Zyvox

1
Zyvox (linezolid)Tablets, injection, suspension

• NDAs 21-130, 21-131, 21-132
• FDA presentation
• Anti-Infective Drugs Advisory Committee
• March 24, 2000

2
Overview

• Clinical pharmacology
• Clinical/statistical analyses of efficacy
• Clinical/statistical analyses of safety
• Development of resistance

3
Clinical pharmacologyPharmacokinetics
4
Clinical pharmacologyPharmacokinetics

• With 600 mg bid dosing
• AUC (PO) 68 - 209 µgh/mL
• After normalization for body weight, AUC 11.2
  - 23.8 µgh/mL

5
Clinical pharmacologyMetabolism 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

6
Efficacy Analyses
7
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)

8
Differences in outcome assessment
failure under certain pre-specified circumstances
9
Analytic populations

• Randomized patients
• ITT (all treated patients)
• MITT (pathogen isolated)

• ITT (all treated patients)
• CE (meet baseline and post-baseline criteria)
• ME
• (susceptible pathogen isolated within baseline
  window)

13
10
Community-acquired pneumonia
11
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

12
Study 33 (Inpatient CAP)Demographics
13
Study 33 (inpatient CAP) Patient populations
14
Study 33 (inpatient CAP) Clinical efficacy
results
N 330 313 109 117
285 274 92 99

Excludes patients with missing outcomes
15
Study 33 (inpatient CAP) 95 confidence intervals
ITT
MITT
CE
ME
Difference in response rate between linezolid and
ceftriaxone/cefpodoxime
FDA
Sponsor
16
Study 33 (inpatient CAP)Results by pathogen (ME
patients)
17
Study 33 (inpatient CAP)Subgroup analyses (CE
patients)
18
Study 33 (inpatient CAP)Effect of missing data
N 330 313 381 366
109 117 128 126
Missing outcomes scored as failures
19
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

20
Study 51 (Outpatient CAP) Demographics
21
Study 51 (outpatient CAP) Patient populations
22
Study 51 (outpatient CAP) Clinical efficacy
results
N 227 222 54 52
213 208 50 48
Excludes patients with missing outcomes
23
Study 51 (outpatient CAP) 95 confidence
intervals
ITT
MITT
CE
ME
Difference in response rate between linezolid and
cefpodoxime
FDA
Sponsor
24
Study 51 (outpatient CAP)Results by pathogen (ME
patients)
25
Study 51 (outpatient CAP)Subgroup analyses (CE
patients)
26
Study 51 (outpatient CAP)Effect of missing data
N 227 222 272 268
54 52 60 60
Missing outcomes scored as failures
27
Hospital-acquired pneumonia
28
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

29
Study 48A (HAP) Demographics
30
Study 48A (HAP) Patient populations
31
Study 48A (HAP) Clinical efficacy results
N 174 164 82 72 122 103
54 41 22 20
Excludes patients with missing outcomes
32
Study 48A (HAP) 95 confidence intervals
ITT
MITT
CE
ME
Difference in response rate between linezolid and
vancomycin
FDA
Sponsor
33
Study 48A (HAP)Results by pathogen (ME patients)
34
Study 48A (HAP)Subgroup analyses (ME patients)
35
Study 48A (HAP)Subgroup analyses (MITT patients)
36
Study 48A (HAP)Effect of missing data
N 174 164 203 193
82 72 94 83
Missing outcomes scored as failures
37
Study 48A (HAP) Mortality rates
N 203 193
203 193
38
Uncomplicated skin and skin structure infections
(uSSSI)
39
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

40
Study 39A (uSSSI) Demographics
41
Study 39A (uSSSI) Patient populations
42
Study 39A (uSSSI) Clinical efficacy results
N 341 322 320 307
97 113
Excludes patients with missing outcomes
43
Study 39A (uSSSI)95 confidence intervals
ITT
CE
ME
Difference in response rate between linezolid and
clarithromycin
FDA
Sponsor
44
Study 39A (uSSSI) Results by pathogen
45
Study 39A (uSSSI)Effect of missing data
N 341 322
382 371
Missing outcomes scored as failures
46
Study 39 (uSSSI) Demographics
47
Study 39 (uSSSI) Patient populations
48
Study 39 (uSSSI) Clinical efficacy results
N 148 149 127 127
43 58
Excludes patients with missing outcomes
49
Study 39 (uSSSI)95 confidence intervals
ITT
CE
ME
Difference in response rate between linezolid and
clarithromycin
FDA
Sponsor
50
Study 39 (uSSSI) Results by pathogen
51
Complicated skin and skin structure infections
(cSSSI)
52
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

53
Study 55 (cSSSI) Demographics
54
Study 55 (cSSSI)Patient populations
55
Study 55 (cSSSI) Clinical efficacy results
N 327 348 269 267
245 242 101 108
Excludes patients with missing outcomes
56
Study 55 (cSSSI) 95 confidence intervals
ITT
ITT-prime
CE
ME
Difference in response rate between linezolid and
oxacillin/dicloxacillin
FDA
Sponsor
57
Study 55 (cSSSI) Results by pathogen
58
Study 55 (cSSSI)Subgroup analyses
59
Study 55 (cSSSI)Effect of missing data
N 327 348 400 419
269 267 316 313
Missing outcomes scored as failures
60
Methicillin-resistant staphylococcal species
(MRSS) infections
61
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

62
Study 31 (MRSS) Demographics
63
Study 31 (MRSS)Patient populations
64
Study 31 (MRSS) Clinical efficacy results
N 181 160 128 112
116 125 59 67
Excludes patients with missing outcomes
65
Study 31 (MRSS)95 confidence intervals
ITT
MITT
CE
ME
Difference in response rate between linezolid and
vancomycin
FDA
Sponsor
66
Study 31 (MRSS)Results by pathogen (ME patients)
67
Study 31 (MRSS)Results by pathogen (MITT
patients)
68
Study 31 (MRSS)Outcome by site of MRSA infection
(ME)
69
Study 31 (MRSS)Outcome by site of MRSA infection
(MITT)
70
Study 31 (MRSS)Effect of missing data
N 181 160 240 220
128 112 157 144
Missing outcomes scored as failures
71
Vancomycin-resistant enterococcal (VRE) infections
72
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

73
Study 54A (VRE) Demographics
74
Study 54A (VRE)Patient populations
75
Study 54A (VRE) Efficacy results
p0.16
p0.15
N 58 46 17 14
Excludes patients with missing outcomes
76
Study 54A (VRE)Results by pathogen
77
Study 54A (VRE)Outcome by site of VRE infection
predominantly complicated IABD infection
78
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

79
Study 54A (VRE)Effect of missing data
N 58 46 65 52
17 14 18 16
Missing outcomes scored as failures
80
Study 54A (VRE)All-cause mortality rates
4/18
9/16
18/52
16/65
N 65 52 18 16
81
Causes of death in patients with VRE bacteremia

• High dose
• VRE infection (1)
• Sepsis (2)
• Respiratory failure (1)

• Low dose
• VRE infection (3)
• Sepsis (1)
• Pneumonia (1)
• GVHD (1)
• AIDS (1)
• Gastric cancer (1)
• Liver rejection (1)

82
Covariate analysis of mortality in bacteremic
patients

• Not prespecified
• Covariates included
• Risk of mortality at baseline
• Age
• Sex
• Adjusted and unadjusted results consistent

83
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

84
Study 54 (VRE)Efficacy results
N 28 35
30 41
Missing outcomes scored as failures
85
Safety analysis

• Clinical adverse events
• Laboratory adverse events
• Potential drug-drug interactions

86
Adverse events
87
Adverse events
88
Drug-related adverse events
89
Discontinuations due to AEs
90
Discontinuations due to drug-related AEs
91
Discontinuations by adverse event
Percentages are relative to number of patients
who discontinued for any adverse event
92
Discontinuations by drug-related AE
Percentages are relative to number of patients
who discontinued for any drug-related adverse
event
93
Laboratory findings
94
Comparator-controlled studies Development of
thrombocytopenia
Percentages are relative to number of patients
with normal platelet counts at baseline
95
Comparator-controlled studies Grade III
thrombocytopenia
Percentages are relative to number of patients
with platelet count gt50K at baseline
96
Effect of linezolid dose ondevelopment of
thrombocytopenia
Percentages are relative to number of patients
with normal platelet counts at baseline
97
Resolution of thrombocytopenia in
comparator-controlled phase III studies
Linezolid
Comparator
200
M12600031
200
100
Patient count
Patient count
100
50
0
100
50
100
0
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
98
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

99
Drug-drug interactions
100
MAO inhibition
101
Linezolid-sympathomimetic amine interactions
102
Selected concomitant medications
103
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

104
Linezolid resistance
105
Linezolid resistance

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

106
Linezolid resistancein 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)

107
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

108
Linezolid resistancein 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

109
Linezolid Review Team

• Biopharmaceutics
• Jenny Zheng, Ph.D.
• Frank Pelsor, Ph.D. (TL)
• Chemistry
• Jim Timper, M.S.
• David Katague, Ph.D. (TL)
• Clinical
• John Alexander, M.D.
• David Ross, M.D., Ph.D.
• Janice Soreth, M.D. (TL)
• Microbiology
• Fred Marsik, Ph.D.
• Albert Sheldon, Ph.D. (TL)

• Pharm/Tox
• Ken Seethaler, Ph.D.
• Robert Osterberg, Ph.D., R.Ph. (TL)
• Project Management
• Beth Duvall-Miller, B.S.
• Statistics
• Erica Brittain, Ph.D.
• Joel Jiang, Ph.D.
• Daphne Lin, Ph.D. (TL)
• Supervisory Review
• Gary Chikami, M.D. (DAIDP)
• Sandra Kweder, M.D. (ODE IV)
• Dianne Murphy, M.D. (ODE IV)