1 Zyvox™ (linezolid) Tablets, injection, suspension NDAs , , 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

4 With 600 mg bid dosing: –AUC (PO) = µg·h/mL –After normalization for body weight, AUC = 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 *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

13 Study 33 (inpatient CAP) Patient populations

14 Study 33 (inpatient CAP) Clinical efficacy results N = Excludes patients with missing outcomes

Study 33 (inpatient CAP) 95% confidence intervals CE ME ITT MITT Difference in response rate between linezolid and ceftriaxone/cefpodoxime FDASponsor

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 *Missing outcomes scored as failures N =

19 Community-acquired pneumonia (Study 51) Study population: 540 outpatients with CAP Design: Multi-center, multi-national, randomized, comparative, evaluator-blind Treatment arms ( 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 = Excludes patients with missing outcomes

Study 51 (outpatient CAP) 95% confidence intervals CE ME ITT MITT Difference in response rate between linezolid and cefpodoxime FDASponsor

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 *Missing outcomes scored as failures N =

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 = Excludes patients with missing outcomes

Study 48A (HAP) 95% confidence intervals CE ME ITT MITT Difference in response rate between linezolid and vancomycin FDASponsor

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 *Missing outcomes scored as failures N =

37 Study 48A (HAP) Mortality rates N =

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 = Excludes patients with missing outcomes

Study 39A (uSSSI) 95% confidence intervals CE ME ITT Difference in response rate between linezolid and clarithromycin FDASponsor

44 Study 39A (uSSSI) Results by pathogen

45 Study 39A (uSSSI) Effect of missing data *Missing outcomes scored as failures N =

46 Study 39 (uSSSI) Demographics

47 Study 39 (uSSSI) Patient populations

48 Study 39 (uSSSI) Clinical efficacy results N = Excludes patients with missing outcomes

Study 39 (uSSSI) 95% confidence intervals CE ME ITT Difference in response rate between linezolid and clarithromycin FDASponsor

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 = Excludes patients with missing outcomes

Study 55 (cSSSI) 95% confidence intervals CE ME ITT ITT-prime Difference in response rate between linezolid and oxacillin/dicloxacillin FDASponsor

57 Study 55 (cSSSI) Results by pathogen

58 Study 55 (cSSSI) Subgroup analyses

59 Study 55 (cSSSI) Effect of missing data *Missing outcomes scored as failures N =

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 = Excludes patients with missing outcomes

Study 31 (MRSS) 95% confidence intervals CE ME ITT MITT Difference in response rate between linezolid and vancomycin FDASponsor

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 *Missing outcomes scored as failures N =

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 p=0.16p=0.15 N = 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 *Missing outcomes scored as failures N =

80 Study 54A (VRE) All-cause mortality rates N = /189/1618/5216/65

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 *Missing outcomes scored as failures N =

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 >50K at baseline

96 Effect of linezolid dose on development of thrombocytopenia* *Percentages are relative to number of patients with normal platelet counts at baseline

Platelet count x 10E Patient count Platelet count x 10E Patient count Resolution of thrombocytopenia in comparator-controlled phase III studies LinezolidComparator M 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 % (grade III: %), 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 < 1 in 10 9 May result in cross-resistance to lincosamides and chloramphenicol

106 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)

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 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

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)