M-1 Anti-Infective Advisory Committee March 24, 2000 ZYVOX ™ (linezolid) Pharmacia and Upjohn

M-1

Anti-Infective Advisory CommitteeAnti-Infective Advisory Committee

March 24, 2000March 24, 2000

ZYVOXZYVOX™™ (linezolid) (linezolid)

Pharmacia and UpjohnPharmacia and Upjohn

M-2

Pharmacia & Upjohn is Seeking Approval of Linezolid for:

• Nosocomial pneumonia

• Community-acquired pneumonia

• Complicated skin and skin structure infections

• Uncomplicated skin and skin structure infections

• Vancomycin-resistant Enterococcus faecalis and Enterococcus faecium infections

M-3

Linezolid - Presentation Agenda

Introduction W. Gary Tarpley, PhDMicrobiology VP, Discovery Research

Clinical Pharmacology Barry Hafkin, MDClinical Trial Results Director, Clinical Research

Early Pediatric Studies Donald Anderson, MD CSO, Research & Development

Conclusion W. Gary Tarpley, PhD

M-4

Most Common Nosocomial Blood Culture Isolates (US Hospitals)

Rank Pathogen (N=12,243) %

1 Coagulase-negative staph 322 S. aureus 163 Enterococcus spp 114 Candida spp 85 E. coli 6

Edmond et al., Clin Infect Dis.1999;29:234-244.

SCOPE Project

M-5

100

80

60

40

20

0

19801975 1985 1990 1995 20001997

GISAGISA33

VREVRE11

PRSPPRSP22

MRSAMRSA11

MRSEMRSE11

Percentage ofPathogens

Resistant toAntibiotics

Increasing Incidence of Resistance in the USMRSE, MRSA, VRE, PRSP, GISA 1980-1999

1NNIS data2TRUST2 project3MMWR, July 11, 1997

M-6

Limitations of Current Antibiotics for Serious Gm+ Infections

• Tolerability

• Formulation / route of administration

• Drug resistance

M-7

New Antibacterials are Required to Treat Gm+ Bacterial Infections

• Novel mechanism of action

• Broad coverage of Gm+ bacteria

• Well-tolerated

• Flexible dosing

M-8

Linezolid: First Antibacterial from a New Structural Class

N O

O

NH

C

O

CH3

F

NO

H5

Morpholino group enhances pharmacokinetic profile & improves water solubility Strategically located

fluorine atom improves activity

C - 5 acylaminomethyl group essential

5 - (S) - configuration necessary

N - Aryl group required

M-9

Linezolid Profile

• Synthetic

• Broad Gm+ antibacterial spectrum

– Coverage of drug-sensitive bacteria and bacteria resistant to any other drug class

• Unique Site of Action

– No pre-existing cross resistance

M-10

Linezolid : Unique Site of Action

Initiation Factors

30S ribosome

mRNA50S

ribosome

30S + mRNA

fMet - tRNA

Elongation Factors

70S Initiation Complex

Peptide Product

Elongation

AminoglycosidesMacrolides Streptogramins

Linezolid blocks formation of the

initiation complex

M-11

Linezolid Profile (cont.)

• 100% oral bioavailability

• Multiple dosage forms

– Solution for IV

– Tablets and suspension for oral

• IV/oral equivalent dosing

– Equal drug exposures after equal doses independent of formulation/route of administration

M-12

Efficacy - Phase III Studies in Adults

55* Complicated 33* Inpatient CAP 31 MRSA

39A* Uncomplicated 51* Outpatient CAP 54A* VRE

48A* HAP

* Pivotal trials

Resistant SST Pneumonia Pathogens

M-13

No. Isolates

Streptococci Staphylococci Enterococci

Preclinical Studies 2,985 4,589 2,169

Sentry Study 630 6,276 1,417 (1998; >30 medical centers)

Phase III Isolates 600 1,738 303

TOTAL 4,215 12,603 3,889

In Vitro Susceptibility Database

M-14

Streptococci: Preclinical Summary

No. Species Category2 Isolates MIC50 MIC90

S. pneumoniae PSSP 303 0.6 1.0

PISP 242 0.6 1.0

PRSP 266 0.6 0.9

S. pyogenes 181 1.1 2.2

S. agalactiae 164 1.9 2.0

Average1

1 Weighted average calculated for pooled studies.2 NCCLS criteria

M-15

Sentry (N = 318)

Phase III (N = 346)

Total N = 664

S. pneumoniae Sentry and Phase III Data

Linezolid MIC (µg/mL)

% o

f Iso

late

s

0

20

40

60

80

100

<0.06 .12 .25 .50 1 2 4 8 16 32 >32

M-16

Staphylococci: Preclinical Summary

No.

Species Category2 Isolates MIC50 MIC90

S. aureus MSSA 916 1.8 2.5

MRSA 973 1.7 3.2

GISA 8 2.0 2.0

S. epidermidis MSSE 183 1.3 2.4

MRSE 216 1.2 2.1

GISE 4 2.0 2.0

Average1


M-17

0

20

40

60

80

100

<0.06 0.125 0.25 0.5 1 2 4 8 16 32 >32


% o

f Iso

late

s

Sentry (N = 4,498)

Phase III (N = 1,370)

Total N = 5,868

S. aureus Sentry and Phase III Data

M-18

Enterococci: Preclinical Summary

No. Species Category2 Isolates MIC50 MIC90

E. faecalis VSE 476 1.2 2.0

VRE 148 1.7 3.1

E. faecium VSE 68 1.9 2.0

VRE 252 1.3 2.4

Average1


M-19

0

20

40

60

80

100

<0.06 0.125 0.25 0.5 1 2 4 8 16 32 >32


% o

f Iso

late

s

Sentry (N = 1,417)

Phase III (N = 303)

Total N = 1,720

Enterococcus spp Sentry and Phase III Data

M-20

Laboratory Prediction of Resistance Mechanism

• Low spontaneous mutation frequency– 1 x 10-9

• Inability to derive resistant mutants by– Chemical mutagenesis– Serial passage through 2-fold drug

concentrations

• Spiral-gradient, serial passage yielded two resistant strains– S. aureus– E. faecalis

M-21

Characterization of Lab-derived Mutants

• Mutations identified in 23S rRNA gene

– S. aureus, G2447U

– E. faecalis, G2576U

• Gene exists in 5-6 copies in Gm+ bacteria

• MIC correlated with ratio of wild-type:mutant genes

• Significant increase in MIC required mutation in at least 2 of 6 gene copies

M-22

Linezolid Efficaciousin Key Animal Models

• Mouse systemic infection

– Oral, IV, SQ

• Mouse soft tissue infection

• Localized Group A streptococcal myonecrosis

• Pneumococcal pneumonia (neutropenic animals)

• Mouse thigh infection model

M-23

Summary

• Broad Gm+ coverage

• Lack of inherent cross-resistance with marketed agents

• Therapy will be initiated principally in the hospital or institutional care setting

• Multiple dosage forms, equivalent IV/oral dosing provides treatment flexibility

M-24






M-25

Steady-State Plasma Concentrations Linezolid PO 600 mg BID (Mean SD, N=16)

Time After Dose, hours

Pla

sma

Co

nc,

µg/

mL

Staphylococcus

EnterococcusStreptococcus

0 2 4 6 8 10 12

0

4

8

16

20

24

28

12

MIC90

M-26

Linezolid Absolute Bioavailability After a Single IV or Oral 375 mg Dose (Mean SD, N = 12)

IV (AUC - 50 µg h/mL)

Oral (AUC - 52 µg h/mL)

Time After Dose, Hours

Pla

sma

Co

nc,

µg

/mL

16

12

8

4

00 2 4 6 8 1210

M-27

Clinical Pharmacology

Oral bioavailibility 100% (based on AUC)

Food effect No effect on AUC Cmax (18%)

Volume of distribution 50 liters

Plasma protein binding 31%

Elimination half-life ~ 6 hours

MAO enzyme Weak, reversible inhibitor

M-28

Linezolid Metabolism

• Linezolid is not a substrate, inhibitor or inducer of P450

• Two primary metabolites

– Oxidation products of linezolid

M-29

Linezolid Elimination

• Elimination

~ 35% as parent compound in urine

~ 50% as two primary metabolites in urine

~ 10% as two primary metabolites in feces

• Primary metabolites accumulate in patientswith CLCR30 mL/min

• Linezolid and metabolites are dialyzable

M-30

Clinical Pharmacology Summary

• No dosage adjustment for

– Route of administration

– Relationship to meals

– Gender or age

– Hepatic or renal impairment

M-31

Linezolid Efficacy Data

M-32




48A* HAP

* Pivotal trials


M-33

Complicated SST (55)

• Randomized, double-blind, equivalence trial

• Dosing regimens:

– Linezolid 600 mg BID IV PO

– Oxacillin 2 g QID IV Dicloxacillin 500 mg QID PO

– Concomitant aztreonam

• Treatment duration: 10-21 days

• Test of cure: 15-21 days PT

• Population: 819 inpatients

M-34

Clinical Cure Complicated SST (55)

85%91% 90%

77%86% 86%

0%

20%

40%

60%

80%

100%

ITT Clin.Eval. Micro.Eval.

Linezolid Oxacillin/Dicloxacillin

259

300

264

291

95% CI: (2.4, 14.1) (–0.7, 9.5) (–3.5, 11.3)

Missing/Indet: 72 / 65 7 / 2 3 / 0

279328

272354

126140

130151

M-35

Pathogen Eradication Rates Complicated SST (55)

Linezolid OX/DXPathogen n/N % n/N %

Staphylococcus aureus 85/93 91 87/103 85Streptococcus agalactiae 7/7 100 4/6 67Streptococcus pyogenes 23/29 79 27/32 84Other Streptococcus spp* 10/11 91 5/5 100

* Includes S anginosus, S bovis, S canis, S mitis, and S intermedius

M-36

Uncomplicated SST (39A)

• Randomized, double-blind equivalence trial• Dosing regimens:

– Linezolid 400 mg BID, PO

– Clarithromycin 250 mg BID, PO



• Population: 753 outpatients

M-37

Clinical Cure Uncomplicated SST (39A)

85%91% 88%

83% 87% 87%

0%

20%

40%

60%

80%

100%


Linezolid Clarithromycin

262301

283310

95% CI: (–4.0, 7.2) (–0.7, 9.2) (–6.2, 9.3)

Missing/Indet: 39 / 48 4 / 8 1 / 5

290343

268323

126143

122141

M-38

Pathogen Eradication Rates Uncomplicated SST (39A)

Linezolid ClarithromycinPathogen n/N % n/N %

Staphylococcus aureus 82/91 90 91/108 84Streptococcus agalactiae 10/10 100 4/5 80Streptococcus pyogenes 5/5 100 11/12 92Other Streptococcus spp* 9/10 90 2/3 67

* Includes S anginosus, S canis, and S intermedius, S mitis, and S sanguis

M-39

Conclusions: SST

Effective in

• Complicated SST

• Uncomplicated SSTdue to

– Staphylococcus aureus

– Streptococcus pyogenes

– Streptococcus agalactiae

M-40




48A* HAP

* Pivotal trials


M-41

Patients Hospitalized with CAP (33)

• Randomized, open-label equivalence trial

• Dosing regimens:– Linezolid 600 mg BID, IV PO

Concomitant aztreonam

– Ceftriaxone 1 gm BID, IVCefpodoxime 200 mg BID, PO



• Population: 747 inpatients

M-42

Clinical Cure Patients Hospitalized with CAP (33)

83%91% 90%

76%

89% 87%

0%

20%

40%

60%

80%

100%


Linezolid Ceftriaxone/cefpodoxime

225254

247272

8193

8089

95% CI: (0.3, 12.8) (–3.0, 7.4) (–6.5, 12.0)

Missing/Indet: 58 / 52 4 / 4 1 / 2

268323

240314

M-43

Pathogen Eradication Rates Hospitalized CAP (33)

Linezolid CTX/CPDPathogen n/N % n/N %

Streptococcus pneumoniae 63/71 89 62/69 90Staphylococcus aureus 18/20 90 13/17 77

M-44

Outpatients with CAP (51)

• Randomized, investigator-blind equivalence trial

• Dosing regimens

– Linezolid 600 mg BID, PO

– Cefpodoxime 200 mg BID, PO



• Population: 540 outpatients

M-45

Clinical Cure Outpatients with CAP (51)

82%90% 90%86%

91%83%

0%

20%

40%

60%

80%

100%


Linezolid Cefpodoxime

185204

182203

3846

4550

95% CI: (–10.3, 3.2) (–6.8, 4.8) (–6.4, 21.1)

Missing/Indet: 45 / 43 4 / 6 1 / 0

188229

191223

M-46

Pathogen Eradication Rates Outpatient CAP (51)

Linezolid CefpodoximePathogen n/N % n/N %

Streptococcus pneumoniae 25/27 93 19/21 91

Staphylococcus aureus 11/12 92 11/12 92

Haemophilus influenzae 10/12 83 13/15 87

Moraxella catarrhalis 3/3 100 1/1 100

Streptococcus pyogenes 1/1 100 1/1 100

M-47

Nosocomial Pneumonia (48A)

• Randomized, double-blind equivalence trial


– Linezolid 600 mg BID, IV

– Vancomycin 1 gm BID, IV




• Population: 396 inpatientsincluding 229 with ventilator-

associated pneumonia

M-48

Clinical CureNosocomial Pneumonia (48A)

53%

66% 70%

52%

68% 68%

0%

20%

40%

60%

80%

100%


Linezolid Vancomycin

26 38

37 53

62 91

71 107

95% CI: (–10.0, 12.6) (–14.9, 11.3) (–17.9, 20.7)

Missing/Indet: 42 / 51 1 / 5 1 / 2

86 161

74 142

M-49

Pathogen Eradication Rates Nosocomial Pneumonia (48A)

Linezolid VancomycinPathogen n/N % n/N %

Streptococcus pneumoniae 9/9 100 9/9 100Staphylococcus aureus 25/41 61 15/23 65

M-50

Conclusions: Pneumonia

Effective in


• Nosocomial pneumoniadue to

– Streptococcus pneumoniae

– Staphylococcus aureus

M-51




48A* HAP

* Pivotal trials


M-52

Methicillin-Resistant Staphylococcus (31)

• Randomized, open-label equivalence trial


– Linezolid 600 mg BID, IV PO

– Vancomycin 1 gm BID, IV



• Population: 460 patients

M-53

Primary Source of Infection (31)

Source Patients

SST Infection 230

Pneumonia 99

Bacteremia 50

UTI 27

Other 54

Total 460

M-54

Clinical Cure - All Patients (31)

57%

77%72%

55%

74% 73%

0%

20%

40%

60%

80%

100%



87117

94122

109192

93169

4664

4562

95% CI: (–8.5, 12.0) (–8.2, 13.6) (–16.3, 14.9)Missing/Indet: 48 / 51 2 / 13 0 / 8

M-55

Clinical Cure - Complicated SST (31)

65%

82% 81%

62%

77% 74%

0%

20%

40%

60%

80%

100%



5166

5668

6499

5487

3037

2635

Missing/Indet: 23 / 21 2 / 8 0 / 4

M-56

Clinical Cure -Nosocomial Pneumonia (31)

51%

77% 75%

50%

74% 75%

0%

20%

40%

60%

80%

100%



1419

1722

2039

1632

9 12

1216

Missing/Indet: 11 / 17 0 / 2 0 / 1

M-57

MRSA Pathogen Eradication (31)

Linezolid Vancomycinn/N % n/N %

ME patients withSST due to MRSA 22/34 65 18/31 58

ME patients with HAP due to MRSA 8/12 67 12/17 71

Total with MRSA 34/56 61 36/57 63

M-58

VRE Study Design Considerations

• No standard therapy, no acceptable comparators

• Dose-comparison study using 600 mg BID vs 200 mg BID (based on PK and animal models)

• Site of infection: pneumonia, SST, UTI, intra-abdominal infections, bacteremia

M-59

VRE (54A, 54)

• Randomized, double-blind, superiority trial

• Dosing regimens



– Concomitant aztreonam or aminoglycosides


• Population: 54A: 145 patients54: 82 of 186 patients

M-60

VRE - Primary Infection Source

Bacteremia 20%

Intra-abdominal infections 21%

UTI 37%

SST 18%

Pneumonia 4%

M-61

Clinical Cure VRE (54A)

67%

89% 86%

54%

74% 76%

0%

20%

40%

60%

80%

100%


LZD 600 mg LZD 200 mg

2838

3944

2229

3035

4263

2852

P-values: 0.1609 0.0807 0.3148Missing/Indet: 16 / 14 4 / 2 1 / 0

M-62

Clinical Cure - Interim Results VRE (54)

62%

75%83%

50%

73%83%

0%

20%

40%

60%

80%

100%


LZD 600 mg LZD 200 mg

1622

1824

1518

1518

1829

1836

Missing/Indet: 5 / 12 1 / 3 1 / 1

M-63

Clinical Cure (CE) by DiagnosisVRE (54A)

Linezolid Linezolid

600 mg BID 200 mg BID

Source of Infection n/N† % n/N† %

Intra-abdominal infections 8/8 100 6/10 60

Bacteremia 9/12 75 3/3 100

UTI 12/13 92 13/19 68

SST 8/9 89 6/6 100

Pneumonia 2/2 100 NA

† Excludes indeterminate and missing.

M-64

Clinical Cure (CE) by Diagnosis - Interim Results VRE (54)

Linezolid Linezolid

600 mg BID 200 mg BID

Source of Infection n/N† % n/N† %

Intra-abdominal infections 4/5 80 4/5 80

Bacteremia 5/5 100 4/5 80

UTI 8/11 73 6/7 86

SST 1/2 50 2/5 40

Pneumonia 0/1 0 NA† Excludes indeterminate and missing.

M-65

Microbiologic Outcome (ME) in VRE (54A)

Linezolid Linezolid600 mg BID 200 mg BID

N=36 N=29

Assessment n %† n %†

Microbiological success* 30 86 17 59

Microbiological failure 5 14 12 41

* p=0.0146† Percentages exclude indeterminate and missing.

M-66

Compassionate Use (25)

• Open-label treatment in patients for whom no alternative was available

• Dosing regimen


– Concomitant antibiotics were permitted

• Treatment duration: up to 3 months

• Population: 230 patients (30Jun99)

750 patients (01Mar00)

M-67

Clinical Cure (CE) Compassionate Use (25)

Linezolid

Site of Infection n/N‡ %

Intra-abdominal infections, peritonitis, other 24/26 92

Bacteremia 19/21 90

Complicated SST 7/9 78

Nosocomial pneumonia 1/1 100

UTI 1/1 100

‡ Excludes indeterminate and missing.

M-68

Conclusions: VRE

• Linezolid 600 mg BID is effective in the treatment of vancomycin-resistant Enterococcus (VRE)

• Clinical and microbiologic outcomes were better in patients randomized to 600 mg BID

• Compassionate use experience supports results in dose-comparative VRE study

M-69

Efficacy Conclusions

• Linezolid was effective in the treatment of

– Complicated skin and skinstructure infections

– Uncomplicated skin and skinstructure infections

– Community-acquired pneumonia

– Nosocomial pneumonia

– MRSA and VRE infections

M-70

Resistance Surveillance

• No resistant Staphylococcus or Streptococcus isolates in more than 3,000 patients treated with linezolid in Phase II/III studies

• Resistance developed in 15 of 832 patients treated with linezolid for enterococcal infections in Phase III and compassionate use

M-71

Resistance Development

ResistantProtocol Patients Enterococcal Isolates

54A 145 1

54 186 5

25 501 9

Probable factors in development of resistance:– Avascular nidus of infection– Extended duration of treatment– Randomized to 200 mg BID

M-72

Linezolid Safety Data

M-73

Early Development Issues

• Mild, reversible inhibition of monoamine oxidase (MAO) enzyme

• Mild, transient increases in hepatic enzymes (3- to 5-fold increase in ALT, AST)

• Mild, transient hematopoietic suppression

M-74

Drug Interactions with MAOIs

• Potent, irreversible MAOIs

– Interaction with serotonergic agents results in serotonin syndrome (cognitive dysfunction, fever, diaphoresis)

– Interaction with adrenergic agents resultsin significant hypertension

• In contrast– Linezolid is a weak, reversible MAOI

M-75

Phase I MAOI Studies

• Dextromethorphan (serotonergic agent) - no change: body temp, cognitive function, sedation, BP, or pulse

• Tyramine coadministration with LZD required 100 mg to raise SBP by 30 mmHg - no food restrictions

• Blood pressure increases seen with phenylpropanolamine and pseudoephedrine (adrenergic agents) potentiated by LZD coadministration

M-76

Linezolid - Phenylpropanolamine Systolic BP Effects

Mean Maximum Change Range from Baseline (mmHg) (mmHg)

Placebo 8 7 103-158

Linezolid 11 7 107-135

Phenylpropanolamine 14 11 106-139

Linezolid + Phenylpropanolamine 38 20 129-176

M-77

Phase II Analysis of PotentialMAOI-Related Drug Interactions

A total of 247 of 867 patients (28%) took potentially interacting drugs

Drug Categories LZD pts with Concomitant Use

sympathomimetic bronchodilators 165

selected analgesics 57

vasopressors 9

cyclic and misc antidepressants 27

indirect-acting sympathomimetics 14

SSRI antidepressants 17

selected antitussive 12

amphetamines and related stimulants 4

serotonin receptor agonists 3

M-78

Phase II MAOI Experience

• No adverse events attributable tolinezolid MAOI effect

– Food restrictions were lifted for Phase III

– Restrictions regarding potentially MAO interacting drugs were modified

M-79

Phase III Analysis of PotentialMAOI-Related Drug Interactions

Drug Categories LZD pts with Concomitant Use

sympathomimetic bronchodilators 417

selected analgesics 111

vasopressors 68

cyclic and misc antidepressants 66

indirect-acting sympathomimetics 64

SSRI antidepressants 52

selected antitussive 32

amphetamines and related stimulants 4

serotonin receptor agonists 3A total of 632 of 2046 patients (31%) took potentially interacting drugs

M-80

Phase III MAOI Experience

• 632 patients were treated with linezolid and potentially interacting drugs

• 13 patients had hypertension as an AE

• In only 1 patient was hypertension judged to be drug-related by the investigator

M-81

65.0 13.6

Blood Pressure Measurements in Phase III Patients with Concomitant MAOI Potentiators

Pre*MeanSD

Post †

MeanSD Range ‡

(min – max)

Systolic BP (mmHg)

Linezolid 129.9 29.2 130.1 22.8 80 – 184Comparator 127.2 24.4 124.4 23.6 77 – 189

Diastolic BP (mmHg)

Linezolid 66.5 14.9 65.7 12.6 36 – 95Comparator 66.9 13.7 34 – 98

*n = 81 and 93 for linezolid and comparator respectively †n = 76 and 92 for linezolid and comparator respectively‡Ranges of post-dose vital signs

M-82

MAOI Conclusions

• Preclinical and Phase I

– Weak, reversible MAOI effect

• Phase II and III

– 879 patients received linezolid and a potentially interacting medication

– 1 episode of attributed hypertension

• Benefit vs risk

M-83

Safety - Phase III Comparator-Controlled Studies

55 Complicated 33 Inpatient CAP 31 MRSA

39A Uncomplicated 51 Outpatient CAP

39 Uncomplicated 48A HAP

Total Patients Treated with Linezolid 2,046

Total Patients Treated with Comparators* 2,001

*vancomycin, ceftriaxone, cefpodoxime, clarithromycin, oxacillin, dicloxacillin


M-84

All AEs 2% (1 of 2)

Phase III Comparator-Controlled Studies

All Linezolid All ComparatorsN=2046 N=2001

MET n % n %

Diarrhea 170 8.3 126 6.3

Headache 134 6.5 110 5.5

Nausea 127 6.2 92 4.6

Vomiting 75 3.7 41 2.0

Insomnia 52 2.5 35 1.7

M-85

All AEs 2% (2 of 2)

Phase III Comparator-Controlled Studies


MET n % n %

Constipation 44 2.2 42 2.1

Trauma 43 2.1 36 1.8

UTI 43 2.1 27 1.3

Rash 40 2.0 44 2.2

Dizziness 41 2.0 38 1.9

Fever 33 1.6 42 2.1

M-86

Drug-Related AEs 1% Phase III Comparator-Controlled Studies


MET n % n %

Diarrhea 89 4.3 65 3.2

Nausea 69 3.4 46 2.3

Headache 44 2.2 27 1.3

Taste alteration 24 1.2 14 0.7

Vag. moniliasis 24 1.2 13 0.6

Vomiting 23 1.1 8 0.4

Abnormal LFTs 21 1.0 7 0.3

M-87

Most Common Serious AEs Phase III Comparator-Controlled Studies


MET n % n %

Pneumonia 26 1.3 24 1.2

Sepsis 19 0.9 19 0.9

Resp. failure 18 0.9 17 0.8

CHF 11 0.5 8 0.4

Multi-organ failure 10 0.5 8 0.4

Dyspnea 10 0.5 7 0.3

Septic shock 9 0.4 6 0.3

M-88

Laboratory Assessments

• Mean changes in laboratory assay values

• Substantially abnormal laboratory assay values were assessed by

– Regression analysis

– Hazard function analysis

– Extreme outlier analysis

M-89

Percent of Patients with Chemistry Assays 2 Times Upper Limit of Normal

All Linezolid All Comparators

Assay n/N % n/N %

ALT (U/L) 145/1959 7.4 139/1919 7.2

AST (U/L) 80/1959 4.1 102/1920 5.3

Creatine kinase (U/L) 103/2017 5.1 65/1976 3.3

Lipase (U/L) 79/2018 3.9 74/1976 3.7

Amylase (U/L) 36/2024 1.8 30/1983 1.5

Total bilirubin (mg/dL) 14/2021 0.7 16/1981 0.8

Studies 31, 33, 39A, 39, 48A, 51, 55

M-90

Cumulative Percentage Over Time - Patients With at Least One Substantially High ALT Value

0

1

2

3

4

5

6

7

8

9

10

0 2 4 6 8 10 12 14 16 18 20 22 24

Time in Days

Per

cen

t S

ub

stan

tial

ly H

igh

Linezolid Comparators

M-91

ALT Values for Linezolid-TreatedPatients with Substantially High Values

ALT

(U

/L)

800

700

600

500

400

300

200

100

0Treatment Phase Post Treatment Phase

N=105Mean (SD) Days Trt = 13.35 (4.13)

Analysis Day

Base

2-3

4-5

6-7

8-9

10-11

12-13

>13

1-3P

4-6P

7-9P

10-12P

13-15P16-18P

19-21P

>21P

M-92

ALT Values for Comparator-TreatedPatients with Substantially High Values

ALT

(U

/L)

800

700

600

500

400

300

200

100

0Treatment Phase Post Treatment Phase

N=98Mean (SD) Days Trt = 13.36 (4.69)

Analysis Day

Base

2-3

4-5

6-7

8-9

10-11

12-13

>13

1-3P

4-6P

7-9P

10-12P

13-15P16-18P

19-21P

>21P

M-93

Percent of Patients with Hematology Assays < 75% of Lower Limit of Normal*

All Linezolid All Comparators

Studies 31, 33, 39A, 39, 48A, 51, 55* 50% of LLN for neutrophils

Assay n/N % n/N %

Hemoglobin (g/dL) 110/2020 5.4 95/1974 4.8

RBC (x 106/mm3) 83/2019 4.1 73/1973 3.7

Hematocrit (%) 78/2016 3.9 65/1973 3.3

WBC (x 103/mm3) 33/2020 1.6 21/1974 1.1

Neutrophils (x 103/mm3) 15/1954 0.8 17/1909 0.9

Platelets (x 103/mm3) 48/2010 2.4 30/1966 1.5

M-94

Cumulative Percentage Over Time - Patients With at Least One Substantially Low Platelet Count

0

1

2

3

4

5

6

7

8

9

10

0 2 4 6 8 10 12 14 16 18 20 22 24

Time in Days

Per

cen

t S

ub

stan

tial

ly L

ow

Linezolid Comparators

M-95

Platelet Counts for Linezolid-TreatedPatients with Substantially Low Values

Treatment Phase Post Treatment Phase

Analysis Day

Base

2-3

4-5

6-7

8-9

10-11

12-13

>13

1-3P

4-6P

7-9P

10-12P

13-15P16-18P

19-21P

>21P

N=27Mean (SD) Days Trt =15.37 (4.49)

1000

900

800

700

600

500

400

300

200

100

0

Pla

tele

t C

ount

(T

hou/

uL)

M-96

Platelet Counts for Comparator-TreatedPatients with Substantially Low Values

Treatment Phase Post Treatment Phase

Analysis Day

Base

2-3

4-5

6-7

8-9

10-11

12-13

>13

1-3P

4-6P

7-9P

10-12P

13-15P16-18P

19-21P

>21P

N=11Mean (SD) Days Trt =12.18 (2.96)

1000

900

800

700

600

500

400

300

200

100

0

Pla

tele

t C

ount

(T

hou/

uL)

M-97

Platelet Conclusions

• Risk factors for decreased platelet counts

– Low baseline values

– >2 weeks of therapy

• Decreases are mild and reversible

• Not associated with clinical consequences

M-98

Safety Conclusions

• Linezolid is well-tolerated in adults treated with 600 mg BID for up to 28 days

• Most common drug-related AEs were diarrhea (4%), nausea (3%), and headache (2%)

• No clear association between adverse events and use of concomitant medications

• Changes in platelet counts were mild and transient

M-99






M-100

Linezolid Pediatric Drug Development

• P&U commitment to early pediatric development

• Unmet medical need is equally urgent for children

– PRSP, MRSA, MRSE & VRE are major pathogens in children

– Few safe & effective therapeutic options exist

– Alternative therapeutic agents are needed for serious infections in healthy and high risk pediatric populations, including neonates

M-101

Linezolid - Pediatric Use Development Program

• Pharmacokinetics (3 mos to 17 yrs)

• PK in neonates - planned

• Safety, Efficacy, PK/PD

• Focus on pneumococcal disease– Community Acquired Pneumonia

– Acute Otitis Media

• Experience with VRE bacteremia

• Currently being planned

Phase II

Phase III

Compassionate Use in Children

Phase I

M-102

Linezolid - Pediatric Use Clinical Pharmacokinetics

• Clearance adjusted by body weight is inversely proportional to age

• Higher clearance in very young patients; further PK analysis planned for patients < 5 years old

• Children 5 years old given 10 mg/kg oral BID had CL, Vd and t½ at steady state similar to adults

M-103

Linezolid - Pediatric UsePhase II Study Design

Hospitalized CAP Acute Otitis Media

Study 45, N=78 Study 49, N=65

Age: 12 mos - 17 yrs* 12 mos - 6 yrs

Route: IV, oral oral only

Dose: 10 mg/kg BID 10 mg/kg BID

Duration: 7 - 28 days 7 - 10 days

Design: Open-label, uncontrolled

Safety: AEs, lab assays, vital signs* 95% age 12 mos - 6 yrs

M-104

Linezolid - Pediatric UseMost Common Drug-Related Adverse Events

Diarrhea 13 9.1

Vomiting 6 4.2

Loose Stools* 5 3.5

Rash 4 2.8

Neutropenia 3 2.1

* Not elsewhere specified

Adverse Event LinezolidMET ITT N=143

n %

M-105

Linezolid - Pediatric UseAll Reported Serious Adverse Events

Bronchiolitis 1 0.7

Convulsions 1 0.7

Neutropenia 1 0.7

Pneumothorax 1 0.7

Vomiting 1 0.7

Linezolid Adverse Event ITT N=143

MET n %

M-106

Linezolid - Pediatric UseConclusions

• Safety & efficacy findings in children are promising

• Additional safety and efficacy studies are being planned and implemented, including pivotal studies

• Preliminary pharmacokinetic data suggests a dosing regimen of 10 mg/kg BID for children 5 years old

• More definitive pharmacokinetic studies in neonates and other pediatric age groups are planned or in progress

M-107






M-108

Linezolid Conclusions

• Addresses unmet medical need

– Broad Gm+ coverage

• Effective treating Gm+ infections withadded advantages:

– PK profile

– Convenience/flexibility

• Well-tolerated

M-109

Pharmacia & Upjohn is Seeking Approval of Linezolid for:

• Nosocomial pneumonia


• Complicated skin and skin structure infections

• Uncomplicated skin and skin structure infections

• Vancomycin-resistant Enterococcus faecalis and Enterococcus faecium infections

Documents

M-1 Anti-Infective Advisory Committee March 24, 2000 ZYVOX ™ (linezolid) Pharmacia and Upjohn