures                      18
       Community-acquired
       pneumonia (Study 51)
• Study population: 540 outpatients with CAP
• Design: Multi-center, multi-national,
  randomized, comparative, evaluator-blind
• Treatment arms ( 10-14 d treatment duration)
  – Linezolid 600 mg po q12h
  – Cefpodoxime 200 mg po q12h
• 1º endpoint: Clinical outcome

                                           19
    Study 51 (Outpatient CAP)
          Demographics
                           Linezolid          Cefpodoxime
                           N           %       N              %
Age (years)
          <18               0            --     1             0.4
         18-44             126         46.3    120            44.8
         45-64              93         34.2    86             32.1
          >65               53         19.5    61             22.8
       Mean  SD               47.6  17.4           48.8  18.4
Gender
          Male             132        48.5     140           52.2
         Female            140        51.5     128           47.8
Race
         White             196        72.1     207           77.2
         Black              30        11.0     28            10.4
  Asian/Pacific Islander    1          0.4      2            0.7
         Mixed              42        15.4     29            10.8
                                                                     20
   Not Allowed to Ask       3          1.1      2            0.7
 Study 51 (outpatient CAP)
    Patient populations
       Total Linezolid Cefpodoxime
ITT    540     272        268
MITT   120      60         60
CE     421     213        208
ME      98      50         48

                                     21
                        Study 51 (outpatient CAP)
                         Clinical efficacy results
                       100                            90
                                  87   85        85        88
                        90   83             81                  81
                        80
    Success rate (%)




                        70
                        60
                                                                     Linezolid
                        50
                                                                     Cefpodoxime
                        40
                        30
                        20
                        10
                         0
                              ITT      MITT       CE       ME
                         N = 227 222   54 52     213 208   50 48

Excludes patients with missing outcomes                                       22
         Study 51 (outpatient CAP)
          95% confidence intervals
ITT


MITT


CE                                 `


ME


 -20   -15    -10    -5     0     5     10     15     20      25
 Difference in response rate between linezolid and cefpodoxime
                          FDA                       Sponsor
   Study 51 (outpatient CAP)
Results by pathogen (ME patients)
                        Linezolid Cefpodoxime
                          N % cured   N    % cured
 S. pneumoniae            27 92.6     22    90.5
 S. pneumoniae bacteremia 3  100.0    6     50.0
 PRSP (PCN MIC  2)     0     -       0      -
 S. aureus              12   91.7     12    75.0
 S. aureus bacteremia   0     -       0      -
 MRSA                   1    100.0    1     0.0
 H. influenzae          13   84.6     16    87.5

                                                 24
  Study 51 (outpatient CAP)
Subgroup analyses (CE patients)
                         Linezolid   Cefpodoxime
                    N      % cured   N    % cured
Bacteremia          3        100.0   5      60.0
Age > 50 y          91       85.7    98     93.9
> 1 lobe involved   46       80.4    39     87.2
> 1 lung involved   30       83.3    27     88.9
RR > 30             9        88.9    7      85.7
Hypotensive         8        75.0    12     83.3
[BUN] > 7 mM        26       76.9    23     95.7
HIV+                4        75.0    2     100.0   25
                    Study 51 (outpatient CAP)
                      Effect of missing data
                   100
                               87               85
                    90    83                         81
                                                            77
                    80
                                     69 72                       70
Success rate (%)




                    70
                    60
                                                                      Linezolid
                    50
                                                                      Cefpodoxime
                    40
                    30
                    20
                    10
                     0
                           ITT       ITT*       MITT        MITT*
                     N=   227 222    272 268    54 52       60 60

                     *Missing outcomes scored as failures                      26
Hospital-acquired pneumonia




                              27
   Hospital-acquired pneumonia
            (Study 48A)
• Study population: 396 patients with HAP
• Design: Multi-center, multi-national,
  randomized, comparative, double-blind
• Treatment arms (7-21 d treatment duration)
  – Linezolid 600 mg IV q12h ± Aztreonam 1-2 g IV q8h
  – Vancomycin 1 g IV q12h ± Aztreonam 1-2 g IV q8h
• 1° endpoints: Clinical/microbiologic outcomes

                                                 28
               Study 48A (HAP)
                 Demographics
                           Linezolid           Vancomycin
                           N            %       N            %
Age (years)
         18-44              34          16.7   43            22.3
         45-64              53          26.1   48            24.9
          >65              116          57.1   102           52.8
       Mean  SD               62.8  18.0           61.3  18.7
APACHE II                       15.7  6.5           15.5 6.9
Gender
          Male             142         70.0    131           67.9
         Female             61         30.0    62            32.1
Race
         White             181         89.2    170           88.1
         Black              11          5.4    10            5.2
  Asian/Pacific Islander    1           0.5     1            0.5
         Mixed              7           3.4    10            5.2    29
       Not Asked            3           1.5     2            1.0
        Study 48A (HAP)
       Patient populations
       Total Linezolid Vancomycin
ITT     396    203        193
MITT    177     94        83
CE      225    122        103
ME      95      54        41
ME2     42      22        20
                                    30
                                Study 48A (HAP)
                             Clinical efficacy results
                       100
                        90
                        80                                           72
    Success rate (%)




                                                           67             65
                        70                                      63
                                       57        57 60
                        60
                             49             46                                 Linezolid
                        50        45
                                                                               Vancomycin
                        40
                        30
                        20
                        10
                         0
                              ITT      MITT       CE       ME        ME2
                         N = 174 164   82 72     122 103   54 41     22 20

Excludes patients with missing outcomes                                                31
                Study 48A (HAP)
             95% confidence intervals
ITT


MITT

                                    `
CE

ME

 -20   -15    -10   -5    0     5       10   15   20   25    30
  Difference in response rate between linezolid and vancomycin
                              FDA                  Sponsor
         Study 48A (HAP)
Results by pathogen (ME patients)
                  Linezolid     Vancomycin
                 N    % cured   N    % cured

 S. pneumoniae   9     100.0    10    90.0

 PRSP            2     100.0    0       -

 S. aureus       38    60.5     23    60.9

 MRSA            22    59.1     10    70.0
                                             33
      Study 48A (HAP)
Subgroup analyses (ME patients)
                        Linezolid      Vancomycin
                        N    % cured    N   % cured
Bacteremia              4     50.0      6    66.7
Ventilator-associated   33    60.6     22    40.9
pneumonia
VAP with MRSA           16    62.5      5    60.0
APACHE II
   11                  18    72.2     12    83.3
  12-15                 12    66.7     16    75.0
  16-19                 10    60.0     5     40.0
                                                    34
  20                   13    61.5     8     25.0
       Study 48A (HAP)
Subgroup analyses (MITT patients)
                         Linezolid      Vancomycin
                         N    % cured   N    % cured
 Bacteremia              10    50.0     10    40.0
 Ventilator-associated   56    53.6     46    30.4
 pneumonia
 VAP with MRSA           21    52.4     17    29.4
 APACHE II
    11                  21    71.4     19    73.7
   12-15                 19    57.9     23    56.5
   16-19                 15    53.3     12    25.0
                                                     35
   20                   26    46.2     18    16.7
                            Study 48A (HAP)
                          Effect of missing data
                   100
                    90
                    80
Success rate (%)




                    70
                                                57
                    60                                      50
                          49                         46               Linezolid
                    50         45    42
                                          38                     40   Vancomycin
                    40
                    30
                    20
                    10
                     0
                           ITT       ITT*       MITT        MITT*
                     N=   174 164    203 193     82 72      94 83

                     *Missing outcomes scored as failures                     36
                             Study 48A (HAP)
                              Mortality rates
                     100
                      90
                      80
Mortality rate (%)




                      70
                      60
                                                                     Linezolid
                      50
                                                                     Vancomycin
                      40
                      30            25
                             18
                      20
                                                         9
                      10                         5
                       0
                             All causes   Due to initial infection
                       N=   203     193        203      193
                                                                             37
Uncomplicated skin and skin
structure infections (uSSSI)



                               38
       Study 39A/39 (uSSSI)
           Description
• Population: 753 North American (39A),
     332 Non-North American patients (39)
• Design: Multi-center, randomized,
  comparative, double-blind
• Treatment arms (7-14 d treatment duration)
  – Linezolid 400 mg po q12h
  – Clarithromycin 250 mg po q12h
• 1º endpoints: Clinical/microbiologic
  outcomes                                 39
                Study 39A (uSSSI)
                  Demographics
                           Linezolid Clarithromycin
                            N        %      N               %
Age (years)
         18-44             212       55.5   200             53.9
         45-64             109       28.5   121             32.6
          >65               61       16.0   50              13.5
       Mean  SD             44.1  17.1          43.9  17.0
Gender
          Male             219      57.3    197            53.1
         Female            163      42.7    174            46.9
Race
         White             318      84.1    322            87.0
         Black              43      11.4    31             8.4
  Asian/Pacific Islander    2        0.5     3             0.8
         Mixed              12       3.2    12             3.2
   Not Allowed to Ask       3        0.8     2             0.5     40
       Study 39A (uSSSI)
       Patient populations
      Total Linezolid Clarithromycin
ITT   753     382          371
CE    627     320          307
ME    210      97          113



                                       41
                                Study 39A (uSSSI)
                              Clinical efficacy results
                       100
                               86 84     88 85     87 86
                        90
                        80
    Success rate (%)




                        70
                        60
                                                            Linezolid
                        50
                                                            Clarithromycin
                        40
                        30
                        20
                        10
                         0
                                ITT       CE        ME
                         N=    341 322   320 307   97 113

Excludes patients with missing outcomes                                 42
                 Study 39A (uSSSI)
               95% confidence intervals
    ITT



        CE
                                     `


    ME


  -20        -15   -10   -5      0       5     10      15     20
Difference in response rate between linezolid and clarithromycin
                              FDA                   Sponsor
        Study 39A (uSSSI)
        Results by pathogen
              Linezolid      Clarithromycin
              N    % cured    N     % cured
S. aureus     93    86.0      105    84.8
MRSA          0      -         0      -
S. pyogenes   5     100.0     11     90.9



                                            44
                           Study 39A (uSSSI)
                          Effect of missing data
                   100
                    90       86         84
                                                  77
                    80                                      73
Success rate (%)




                    70
                    60
                                                                 Linezolid
                    50
                                                                 Clarithromycin
                    40
                    30
                    20
                    10
                     0
                                  ITT                  ITT*
                     N=     341         322      382      371

                     *Missing outcomes scored as failures                    45
                  Study 39 (uSSSI)
                   Demographics
                           Linezolid Clarithromycin
                            N        %      N               %
Age (years)
         18-44              99       59.6   103             62.0
         45-64              48       28.9   50              30.1
          >65               19       11.4   13               7.8
       Mean  SD             41.7  16.3          41.1  16.9
Gender
          Male              95       57.2   90             54.2
         Female             71       42.8   76             45.8
Race
         White              88       53.0   85             51.2
         Black              10        6.0   11             6.6
  Asian/Pacific Islander    45       27.1   46             27.7
         Mixed              22       13.3   23             13.9
   Not Allowed to Ask       1         0.6    1             0.6     46
        Study 39 (uSSSI)
       Patient populations
      Total Linezolid Clarithromycin
ITT   332     166          166
CE    254     127          127
ME    101      43           58



                                       47
                                 Study 39 (uSSSI)
                              Clinical efficacy results
                       100                         95 97
                               88 91     89 90
                        90
                        80
    Success rate (%)




                        70
                        60
                                                             Linezolid
                        50
                                                             Clarithromycin
                        40
                        30
                        20
                        10
                         0
                                ITT        CE       ME
                         N=    148 149   127 127   43   58

Excludes patients with missing outcomes                                  48
                  Study 39 (uSSSI)
               95% confidence intervals
    ITT



        CE
                                     `


    ME


  -20        -15   -10   -5      0       5     10      15     20
Difference in response rate between linezolid and clarithromycin
                              FDA                   Sponsor
         Study 39 (uSSSI)
        Results by pathogen
              Linezolid      Clarithromycin
              N    % cured     N   % cured
S. aureus     39    97.4      54     96.3
MRSA          1     100.0      4     100.0
S. pyogenes   7     85.7       7     100.0



                                             50
Complicated skin and skin
structure infections (cSSSI)



                               51
  Complicated skin/skin structure
      infections (Study 55)
• Population: 819 patients with cSSSI
• Study design: Multi-center, multi-national,
  randomized, comparative, double-blind
• Treatment arms (10-21 d treatment duration)
  – Linezolid 600 mg IV q12h / Linezolid 600 mg po bid
  – Oxacillin 2 g IV q6h / Dicloxacillin 500 mg po q6h
• 1° endpoints: Clinical/microbiological outcomes

                                                   52
                  Study 55 (cSSSI)
                   Demographics
                           Linezolid          Oxacillin
                           N           %      N             %
Age (years)
         18-44             194         48.5   180           43.0
         45-64             139         34.8   133           31.7
          >65               67         16.8   106           25.3
       Mean  SD               46.8  17.1          49.2  18.5
Gender
          Male             252        63.0    255           60.9
         Female            148        37.0    164           39.1
Race
         White             227        56.8    230           54.9
         Black              49        12.3    69            16.5
  Asian/Pacific Islander    38         9.5    42            10.0
         Mixed              84        21.0    76            18.1
   Not Allowed to Ask       2          0.5     2            0.5
                                                                   53
       Study 55 (cSSSI)
      Patient populations
            Total Linezolid Oxacillin
ITT         819      400       419
ITT-prime   629      316       313
CE          487      245       242
ME          209      101       108

                                        54
                                 Study 55 (cSSSI)
                              Clinical efficacy results
                       100                            90
                        90     85         86               85    85 82
                                    79         82
                        80
    Success rate (%)




                        70
                        60
                                                                          Linezolid
                        50
                                                                          Oxacillin
                        40
                        30
                        20
                        10
                         0
                               ITT       ITT-prime     CE         ME
                         N=   327 348    269 267     245 242    101 108

Excludes patients with missing outcomes                                          55
                  Study 55 (cSSSI)
               95% confidence intervals
    ITT


    ITT-prime


        CE                            `


    ME


  -20        -15   -10    -5      0       5      10      15     20
Difference in response rate between linezolid and oxacillin/dicloxacillin
                               FDA                    Sponsor
          Study 55 (cSSSI)
         Results by pathogen
                    Linezolid    Oxacillin
                N      % cured   N    % cured
S. aureus       83      88.0     84    85.7
MRSA            3        66.7    0      -
S. pyogenes     26       69.2    28    75.0
S. agalactiae   6        100.0   6     50.0
E. faecalis     2         0.0    5     80.0
E. faecium      2        50.0    0      -     57
           Study 55 (cSSSI)
          Subgroup analyses
                    Linezolid      Oxacillin
                    N    % cured   N    % cured
Age 65             38    86.8     62    82.3
Diabetes mellitus   61    78.7     65    67.7
Peripheral          10    60.0     18    44.4
vascular disease


                                            58
                            Study 55 (cSSSI)
                          Effect of missing data
                   100
                    90    85                      86
                               79                      82
                    80                70                    73 70
Success rate (%)




                    70                     65
                    60
                                                                       Linezolid
                    50
                                                                       Oxacillin
                    40
                    30
                    20
                    10
                     0
                           ITT        ITT*      ITT-prime ITT-prime*
                     N=   327 348    400 419     269 267    316 313

                     *Missing outcomes scored as failures                     59
     Methicillin-resistant
staphylococcal species (MRSS)
          infections


                            60
             MRSS infections
               (Study 31)
• Population: 460 patients with MRSS infection
  (Pneumonia, SSSI, UTI, BUO)
• Design: Multi-center, multi-national,
  randomized, comparative, open-label
• Treatment arms (7-28 treatment duration)
  –   Linezolid 600 mg IV q12h
  –   Vancomycin 1 g IV q12h
  –   Concomitant aztreonam/gentamicin allowed
  –   1° endpoints: Clinical/microbiologic outcomes   61
                  Study 31 (MRSS)
                    Demographics
                           Linezolid          Vancomycin
                           N           %       N            %
Age (years)
         15-44              32         13.3    59           26.8
         45-64              78         32.5    52           23.6
          >65              130         54.2   109           49.5
       Mean  SD               63.9  16.1          59.8  20.2
Gender
          Male             143        59.6    131           59.5
         Female             97        40.4     89           40.5
Race
         White             195        81.3    168           76.4
         Black              18        7.5      30           13.6
  Asian/Pacific Islander    4         1.7      5            2.3
         Mixed              23        9.6      17           7.7
                                                                   62
        Study 31 (MRSS)
       Patient populations
       Total Linezolid Vancomycin
ITT    460     240        220
MITT   301     157        144
CE     241     116        125
ME     126      59        67

                                    63
                                Study 31 (MRSS)
                             Clinical efficacy results
                       100
                        90                       80
                        80                                 76
                                                      72        72
    Success rate (%)




                        70                  66
                              61 63    59
                        60
                                                                     Linezolid
                        50
                                                                     Vancomycin
                        40
                        30
                        20
                        10
                         0
                              ITT      MITT       CE        ME
                         N = 181 160   128 112   116 125   59 67

Excludes patients with missing outcomes                                      64
                 Study 31 (MRSS)
              95% confidence intervals
ITT


MITT


CE                                    `


ME


  -25   -20    -15   -10   -5     0       5   10   15   20     25
Difference in response rate between linezolid and vancomycin
                                FDA                 Sponsor
         Study 31 (MRSS)
Results by pathogen (ME patients)
                 Linezolid    Vancomycin
             N      % cured   N    % cured

 S. aureus   52       76.9    57    71.9

 MSSA        1         0.0     0      -

 MRSA        51       78.4    57    71.9

 MRSE        7        71.4     9    77.8
                                           66
          Study 31 (MRSS)
Results by pathogen (MITT patients)
                   Linezolid    Vancomycin
              N       % cured   N    % cured

  S. aureus   112       58.0    94    64.9

  MSSA         4        75.0     3    66.7

  MRSA        104       55.8    88    65.9

  MRSE        14        57.1    13    76.9
                                             67
          Study 31 (MRSS)
Outcome by site of MRSA infection (ME)
                       Linezolid      Vancomycin
                  N        % cured     N        % cured
  All sources     51        78.4       57        71.9
  Pneumonia       10        90.0       17        70.6
     Bacteremic        3      100.0         3      66.7
  SSSI            33        78.8       33        72.7
     Bacteremic        4      50.0          2     100.0
  UTI             0           -        2         100.0
  BUO             2         100.0      1         100.0
  Other           6         50.0       4         50.0
     Bacteremic        3      33.3          4         68
                                                   50.0
            Study 31 (MRSS)
Outcome by site of MRSA infection (MITT)
                        Linezolid     Vancomycin
                   N        % cured    N       % cured
   All sources     104       55.8     88        65.9
   Pneumonia       28        42.9     28        53.6
      Bacteremic        8      50.0        5      40.0
   SSSI            52        69.2     44        77.3
      Bacteremic        7      42.9        3     100.0
   UTI              6        33.3      4        100.0
      Bacteremic        1     0.0          0      -
   BUO              5        40.0      4         40.0
   Other           13        46.2      7        42.9
                                                   69
      Bacteremic        6      50.0        6      50.0
                           Study 31 (MRSS)
                         Effect of missing data
                   100
                    90
                    80
Success rate (%)




                    70                               66
                         61 63                  59
                    60
                                     46 46                   48 51    Linezolid
                    50
                                                                      Vancomycin
                    40
                    30
                    20
                    10
                     0
                          ITT        ITT*       MITT        MITT*
                     N = 181 160    240 220     128 112     157 144

                     *Missing outcomes scored as failures                     70
    Vancomycin-resistant
enterococcal (VRE) infections



                                71
     VRE infections (Study 54A)
• Population: 145 adult patients with known or
  suspected VRE infection (SST, UTI, BUO, IABD)
• Design: Multi-center, randomized, dose-
  comparison, double-blind, superiority
• Treatment arms
  – Linezolid 600 mg IV q12h
  – Linezolid 200 mg IV q12h
  Concomitant aztreonam or aminoglycosides allowed
• 1º endpoint: Clinical outcome                  72
                  Study 54A (VRE)
                    Demographics
                           High Dose           Low Dose
                           N            %      N            %
Age (years)
         18-44             12           15.2   10           15.2
         45-64             21           26.6   20           30.3
          >65              46           58.2   36           54.5
       Mean  SD                63.8  16.6         63.6  18.2
Gender
          Male             36          45.6    30           45.5
         Female            43          54.4    36           54.4
Race
         White             60          75.9    49           74.2
         Black             18          22.8    15           22.7
  Asian/Pacific Islander   0            --     1            1.5
         Mixed             1           1.3     1            1.5
                                                                   73
       Study 54A (VRE)
      Patient populations
             Total High-dose Low-dose
                   (600 mg) (200 mg)
ITT           145     79        66
MITT-VRE     117     65        52
Bacteremic    34     18        16
MITT-VRE

                                        74
                              Study 54A (VRE)
                               Efficacy results
                       100
                        90
                        80
    Success rate (%)




                              67
                        70
                                               59
                        60         52
                                                                 High-dose
                        50
                                                                 Low-dose
                        40
                                                     29
                        30
                        20
                        10    p=0.16            p=0.15
                         0
                              MITT-VRE   MITT-VRE (bacteremic)
                         N=   58    46        17     14
Excludes patients with missing outcomes                                 75
          Study 54A (VRE)
         Results by pathogen
                   High-dose      Low-dose
                   (600 mg)       (200 mg)
                   N    % cured   N    % cured

VanR E. faecium    57    66.7     45    53.3

VanR E. faecalis   4     75.0     2      0.0



                                               76
      Study 54A (VRE)
Outcome by site of VRE infection
                         High-dose            Low-dose
                         (600 mg)             (200 mg)
                         N     % cured       N    % cured
 MITT-VRE (All sites)   58       67.2        46    52.2
 BUO                    10       50.0        7     28.6

 SSTI                   13       69.2        5     100.0

 UTI                    19       63.2        20    60.0
 Pneumonia               3       66.7        1      0.0
 Other*                 13       84.6        13    38.6

 *predominantly complicated IABD infection                  77
           Covariate analyses
• Covariate analyses were not prespecified
• Multivariate analysis performed by FDA
  using:
  –   Risk of mortality at baseline
  –   1º diagnosis
  –   Age, sex, weight
  –   Bacteremia
• Adjusted and unadjusted results consistent
                                         78
                            Study 54A (VRE)
                          Effect of missing data
                   100
                    90
                    80
Success rate (%)




                          67
                    70               60          59
                    60         52                           56
                                          46                            High-dose
                    50
                                                                        Low-dose
                    40                                29
                    30                                           25
                    20
                    10
                     0
                         MITT-VRE    MITT-        VRE        VRE
                                     VRE*      bacteremia bacteremia*
                     N=   58   46     65 52       17 14      18 16

                     *Missing outcomes scored as failures                      79
                                         Study 54A (VRE)
                                     All-cause mortality rates
                               100
All-cause mortality rate (%)




                                90
                                80
                                70
                                60
                                                                                High-dose
                                50
                                                                                Low-dose
                                40
                                30
                                20
                                10      16/65   18/52        4/18   9/16
                                 0
                                        MITT-VRE        MITT-VRE (bacteremic)
                                 N=     65    52             18     16
                                                                                       80
   Causes of death in patients
     with VRE bacteremia
• High dose                   • Low dose
  – VRE infection (1)           –   VRE infection (3)
  – Sepsis (2)                  –   Sepsis (1)
  – Respiratory failure (1)     –   Pneumonia (1)
                                –   GVHD (1)
                                –   AIDS (1)
                                –   Gastric cancer (1)
                                –   Liver rejection (1)


                                                          81
Covariate analysis of mortality
   in bacteremic patients
• Not prespecified
• Covariates included:
  – Risk of mortality at baseline
  – Age
  – Sex
• Adjusted and unadjusted results consistent


                                         82
     History: Studies 54A & 54
• Study 54 originally planned for 500 patients
• In 6/99, blinded decision to submit patients
  already enrolled as Study 54A (145 patients)
  – Submitted as stand-alone study
  – “all alpha spent” on this trial
• Study 54 continued as “supportive trial”
  – Data on 82 patients submitted to FDA in 12/99
  – Bolstering NS results of 54A with these results
    could correspond to multiple looks without
    appropriate (prespecified) statistical adjustment
                                                  83
                               Study 54 (VRE)
                               Efficacy results
                   100
                    90
                    80
Success rate (%)




                    70        64
                                                      60
                    60
                                   49                                           High-dose
                    50                                         42
                                                                                Low-dose
                    40
                    30
                    20
                    10
                     0
                              MITT-VRE              MITT-VRE*
                         N=   28   35                  30      41
                                                                                       84
                                         *Missing outcomes scored as failures
           Safety analysis
• Clinical adverse events
• Laboratory adverse events
• Potential drug-drug interactions




                                     85
Adverse events




                 86
                                  Adverse events
                 80
                                              68
                 70          60                 62
                      5755                                            56
Incidence (%)




                 60                                                     50
                                 43                    47     47
                 50                                      41     41           Linezolid
                 40                   3134                                   Comparator
                 30
                 20
                 10
                  0
                                   P)




                                                            )
                    P)


                            P)




                                              )


                                                            )




                                                                      ll
                                                          SI
                                            SS


                                                         SI




                                                                     A
                                  A
                   A


                           A




                                                       SS
                                                       SS
                                           R
                 (C


                         (C


                                 (H

                                        (M




                                                     (u
                                                  (c
                33


                      51


                             48




                                             55

                                                  9A
                                      31




                                                     /3
                                                   39




                                                                                     87
                Drug-related adverse events
                 35           32
                 30                                             25
Incidence (%)




                 25   21                                                22
                                                                  20
                 20                18           18       1717                     Linezolid
                                          16                                 16
                 15                     13                                        Comparator
                         11
                 10                                  8
                  5
                  0
                                     P)




                                                               )
                    P)


                              P)




                                                )


                                                               )




                                                                        ll
                                                             SI
                                              SS


                                                            SI




                                                                       A
                                    A
                   A


                             A




                                                          SS
                                                          SS
                                             R
                 (C


                           (C


                                   (H

                                          (M




                                                        (u
                                                    (c
                33


                      51


                               48




                                               55

                                                     9A
                                        31




                                                       /3
                                                     39




                                                                                          88
                Discontinuations due to AEs
                 12
                              10             10
                 10
Incidence (%)




                 8        7
                      6                  6                        6   6         6       Linezolid
                 6                                    5                             5
                                                  4                       4             Comparator
                 4                 3                          3
                 2
                 0
                                        P)




                                                                 )
                    P)


                             P)




                                                 )


                                                                 )




                                                                               ll
                                                               SI
                                               SS


                                                              SI




                                                                              A
                                       A
                   A


                            A




                                                            SS
                                                            SS
                                              R
                 (C


                          (C


                                  (H

                                             (M




                                                          (u
                                                      (c
                33


                      51


                              48




                                                  55

                                                       9A
                                        31




                                                         /3
                                                       39




                                                                                                89
            Discontinuations due to drug-
                     related AEs
                  4            3.7                          3.6 3.5
                3.5
Incidence (%)




                  3
                      2.4                                          2.4 2.4
                2.5                      2.1 2.1                         1.9   Linezolid
                  2                    1.5     1.4                             Comparator
                1.5                                         1
                  1              0.7
                0.5      0.3
                  0
                                      P)




                                                               )
                    P)


                            P)




                                               )


                                                               )




                                                                       ll
                                                             SI
                                             SS


                                                            SI




                                                                      A
                                     A
                   A


                           A




                                                          SS
                                                          SS
                                            R
                 (C


                         (C


                                 (H

                                           (M




                                                        (u
                                                   (c
                33


                      51


                               48




                                                55

                                                     9A
                                       31




                                                       /3
                                                     39




                                                                                       90
 Discontinuations by adverse event
                    10   9           9
                     9           8
                     8                   7
    Incidence (%)




                     7                           6       6       6
                     6                                                   5       5       Linezolid
                     5       4                       4       4
                     4                                               3       3           Comparator
                     3
                     2                       1
                     1                                                               0
                     0
                                  a
                                 ia




                               ng
                                  e
                                  a




                                ea




                                                                         ss
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                    N




                       ea
                       eu




                                                                 A
                      D
                      D




                     V
                     H
                    Pn




Percentages are relative to number of patients who discontinued
for any adverse event                                                                            91
  Discontinuations by drug-related
                AE
                    25   22
    Incidence (%)




                    20            16
                    15                     12       1211                                 13   Linezolid
                    10        8                 8                                             Comparator
                                                           6       6       6
                                       3                               3       3     4
                    5
                                                               0
                    0
                                         a
                                         a




                                        Ts

                                        ia
                                       ng
                                         e
                                         a




                                                                                     h
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                                      he
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                    N




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                              cy
                              D




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                              V




                             m
                             H




                           bo

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                          m

                        bn
                       ro

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                    Th




Percentages are relative to number of patients who discontinued
for any drug-related adverse event                                                                    92
Laboratory findings




                      93
   Comparator-controlled studies:
         Development of
       thrombocytopenia*
         Incidence of thrombocytopenia (%)




       12                           11
       10
        8
                                6                            Linezolid
        6                   5
                                                             Comparator
        4   3       3                        3
                        2                2       2   2
        2       1                                        1
        0
                   P)




                    )
                   P)


                   P)




                    )


                    )


                  SI
                 SS


                 SI
                A
                A


                A




               SS
               SS
               R
             (C


             (C


             (H


           (M




            (u
            (c
          33


          51


          48




         55


        9A
       31




     /3
   39



*Percentages are relative to number of patients with
normal platelet counts at baseline                                   94
   Comparator-controlled studies:
    Grade III thrombocytopenia*
         Incidence of thrombocytopenia (%)




        3
                                   2.5
      2.5
        2                    1.6
                                                           Linezolid
      1.5
                                                           Comparator
        1
            0.5            0.5       0.4
      0.5      0.3                         0.3
                     0 0                         0   0 0
        0
                   P)




                    )
                   P)


                   P)




                    )


                    )


                  SI
                 SS


                 SI
                A
                A


                A




               SS
               SS
               R
             (C


             (C


             (H


           (M




            (u
            (c
          33


          51


          48




         55


        9A
       31




     /3
   39



*Percentages are relative to number of patients with
platelet count >50K at baseline                                    95
                                            Effect of linezolid dose on
                                                 development of
                                               thrombocytopenia*
   Incidence of thrombocytopenia (%)




                                       14   13
                                       12        11
                                       10
                                        8                       6                          High-dose (>1 g/d)
                                        6              5                          5        Low-dose (<1 g/d)
                                        4                  3            3             3
                                                                            2
                                        2
                                        0
                                            Study       All     Study   All        All
                                             54A       phase      11  phase II    phase
                                                        III           studies     II/III
                                                      studies                    studies
*Percentages are relative to number of patients with
normal platelet counts at baseline                                                                         96
                   Resolution of thrombocytopenia in comparator-controlled phase III studies
                                        Linezolid                                                   Comparator
M12600031 200

                                                                                         200
         Patient count




                                                                               Patient count
                   100

                                                                                         100




                         0                50                   100                             0    50               100
                                      Platelet count x 10E-3
                                                                                                   Platelet count x 10E-3


        Sorting is by delta amount           (smallest sort value at bottom)

                         Direction:
                         Increase
                         No change
                         Decrease
                         Start
                         End
                                                                                                                            97
 Summary: thrombocytopenia
  in linezolid-treated patients
• Incidence was 1 - 13% (grade III: 0-
  2.5%), depending on patient population
• Higher doses associated with  incidence
• Thrombocytopenia appeared to resolve in
  patients with laboratory follow-up
• No related adverse events identified
• No apparent effect on other cell lines
                                         98
Drug-drug interactions




                         99
             MAO inhibition
   Drug        Type of       Ki (µM) Cmax
              inhibition MAO-A MAO-B (µM)
clorgyline   Irreversible 0.0013   0.71      -
               MAO-A
selegiline   Irreversible   2      0.004   0.0045
               MAO-B
linezolid    Reversible     56     0.71     53.4


                                             100
Linezolid-sympathomimetic amine
           interactions
             Maximum change in systolic blood pressure

        70
        60                                    Placebo
        50
                                              Phenylpropanolamine
mm Hg




        40
        30                                    Linezolid + placebo
        20
                                              Linezolid +
        10                                    phenylpropanolamine
         0
                Maximum change in SBP

                                                                    101
                                  Comparator
                                  Linezolid




                                                                                 102
Selected concomitant




                                                                          s
                                                                       or
                                                                    ss
                                                                re
                                                             op
                                                          as
     medications




                                                        V             es
                                                                   iv
                                                                 ss
                                                             itu            rs
                                                          nt              to
                                                        A             ila
                                                                  od
                                                               ch
                                                           on
                                                        Br
                                                                   Is
                                                              R                  es
                                                         SS                    in
                                                                         am
                                                                    ct
                                                            re
                                                          di
                                                        In
                                                               l   ics
                                                            yc
                                                        C
                                                                         ics
                                                                es
                                                              lg
                                                            na
                                                        A

                       25

                            20

                                 15

                                           10

                                                5

                                                    0
   Potential drug-drug interaction
                events
• Database examined for potential MAOI-
  associated drug-drug interaction events
• Only small numbers of events found
• No clear association between adverse events
  examined and use of concomitant medications
• Classic MAOI-associated events not seen
  – No hypertensive crises
  – No cases of serotonin syndrome

                                                103
Linezolid resistance




                       104
         Linezolid resistance
•   Has been induced in laboratory
•   Mechanism - G  U on 23S rRNA
•   Frequency < 1 in 109
•   May result in cross-resistance to
    lincosamides and chloramphenicol



                                        105
          Linezolid resistance
            in clinical trials
• Only seen with Enterococcus spp.
• Fifteen cases in NDA database as of 12/31/99
   – 9/15 in compassionate use study (Study 25)
   – 6/15 in dose-comparison studies (Studies 54A/54)
• Mean duration of therapy was 32 ± 9.9 d
• 14/15 cases were E. faecium; 1/15 was E. faecalis
• Increase in MIC to:
   – 8 µg/mL (6 isolates)
   – 16 µg/mL (8 isolates)
   – 32 µg/mL (1 isolate - E. faecalis)                 106
          Linezolid resistance
   in compassionate use trial (Study 25)

• 9/15 occurred during compassionate use
  – 8/9 E. faecium, 1/ 9 E. faecalis
• 6/9 patients considered failures
• 3/9 patients considered cured




                                           107
               Linezolid resistance
            in dose-comparison trials

• 6/15 occurred in studies 54A/54 (all E.
  faecium)
     • 4 in low-dose group; 3/4 considered failures
     • 2 in high-dose group; 1/2 considered failures




                                                       108
        Linezolid Review Team
• Biopharmaceutics                • Pharm/Tox
   – Jenny Zheng, Ph.D.               – Ken Seethaler, Ph.D.
   – Frank Pelsor, Ph.D. (TL)         – Robert Osterberg, Ph.D., R.Ph.
• Chemistry                             (TL)
   – Jim Timper, M.S.             • Project Management
   – David Katague, Ph.D. (TL)        – Beth Duvall-Miller, B.S.
• Clinical                        • Statistics
   – John Alexander, M.D.             – Erica Brittain, Ph.D.
   – David Ross, M.D., Ph.D.          – Joel Jiang, Ph.D.
   – Janice Soreth, M.D. (TL)         – Daphne Lin, Ph.D. (TL)
• Microbiology                    • Supervisory Review
   – Fred Marsik, Ph.D.               – Gary Chikami, M.D. (DAIDP)
   – Albert Sheldon, Ph.D. (TL)       – Sandra Kweder, M.D. (ODE IV)
                                                               109
                                      – Dianne Murphy, M.D. (ODE IV)

								
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