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 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

4

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

5

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

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

Sponsor FDA

Alive at TOC but no post-baselineassessment

Failure Missing*

Alive at EOT but died before TOC Missing* Failure

D/C’d for lack of efficacy Generallyfailure

Failure

*failure under certain pre-specified circumstances

9 13

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)

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

Linezolid CeftriaxoneN % N %

Age (years)<18 8 2.1 5 1.4

18-44 120 31.5 112 30.645-64 110 28.9 113 30.9>65 143 37.5 136 37.2

Mean SD 54.6 20.1 54.7 19.2

GenderMale 228 59.8 209 57.1

Female 153 40.2 157 42.9

RaceWhite 246 64.6 241 65.8Black 46 12.1 44 12.0

Asian/Pacific Islander 34 8.9 37 10.1Mixed 55 14.4 44 12.0

13

Study 33 (inpatient CAP) Patient populationsTotal Linezolid Ceftriaxone

ITT 747 381 366

MITT 254 128 126

CE 559 285 274

ME 191 92 99

14

Study 33 (inpatient CAP) Clinical efficacy results

81 84 86 87

77 7782 82

0

10

20

30

40

50

60

70

80

90

100

ITT MITT CE ME

Su

cces

s ra

te (

%)

Linezolid

Ceftriaxone

N = 330 313 109 117 285 274 92 99

Excludes patients with missing outcomes

Study 33 (inpatient CAP) 95% confidence intervals

-20 -15 -10 -5 0 5 10 15 20

`CE

ME

ITT

MITT

Difference in response rate between linezolid and ceftriaxone/cefpodoxime

FDA Sponsor

16

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

no aztreonam87

62.557.1

1210

83.390.0

17

Study 33 (inpatient CAP)Subgroup analyses (CE patients)

Linezolid CeftriaxoneN % 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

18

Study 33 (inpatient CAP)Effect of missing data

81

70

84

7177

66

7771

0102030405060708090

100

ITT ITT* MITT MITT*

Su

cces

s ra

te (

%)

LinezolidCeftriaxone

*Missing outcomes scored as failures

N = 330 313 381 366 109 117 128 126

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

Linezolid CefpodoximeN % N %

Age (years)<18 0 -- 1 0.4

18-44 126 46.3 120 44.845-64 93 34.2 86 32.1>65 53 19.5 61 22.8

Mean SD 47.6 17.4 48.8 18.4

GenderMale 132 48.5 140 52.2

Female 140 51.5 128 47.8

RaceWhite 196 72.1 207 77.2Black 30 11.0 28 10.4

Asian/Pacific Islander 1 0.4 2 0.7Mixed 42 15.4 29 10.8

Not Allowed to Ask 3 1.1 2 0.7

21

Study 51 (outpatient CAP) Patient populationsTotal Linezolid Cefpodoxime

ITT 540 272 268

MITT 120 60 60

CE 421 213 208

ME 98 50 48

22

Study 51 (outpatient CAP) Clinical efficacy results

83 85 85 888781

9081

0102030405060708090

100

ITT MITT CE ME

Su

cces

s ra

te (

%)

LinezolidCefpodoxime

N = 227 222 54 52 213 208 50 48

Excludes patients with missing outcomes

Study 51 (outpatient CAP) 95% confidence intervals

-20 -15 -10 -5 0 5 10 15 20 25

`CE

ME

ITT

MITT

Difference in response rate between linezolid and cefpodoxime

FDA Sponsor

24

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

25

Study 51 (outpatient CAP)Subgroup analyses (CE patients)

Linezolid CefpodoximeN % 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

26

Study 51 (outpatient CAP)Effect of missing data

83

69

8577

87

7281

70

0102030405060708090

100

ITT ITT* MITT MITT*

Su

cces

s ra

te (

%)

Linezolid

Cefpodoxime

*Missing outcomes scored as failures

N = 227 222 272 268 54 52 60 60

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

Linezolid VancomycinN % N %

Age (years)18-44 34 16.7 43 22.345-64 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

GenderMale 142 70.0 131 67.9

Female 61 30.0 62 32.1

RaceWhite 181 89.2 170 88.1Black 11 5.4 10 5.2

Asian/Pacific Islander 1 0.5 1 0.5Mixed 7 3.4 10 5.2

Not Asked 3 1.5 2 1.0

30

Study 48A (HAP) Patient populationsTotal Linezolid Vancomycin

ITT 396 203 193

MITT 177 94 83

CE 225 122 103

ME 95 54 41

ME2 42 22 20

31

Study 48A (HAP) Clinical efficacy results

4957 57

6772

45 46

60 63 65

0102030405060708090

100

ITT MITT CE ME ME2

Su

cces

s ra

te (

%)

LinezolidVancomycin

N = 174 164 82 72 122 103 54 41 22 20

Excludes patients with missing outcomes

Study 48A (HAP) 95% confidence intervals

-20 -15 -10 -5 0 5 10 15 20 25 30

`CE

ME

ITT

MITT

Difference in response rate between linezolid and vancomycin

FDA Sponsor

33

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

34

Study 48A (HAP)Subgroup analyses (ME patients)

Linezolid Vancomycin

N % cured N % cured

Bacteremia 4 50.0 6 66.7

Ventilator-associatedpneumonia

33 60.6 22 40.9

VAP with MRSA 16 62.5 5 60.0

APACHE II11

12-1516-1920

18121013

72.266.760.061.5

121658

83.375.040.025.0

35

Study 48A (HAP)Subgroup analyses (MITT patients)

Linezolid Vancomycin

N % cured N % cured

Bacteremia 10 50.0 10 40.0

Ventilator-associatedpneumonia

56 53.6 46 30.4

VAP with MRSA 21 52.4 17 29.4

APACHE II11

12-1516-1920

21191526

71.457.953.346.2

19231218

73.756.525.016.7

36

Study 48A (HAP)Effect of missing data

4942

5750

4538

4640

0102030405060708090

100

ITT ITT* MITT MITT*

Su

cces

s ra

te (

%)

LinezolidVancomycin

*Missing outcomes scored as failures

N = 174 164 203 193 82 72 94 83

37

Study 48A (HAP) Mortality rates

18

5

25

9

0102030405060708090

100

All causes Due to initial infection

Mor

talit

y ra

te (

%)

LinezolidVancomycin

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

Linezolid ClarithromycinN % N %

Age (years)18-44 212 55.5 200 53.945-64 109 28.5 121 32.6>65 61 16.0 50 13.5

Mean SD 44.1 17.1 43.9 17.0

GenderMale 219 57.3 197 53.1

Female 163 42.7 174 46.9

RaceWhite 318 84.1 322 87.0Black 43 11.4 31 8.4

Asian/Pacific Islander 2 0.5 3 0.8Mixed 12 3.2 12 3.2

Not Allowed to Ask 3 0.8 2 0.5

41

Study 39A (uSSSI) Patient populations

Total Linezolid Clarithromycin

ITT 753 382 371

CE 627 320 307

ME 210 97 113

42

Study 39A (uSSSI) Clinical efficacy results

86 88 8784 85 86

0102030405060708090

100

ITT CE ME

Su

cces

s ra

te (

%)

LinezolidClarithromycin

N = 341 322 320 307 97 113

Excludes patients with missing outcomes

Study 39A (uSSSI)95% confidence intervals

-20 -15 -10 -5 0 5 10 15 20

`

CE

ME

ITT

Difference in response rate between linezolid and clarithromycin

FDA Sponsor

44

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

45

Study 39A (uSSSI)Effect of missing data

8677

84

73

0102030405060708090

100

ITT ITT*

Su

cces

s ra

te (

%)

LinezolidClarithromycin

*Missing outcomes scored as failures

N = 341 322 382 371

46

Study 39 (uSSSI) Demographics

Linezolid ClarithromycinN % N %

Age (years)18-44 99 59.6 103 62.045-64 48 28.9 50 30.1>65 19 11.4 13 7.8

Mean SD 41.7 16.3 41.1 16.9

GenderMale 95 57.2 90 54.2

Female 71 42.8 76 45.8

RaceWhite 88 53.0 85 51.2Black 10 6.0 11 6.6

Asian/Pacific Islander 45 27.1 46 27.7Mixed 22 13.3 23 13.9

Not Allowed to Ask 1 0.6 1 0.6

47

Study 39 (uSSSI) Patient populations

Total Linezolid Clarithromycin

ITT 332 166 166

CE 254 127 127

ME 101 43 58

48

Study 39 (uSSSI) Clinical efficacy results

88 899591 90

97

0102030405060708090

100

ITT CE ME

Su

cces

s ra

te (

%)

LinezolidClarithromycin

N = 148 149 127 127 43 58

Excludes patients with missing outcomes

Study 39 (uSSSI)95% confidence intervals

-20 -15 -10 -5 0 5 10 15 20

`

CE

ME

ITT

Difference in response rate between linezolid and clarithromycin

FDA Sponsor

50

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

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

Linezolid OxacillinN % N %

Age (years)18-44 194 48.5 180 43.045-64 139 34.8 133 31.7>65 67 16.8 106 25.3

Mean SD 46.8 17.1 49.2 18.5

GenderMale 252 63.0 255 60.9

Female 148 37.0 164 39.1

RaceWhite 227 56.8 230 54.9Black 49 12.3 69 16.5

Asian/Pacific Islander 38 9.5 42 10.0Mixed 84 21.0 76 18.1

Not Allowed to Ask 2 0.5 2 0.5

54

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

55

Study 55 (cSSSI) Clinical efficacy results

85 86 9085

79 82 85 82

0102030405060708090

100

ITT ITT-prime CE ME

Su

cces

s ra

te (

%)

LinezolidOxacillin

N = 327 348 269 267 245 242 101 108

Excludes patients with missing outcomes

Study 55 (cSSSI) 95% confidence intervals

-20 -15 -10 -5 0 5 10 15 20

`CE

ME

ITT

ITT-prime

Difference in response rate between linezolid and oxacillin/dicloxacillin

FDA Sponsor

57

Study 55 (cSSSI) Results by pathogen

Linezolid OxacillinN % 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 -

58

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

Peripheralvascular disease

10 60.0 18 44.4

59

Study 55 (cSSSI)Effect of missing data

85

70

86

7379

65

82

70

0102030405060708090

100

ITT ITT* ITT-prime ITT-prime*

Su

cces

s ra

te (

%)

LinezolidOxacillin

*Missing outcomes scored as failures

N = 327 348 400 419 269 267 316 313

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

Linezolid VancomycinN % N %

Age (years)15-44 32 13.3 59 26.845-64 78 32.5 52 23.6>65 130 54.2 109 49.5

Mean SD 63.9 16.1 59.8 20.2

GenderMale 143 59.6 131 59.5

Female 97 40.4 89 40.5

RaceWhite 195 81.3 168 76.4Black 18 7.5 30 13.6

Asian/Pacific Islander 4 1.7 5 2.3Mixed 23 9.6 17 7.7

63

Study 31 (MRSS)Patient populationsTotal Linezolid Vancomycin

ITT 460 240 220

MITT 301 157 144

CE 241 116 125

ME 126 59 67

64

Study 31 (MRSS) Clinical efficacy results

61 59

80 76

63 6672 72

0102030405060708090

100

ITT MITT CE ME

Su

cces

s ra

te (

%)

Linezolid

Vancomycin

N = 181 160 128 112 116 125 59 67

Excludes patients with missing outcomes

Study 31 (MRSS)95% confidence intervals

-25 -20 -15 -10 -5 0 5 10 15 20 25

`CE

ME

ITT

MITT

Difference in response rate between linezolid and vancomycin

FDA Sponsor

66

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

67

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

68

Study 31 (MRSS)Outcome by site of MRSA infection (ME)

Linezolid VancomycinN % cured N % cured

All sources 51 78.4 57 71.9

PneumoniaBacteremic

103

90.0 100.0

173

70.666.7

SSSIBacteremic

334

78.850.0

332

72.7100.0

UTI 0 - 2 100.0

BUO 2 100.0 1 100.0

OtherBacteremic

63

50.033.3

44

50.050.0

69

Study 31 (MRSS)Outcome by site of MRSA infection (MITT)

Linezolid VancomycinN % cured N % cured

All sources 104 55.8 88 65.9

PneumoniaBacteremic

288

42.950.0

285

53.640.0

SSSIBacteremic

527

69.242.9

443

77.3100.0

UTIBacteremic

61

33.30.0

40

100.0-

BUO 5 40.0 4 40.0

OtherBacteremic

136

46.250.0

76

42.950.0

70

Study 31 (MRSS)Effect of missing data

61

46

59

48

63

46

66

51

0102030405060708090

100

ITT ITT* MITT MITT*

Su

cces

s ra

te (

%)

LinezolidVancomycin

*Missing outcomes scored as failures

N = 181 160 240 220 128 112 157 144

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

High Dose Low DoseN % N %

Age (years)18-44 12 15.2 10 15.245-64 21 26.6 20 30.3>65 46 58.2 36 54.5

Mean SD 63.8 16.6 63.6 18.2

GenderMale 36 45.6 30 45.5

Female 43 54.4 36 54.4

RaceWhite 60 75.9 49 74.2Black 18 22.8 15 22.7

Asian/Pacific Islander 0 -- 1 1.5Mixed 1 1.3 1 1.5

74

Study 54A (VRE)Patient populations

Total High-dose(600 mg)

Low-dose(200 mg)

ITT 145 79 66

MITT-VRE 117 65 52

BacteremicMITT-VRE

34 18 16

75

Study 54A (VRE) Efficacy results

6759

52

29

0102030405060708090

100

MITT-VRE MITT-VRE (bacteremic)

Su

cces

s ra

te (

%)

High-doseLow-dose

p=0.16 p=0.15

N = 58 46 17 14

Excludes patients with missing outcomes

76

Study 54A (VRE)Results by pathogen

High-dose(600 mg)

Low-dose(200 mg)

N % cured N % cured

VanR E. faecium 57 66.7 45 53.3

VanR E. faecalis 4 75.0 2 0.0

77

Study 54A (VRE)Outcome by site of VRE infection

High-dose(600 mg)

Low-dose(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

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

6760 59 5652

46

29 25

0102030405060708090

100

MITT-VRE MITT-VRE*

VREbacteremia

VREbacteremia*

Su

cces

s ra

te (

%)

High-doseLow-dose

*Missing outcomes scored as failures

N = 58 46 65 52 17 14 18 16

80

Study 54A (VRE)All-cause mortality rates

0102030405060708090

100

MITT-VRE MITT-VRE (bacteremic)

All-

cau

se m

orta

lity

rate

(%

)

High-doseLow-dose

N = 65 52 18 16

4/18 9/1618/5216/65

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

64 60

4942

0102030405060708090

100

MITT-VRE MITT-VRE*

Su

cces

s ra

te (

%)

High-doseLow-dose

*Missing outcomes scored as failures

N = 28 35 30 41

85

Safety analysis

• Clinical adverse events

• Laboratory adverse events

• Potential drug-drug interactions

86

Adverse events

87

Adverse events

57 60

31

68

47 475655

4334

62

41 4150

01020304050607080

Inci

denc

e (%

)

LinezolidComparator

88

Drug-related adverse events

21

32

1318 17

2522

11

18 16

8

1720

16

05

101520253035

Inci

denc

e (%

)

LinezolidComparator

89

Discontinuations due to AEs

6

10

6

43

6 67

3

10

56

45

0

2

4

6

8

10

12

Inci

denc

e (%

)

LinezolidComparator

90

Discontinuations due to drug-related AEs

2.4

3.7

1.5

2.1

1

3.5

2.4

0.30.7

2.1

1.4

3.6

2.41.9

00.5

11.5

22.5

33.5

4

Inci

denc

e (%

)

LinezolidComparator

91

Discontinuations by adverse event

98

76 6 6

5 54

9

1

4 43 3

00123456789

10

Inci

den

ce (

%)

Linezolid

Comparator

Percentages are relative to number of patients who discontinued for any adverse event

92

Discontinuations by drug-related AE

22

1612 12

6 6 64

8

3

811

03 3

13

0

5

10

15

20

25

Inci

den

ce (

%)

Linezolid

Comparator

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*

3 3

5

11

32

12

6

2 21

0

2

4

6

8

10

12

Inci

denc

e of

thr

ombo

cyto

peni

a (%

)

LinezolidComparator

*Percentages are relative to number of patients with normal platelet counts at baseline

95

Comparator-controlled studies: Grade III thrombocytopenia*

0.5

0

0.5

2.5

0.30

0.30

1.6

0.40 0

0

0.5

1

1.5

2

2.5

3

Inci

denc

e of

thr

ombo

cyto

peni

a (%

)

LinezolidComparator

*Percentages are relative to number of patients with platelet count >50K at baseline

96

Effect of linezolid dose ondevelopment of

thrombocytopenia*13

56

3

5

11

32

3

0

2

4

6

8

10

12

14

Study54A

Allphase

IIIstudies

Study11

Allphase IIstudies

AllphaseII/III

studies

In

cid

ence

of

thro

mb

ocyt

open

ia (

%)

High-dose (>1 g/d)Low-dose (<1 g/d)

*Percentages are relative to number of patients with normal platelet counts at baseline

97

50100Platelet count x 10E-3 100

200

Pa

tie

nt

co

un

t

050

100

Platelet count x 10E-3

0

100

200

Pa

tie

nt

co

un

tResolution of thrombocytopenia in comparator-controlled phase III studies

Linezolid Comparator

M12600031

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

Direction:

IncreaseNo changeDecreaseStartEnd

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

Drug Type ofinhibition

Ki

MAO-A(µM)MAO-B

Cmax

(µM)

clorgyline IrreversibleMAO-A

0.0013 0.71 -

selegiline IrreversibleMAO-B

2 0.004 0.0045

linezolid Reversible 56 0.71 53.4

101

Linezolid-sympathomimetic amine interactions

Maximum change in systolic blood pressure

0

10

20

30

40

50

60

70

Maximum change in SBP

mm

Hg

Placebo

Phenylpropanolamine

Linezolid + placebo

Linezolid +phenylpropanolamine

102

Selected concomitant medications

0

5

10

15

20

25

LinezolidComparator

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 < 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)