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

2. 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

3. M-3 Linezolid - Presentation Agenda Introduction W. Gary Tarpley, PhD Microbiology VP, Discovery Research Clinical Pharmacology Barry Hafkin, MD Clinical Trial Results Director, Clinical Research Early Pediatric StudiesDonald Anderson, MD CSO, Research & Development ConclusionW. Gary Tarpley, PhD

4. M-4 Most Common Nosocomial Blood Culture Isolates (US Hospitals) RankPathogen (N=12,243) % 1Coagulase-negative staph32 2S. aureus16 3Enterococcus spp11 4Candida spp8 5E. coli6 Edmond et al., Clin Infect Dis.1999;29:234-244. SCOPE Project

5. M-5 100 80 60 40 20 0 198019751985199019952000 1997 GISA 3 VRE 1 PRSP 2 MRSA 1 MRSE 1 Percentage of Pathogens Resistant to Antibiotics Increasing Incidence of Resistance in the US MRSE, MRSA, VRE, PRSP, GISA 1980-1999 1 NNIS data 2 TRUST2 project 3 MMWR, July 11, 1997

6. M-6 Limitations of Current Antibiotics for Serious Gm+ Infections Tolerability Formulation / route of administration Drug resistance

7. M-7 New Antibacterials are Required to Treat Gm+ Bacterial Infections Novel mechanism of action Broad coverage of Gm+ bacteria Well-tolerated Flexible dosing

8. M-8 Linezolid: First Antibacterial from a New Structural Class N O O N H C O CH 3 F NO H 5 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

9. 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

10. M-10 Linezolid : Unique Site of Action Initiation Factors 30S ribosome mRNA 50S ribosome 30S + mRNA fMet - tRNA Elongation Factors 70S Initiation Complex Peptide Product Elongation Aminoglycosides Macrolides Streptogramins Linezolid blocks formation of the initiation complex

11. 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

12. 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

13. M-13 No. Isolates StreptococciStaphylococciEnterococci Preclinical Studies2,9854,5892,169 Sentry Study6306,2761,417 (1998; >30 medical centers) Phase III Isolates6001,738303 TOTAL4,21512,6033,889 In Vitro Susceptibility Database

14. M-14 Streptococci: Preclinical Summary No. SpeciesCategory 2 IsolatesMIC 50 MIC 90 S. pneumoniae PSSP3030.61.0 PISP2420.61.0 PRSP2660.60.9 S. pyogenes1811.12.2 S. agalactiae1641.92.0 Average 1 1 Weighted average calculated for pooled studies. 2 NCCLS criteria

15. M-15 Sentry (N = 318) Phase III (N = 346) Total N = 664 S. pneumoniae Sentry and Phase III Data Linezolid MIC (µg/mL) % of Isolates 0 20 40 60 80 100 <0.06.12.25.50124 81632>32

16. M-16 Staphylococci: Preclinical Summary No. SpeciesCategory 2 IsolatesMIC 50 MIC 90 S. aureusMSSA9161.82.5 MRSA9731.73.2 GISA 82.02.0 S. epidermidisMSSE1831.32.4 MRSE2161.22.1 GISE 42.02.0 Average 1 1 Weighted average calculated for pooled studies. 2 NCCLS criteria

17. M-17 0 20 40 60 80 100 <0.060.1250.250.512481632>32 Linezolid MIC (µg/mL) % of Isolates Sentry (N = 4,498) Phase III (N = 1,370) Total N = 5,868 S. aureus Sentry and Phase III Data

18. M-18 Enterococci: Preclinical Summary No. SpeciesCategory 2 IsolatesMIC 50 MIC 90 E. faecalisVSE4761.22.0 VRE1481.73.1 E. faeciumVSE681.92.0 VRE2521.32.4 Average 1 1 Weighted average calculated for pooled studies. 2 NCCLS criteria

19. M-19 0 20 40 60 80 100 <0.060.1250.250.512481632>32 Linezolid MIC (µg/mL) % of Isolates Sentry (N = 1,417) Phase III (N = 303) Total N = 1,720 Enterococcus spp Sentry and Phase III Data

20. 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

21. 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

22. M-22 Linezolid Efficacious in 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

23. 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

24. M-24 Linezolid - Presentation Agenda Introduction W. Gary Tarpley, PhD Microbiology VP, Discovery Research Clinical Pharmacology Barry Hafkin, MD Clinical Trial Results Director, Clinical Research Early Pediatric StudiesDonald Anderson, MD CSO, Research & Development ConclusionW. Gary Tarpley, PhD

25. M-25 Steady-State Plasma Concentrations Linezolid PO 600 mg BID (Mean  SD, N=16) Time After Dose, hours Plasma Conc, µg/mL Staphylococcus Enterococcus Streptococcus 024681012 0 4 8 16 20 24 28 12 MIC 90

26. 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 Plasma Conc, µg/mL 16 12 8 4 0 02468 10

27. M-27 Clinical Pharmacology Oral bioavailibility100% (based on AUC) Food effectNo effect on AUC  Cmax (18%) Volume of distribution50 liters Plasma protein binding31% Elimination half-life ~ 6 hours MAO enzymeWeak, reversible inhibitor

28. M-28 Linezolid Metabolism Linezolid is not a substrate, inhibitor or inducer of P450 Two primary metabolites –Oxidation products of linezolid

29. 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 patients with CL CR  30 mL/min Linezolid and metabolites are dialyzable

30. M-30 Clinical Pharmacology Summary No dosage adjustment for –Route of administration –Relationship to meals –Gender or age –Hepatic or renal impairment

31. M-31 Linezolid Efficacy Data

32. M-32 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

33. 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

34. M-34 Clinical Cure Complicated SST (55) LinezolidOxacillin/Dicloxacillin 259 300 26 4 29 1 95% CI:(2.4, 14.1) (–0.7, 9.5) (–3.5, 11.3) Missing/Indet:72 / 657 / 23 / 0 279 328 272 354 126 140 130 151

35. M-35 Pathogen Eradication Rates Complicated SST (55) Linezolid OX/DX Pathogenn/N%n/N% Staphylococcus aureus85/939187/10385 Streptococcus agalactiae7/71004/667 Streptococcus pyogenes23/297927/3284 Other Streptococcus spp*10/11915/5100 * Includes S anginosus, S bovis, S canis, S mitis, and S intermedius

36. M-36 Uncomplicated SST (39A) Randomized, double-blind equivalence trial Dosing regimens: –Linezolid400 mg BID, PO –Clarithromycin250 mg BID, PO Treatment duration:7-14 days Test of cure:7-14 days PT Population:753 outpatients

37. M-37 Clinical Cure Uncomplicated SST (39A) LinezolidClarithromycin 262 301 283 310 95% CI: (–4.0, 7.2)(–0.7, 9.2)(–6.2, 9.3) Missing/Indet:39 / 484 / 81 / 5 290 343 268 323 126 143 122 141

38. M-38 Pathogen Eradication Rates Uncomplicated SST (39A) Linezolid Clarithromycin Pathogenn/N%n/N% Staphylococcus aureus82/919091/10884 Streptococcus agalactiae10/101004/580 Streptococcus pyogenes5/510011/1292 Other Streptococcus spp*9/10902/367 * Includes S anginosus, S canis, and S intermedius, S mitis, and S sanguis

39. M-39 Conclusions: SST Effective in Complicated SST Uncomplicated SST due to –Staphylococcus aureus –Streptococcus pyogenes –Streptococcus agalactiae

40. M-40 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

41. M-41 Patients Hospitalized with CAP (33) Randomized, open-label equivalence trial Dosing regimens: –Linezolid600 mg BID, IV  PO Concomitant aztreonam –Ceftriaxone1 gm BID, IV Cefpodoxime200 mg BID, PO Treatment duration:7-14 days Test of cure:15-21 days PT Population:747 inpatients

42. M-42 Clinical Cure Patients Hospitalized with CAP (33) LinezolidCeftriaxone/cefpodoxime 225 254 247 272 81 93 80 89 95% CI: (0.3, 12.8)(–3.0, 7.4)(–6.5, 12.0) Missing/Indet:58 / 524 / 41 / 2 268 323 240 314

43. M-43 Pathogen Eradication Rates Hospitalized CAP (33) Linezolid CTX/CPD Pathogenn/N%n/N% Streptococcus pneumoniae63/718962/6990 Staphylococcus aureus18/209013/1777

44. M-44 Outpatients with CAP (51) Randomized, investigator-blind equivalence trial Dosing regimens –Linezolid600 mg BID, PO –Cefpodoxime200 mg BID, PO Treatment duration:10-14 days Test of cure:15-21 days PT Population:540 outpatients

45. M-45 Clinical Cure Outpatients with CAP (51) LinezolidCefpodoxime 185 204 182 203 38 46 45 50 95% CI: (–10.3, 3.2)(–6.8, 4.8)(–6.4, 21.1) Missing/Indet:45 / 434 / 61 / 0 188 229 191 223

46. M-46 Pathogen Eradication Rates Outpatient CAP (51) Linezolid Cefpodoxime Pathogenn/N%n/N% Streptococcus pneumoniae25/279319/2191 Staphylococcus aureus11/129211/1292 Haemophilus influenzae10/128313/1587 Moraxella catarrhalis3/31001/1100 Streptococcus pyogenes1/11001/1100

47. M-47 Nosocomial Pneumonia (48A) Randomized, double-blind equivalence trial Dosing regimens: –Linezolid600 mg BID, IV –Vancomycin1 gm BID, IV –Concomitant aztreonam Treatment duration:7-21 days Test of cure:15-21 days PT Population:396 inpatients including 229 with ventilator- associated pneumonia

48. M-48 Clinical Cure Nosocomial Pneumonia (48A) LinezolidVancomycin 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 / 511 / 51 / 2 86 161 74 142

49. M-49 Pathogen Eradication Rates Nosocomial Pneumonia (48A) Linezolid Vancomycin Pathogenn/N%n/N% Streptococcus pneumoniae9/91009/9100 Staphylococcus aureus25/416115/2365

50. M-50 Conclusions: Pneumonia Effective in Community-acquired pneumonia Nosocomial pneumonia due to –Streptococcus pneumoniae –Staphylococcus aureus

51. M-51 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

52. M-52 Methicillin-Resistant Staphylococcus (31) Randomized, open-label equivalence trial Dosing regimens: –Linezolid600 mg BID, IV  PO –Vancomycin1 gm BID, IV –Concomitant aztreonam Treatment duration:7-28 days Population:460 patients

53. M-53 Primary Source of Infection (31) SourcePatients SST Infection230 Pneumonia99 Bacteremia 50 UTI27 Other54 Total460

54. M-54 Clinical Cure - All Patients (31) LinezolidVancomycin 87 117 94 122 109 192 93 169 46 64 45 62 95% CI: (–8.5, 12.0)(–8.2, 13.6)(–16.3, 14.9) Missing/Indet:48 / 512 / 130 / 8

55. M-55 Clinical Cure - Complicated SST (31) LinezolidVancomycin 51 66 56 68 64 99 54 87 30 37 26 35 Missing/Indet:23 / 212 / 80 / 4

56. M-56 Clinical Cure - Nosocomial Pneumonia (31) LinezolidVancomycin 14 19 17 22 20 39 16 32 9 12 16 Missing/Indet:11 / 170 / 20 / 1

57. M-57 MRSA Pathogen Eradication (31) Linezolid Vancomycin n/N%n/N% ME patients with SST due to MRSA22/346518/3158 ME patients with HAP due to MRSA8/126712/1771 Total with MRSA34/566136/5763

58. 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

59. M-59 VRE (54A, 54) Randomized, double-blind, superiority trial Dosing regimens –Linezolid600 mg BID, IV  PO –Linezolid200 mg BID, IV  PO –Concomitant aztreonam or aminoglycosides Treatment duration:7-28 days Population:54A:145 patients 54: 82 of 186 patients

60. M-60 VRE - Primary Infection Source Bacteremia20% Intra-abdominal infections21% UTI 37% SST 18% Pneumonia 4%

61. M-61 Clinical Cure VRE (54A) LZD 600 mgLZD 200 mg 28 38 39 44 22 29 30 35 42 63 28 52 P-values:0.16090.08070.3148 Missing/Indet:16 / 144 / 21 / 0

62. M-62 Clinical Cure - Interim Results VRE (54) LZD 600 mgLZD 200 mg 16 22 18 24 15 18 18 29 18 36 Missing/Indet:5 / 121 / 31 / 1

63. M-63 Clinical Cure (CE) by Diagnosis VRE (54A) Linezolid 600 mg BID200 mg BID Source of Infectionn/N † % n/N † % Intra-abdominal infections 8/8100 6/1060 Bacteremia9/1275 3/3100 UTI12/139213/1968 SST8/989 6/6100 Pneumonia2/2100NA † Excludes indeterminate and missing.

64. M-64 Clinical Cure (CE) by Diagnosis - Interim Results VRE (54) Linezolid 600 mg BID200 mg BID Source of Infectionn/N † % n/N † % Intra-abdominal infections 4/5 80 4/580 Bacteremia5/5100 4/580 UTI8/11736/786 SST1/2502/540 Pneumonia0/10NA † Excludes indeterminate and missing.

65. M-65 Microbiologic Outcome (ME) in VRE (54A) Linezolid 600 mg BID200 mg BID N=36N=29 Assessmentn% † n% † Microbiological success*30861759 Microbiological failure5141241 * p=0.0146 † Percentages exclude indeterminate and missing.

66. M-66 Compassionate Use (25) Open-label treatment in patients for whom no alternative was available Dosing regimen –Linezolid600 mg BID, IV  PO –Concomitant antibiotics were permitted Treatment duration:up to 3 months Population:230 patients (30Jun99) 750 patients (01Mar00)

67. M-67 Clinical Cure (CE) Compassionate Use (25) Linezolid Site of Infectionn/N ‡ % Intra-abdominal infections, peritonitis, other24/2692 Bacteremia19/2190 Complicated SST 7/978 Nosocomial pneumonia1/1100 UTI1/1100 ‡ Excludes indeterminate and missing.

68. 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

69. M-69 Efficacy Conclusions Linezolid was effective in the treatment of –Complicated skin and skin structure infections –Uncomplicated skin and skin structure infections –Community-acquired pneumonia –Nosocomial pneumonia –MRSA and VRE infections

70. 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

71. M-71 Resistance Development Resistant ProtocolPatientsEnterococcal Isolates 54A1451 541865 255019 Probable factors in development of resistance: –Avascular nidus of infection –Extended duration of treatment –Randomized to 200 mg BID

72. M-72 Linezolid Safety Data

73. 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

74. 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 results in significant hypertension In contrast –Linezolid is a weak, reversible MAOI

75. 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

76. M-76 Linezolid - Phenylpropanolamine Systolic BP Effects Mean Maximum Change Range from Baseline (mmHg)(mmHg) Placebo8  7103-158 Linezolid11  7107-135 Phenylpropanolamine14  11106-139 Linezolid + Phenylpropanolamine 38  20129-176

77. M-77 Phase II Analysis of Potential MAOI-Related Drug Interactions A total of 247 of 867 patients (28%) took potentially interacting drugs Drug Categories LZD pts with Concomitant Use sympathomimetic bronchodilators165 selected analgesics57 vasopressors9 cyclic and misc antidepressants27 indirect-acting sympathomimetics14 SSRI antidepressants17 selected antitussive12 amphetamines and related stimulants4 serotonin receptor agonists3

78. M-78 Phase II MAOI Experience No adverse events attributable to linezolid MAOI effect –Food restrictions were lifted for Phase III –Restrictions regarding potentially MAO interacting drugs were modified

79. M-79 Phase III Analysis of Potential MAOI-Related Drug Interactions Drug Categories LZD pts with Concomitant Use sympathomimetic bronchodilators417 selected analgesics111 vasopressors68 cyclic and misc antidepressants66 indirect-acting sympathomimetics64 SSRI antidepressants52 selected antitussive32 amphetamines and related stimulants4 serotonin receptor agonists3 A total of 632 of 2046 patients (31%) took potentially interacting drugs

80. 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

81. M-81 65.0  13.6 Blood Pressure Measurements in Phase III Patients with Concomitant MAOI Potentiators Pre* Mean  SD Post † Mean  SD Range ‡ (min – max) Systolic BP (mmHg) Linezolid 129.9  29.2130.1  22.8 80 – 184 Comparator 127.2  24.4 124.4  23.6 77 – 189 Diastolic BP (mmHg) Linezolid 66.5  14.965.7  12.6 36 – 95 Comparator 66.9  13.7 34 – 98 *n = 81 and 93 for linezolid andcomparator respectively † n = 76 and 92 for linezolid andcomparator respectively ‡ Ranges of post-dose vital signs

82. 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

83. 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 Linezolid2,046 Total Patients Treated with Comparators*2,001 *vancomycin, ceftriaxone, cefpodoxime, clarithromycin, oxacillin, dicloxacillin Resistant SST Pneumonia Pathogens

84. M-84 All AEs  2% (1 of 2) Phase III Comparator-Controlled Studies All LinezolidAll Comparators N=2046N=2001 METn%n% Diarrhea 170 8.31266.3 Headache1346.51105.5 Nausea1276.2924.6 Vomiting753.7412.0 Insomnia522.5351.7

85. M-85 All AEs  2% (2 of 2) Phase III Comparator-Controlled Studies All LinezolidAll Comparators N=2046N=2001 METn%n% Constipation442.2422.1 Trauma432.1361.8 UTI432.1271.3 Rash402.0442.2 Dizziness412.0381.9 Fever 33 1.6422.1

86. M-86 Drug-Related AEs  1% Phase III Comparator-Controlled Studies All LinezolidAll Comparators N=2046N=2001 METn%n% Diarrhea 89 4.3653.2 Nausea693.4462.3 Headache442.2271.3 Taste alteration241.2140.7 Vag. moniliasis241.2130.6 Vomiting231.180.4 Abnormal LFTs211.070.3

87. M-87 Most Common Serious AEs Phase III Comparator-Controlled Studies All LinezolidAll Comparators N=2046N=2001 METn%n% Pneumonia261.3241.2 Sepsis190.9190.9 Resp. failure180.9170.8 CHF110.580.4 Multi-organ failure100.580.4 Dyspnea100.570.3 Septic shock90.460.3

88. 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

89. M-89 Percent of Patients with Chemistry Assays  2 Times Upper Limit of Normal All LinezolidAll Comparators Assayn/N%n/N% ALT (U/L)145/19597.4139/19197.2 AST (U/L)80/19594.1102/1920 5.3 Creatine kinase (U/L)103/20175.165/19763.3 Lipase (U/L)79/20183.974/19763.7 Amylase (U/L)36/20241.830/19831.5 Total bilirubin (mg/dL)14/20210.716/19810.8 Studies 31, 33, 39A, 39, 48A, 51, 55

90. 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 02468 12141618202224 Time in Days Percent Substantially High LinezolidComparators

91. M-91 ALT Values for Linezolid-Treated Patients with Substantially High Values ALT (U/L) 800 700 600 500 400 300 200 100 0 Treatment PhasePost Treatment Phase N=105 Mean (SD) Days Trt = 13.35 (4.13) Analysis Day Base 2-34-56-7 8-9 10-1112-13 >13 1-3P 4-6P 7-9P 10-12P13-15P16-18P19-21P >21P

92. M-92 ALT Values for Comparator-Treated Patients with Substantially High Values ALT (U/L) 800 700 600 500 400 300 200 100 0 Treatment PhasePost Treatment Phase N=98 Mean (SD) Days Trt = 13.36 (4.69) Analysis Day Base 2-34-56-7 8-9 10-1112-13 >13 1-3P 4-6P 7-9P 10-12P13-15P16-18P19-21P >21P

93. M-93 Percent of Patients with Hematology Assays < 75% of Lower Limit of Normal* All LinezolidAll Comparators Studies 31, 33, 39A, 39, 48A, 51, 55 *  50% of LLN for neutrophils Assayn/N%n/N% Hemoglobin (g/dL)110/20205.495/19744.8 RBC (x 10 6 /mm 3 )83/20194.173/19733.7 Hematocrit (%)78/20163.965/19733.3 WBC (x 10 3 /mm 3 )33/20201.621/19741.1 Neutrophils (x 10 3 /mm 3 )15/19540.817/19090.9 Platelets (x 10 3 /mm 3 )48/20102.430/19661.5

94. 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 02468 12141618202224 Time in Days Percent Substantially Low LinezolidComparators

95. M-95 Platelet Counts for Linezolid-Treated Patients with Substantially Low Values Treatment PhasePost Treatment Phase Analysis Day Base 2-34-56-7 8-9 10-1112-13 >13 1-3P 4-6P 7-9P 10-12P13-15P16-18P19-21P >21P N=27 Mean (SD) Days Trt =15.37 (4.49) 1000 900 800 700 600 500 400 300 200 100 0 Platelet Count (Thou/uL)

96. M-96 Platelet Counts for Comparator-Treated Patients with Substantially Low Values Treatment PhasePost Treatment Phase Analysis Day Base 2-34-56-7 8-9 10-1112-13 >13 1-3P 4-6P 7-9P 10-12P13-15P16-18P19-21P >21P N=11 Mean (SD) Days Trt =12.18 (2.96) 1000 900 800 700 600 500 400 300 200 100 0 Platelet Count (Thou/uL)

97. 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

98. 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

99. M-99 Linezolid - Presentation Agenda Introduction W. Gary Tarpley, PhD Microbiology VP, Discovery Research Clinical Pharmacology Barry Hafkin, MD Clinical Trial Results Director, Clinical Research Early Pediatric StudiesDonald Anderson, MD CSO, Research & Development ConclusionW. Gary Tarpley, PhD

100. 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

101. 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

102. 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

103. M-103 Linezolid - Pediatric Use Phase II Study Design Hospitalized CAPAcute Otitis Media Study 45, N=78Study 49, N=65 Age:12 mos - 17 yrs*12 mos - 6 yrs Route:IV, oraloral only Dose:10 mg/kg BID10 mg/kg BID Duration:7 - 28 days7 - 10 days Design: Open-label, uncontrolled Safety: AEs, lab assays, vital signs * 95% age 12 mos - 6 yrs

104. M-104 Linezolid - Pediatric Use Most Common Drug-Related Adverse Events Diarrhea139.1 Vomiting64.2 Loose Stools*53.5 Rash42.8 Neutropenia32.1 * Not elsewhere specified Adverse EventLinezolid MET ITT N=143 n%

105. M-105 Linezolid - Pediatric Use All Reported Serious Adverse Events Bronchiolitis10.7 Convulsions10.7 Neutropenia10.7 Pneumothorax10.7 Vomiting10.7 Linezolid Adverse Event ITT N=143 MET n%

106. M-106 Linezolid - Pediatric Use Conclusions 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

107. M-107 Linezolid - Presentation Agenda Introduction W. Gary Tarpley, PhD Microbiology VP, Discovery Research Clinical Pharmacology Barry Hafkin, MD Clinical Trial Results Director, Clinical Research Early Pediatric StudiesDonald Anderson, MD CSO, Research & Development ConclusionW. Gary Tarpley, PhD

108. M-108 Linezolid Conclusions Addresses unmet medical need –Broad Gm+ coverage Effective treating Gm+ infections with added advantages: –PK profile –Convenience/flexibility Well-tolerated

109. M-109 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