1. 1 Factive ® (gemifloxacin) NDA 21-158 March 4, 2003 Anti Infective Drugs Advisory Committee Meeting Edward Cox, M.D., M.P.H. Deputy Director, Office of Drug Evaluation IV Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. 2 FDA Presentations Microbiology Peter Dionne, MS Community-Acquired Pneumonia Regina Alivisatos, MD Acute Bacterial Exacerbation of Chronic Bronchitis Eileen Navarro, MD Safety Maureen Tierney, MD, MSc Summary Edward Cox, MD, MPH

3. 3 MICROBIOLOGY OF FACTIVE ® GEMIFLOXACIN MESYLATE NDA 21-158 Peter A. Dionne Microbiologist DSPIDP

4. 4 OVERVIEW Activity compared to other Quinolones Activity against Resistant S. pneumoniae Activity against S. pneumoniae Mutants Efficacy against S. pneumoniae in Rat Pneumonia model

5. 5 In vitro Activity of Gemifloxacin and Comparators {MIC90s}

6. 6 Comparative PK Data for Quinolones

7. 7 Gemi MICs are Lower against Gram positive bacteria compared to other quinolones Gemi MICs are about equal to other quinolones against Gram negative bacteria Gemi PK parameters weaken the significance of lower MICs against Gram + Gemi PK parameters may affect efficacy against Enterobacteriaceae

8. 8 Activity Against PEN-R S. pneumoniae

9. 9 Activity Against Quinolone-R S. pneumoniae

10. 10 MICs of Selected S. pneumoniae Mutants

11. 11 Susceptibility of Cipro-R S. pneumoniae

12. 12 Activity Against 44 S. pneumoniae Second Step Mutants [# at each MIC]

13. 13 S. pneumoniae MICs against Pen-R = MICs against Pen-S as with all quinolones Gemi MICs against Quin-R S. pneumoniae are in the range of 0.25-1 mcg/mL; Moxi MICs about 4 mcg/mL S. pneumoniae double-mutants have Gemi MICs 0.25 mcg/mL; Moxi ~ 2 mcg/mL; Levo ~32 mcg/mL Gemi PK values about 6 times lower than Moxi PK

14. 14 Efficacy of Gemifloxacin Compared to Levofloxacin in RTI in Rats (Gemi MIC < 0.03 mcg/mL]

15. 15 Efficacy of Gemifloxacin Compared to Levofloxacin in RTI in Rats [Gemi MICs > 0.125 mcg/mL]

16. 16 Efficacy of Gemifloxacin Compared to Moxifloxacin and Gatifloxacin in RTI in Rats

17. 17 In rat S. pneumoniae RTI infection model Isolates with Gemi MICs < 0.03 mcg/mL once daily dosing is effective and CFU/lung reaches close to level of detection (< 1.7 CFU/lung] Isolates with Gemi MICs > 0.125 mcg/mL must be dosed BID for efficacy and CFU/lung is > level of detection Gemi better than Levo; Gemi about same as Moxi and Gati

18. 18 Summary GEMI ~ MOXI > LEVO

19. 19 Community Acquired Pneumonia Factive (gemifloxacin) NDA 21-158 Regina Alivisatos, MD

20. 20 Sponsor’s Proposed Indication Community-acquired pneumonia caused by Streptococcus pneumoniae (including penicillin-, clarithromycin- and cefuroxime-resistant strains), Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella catarrhalis; Mycoplasma pneumoniae; Chlamydia pneumoniae; Legionella pneumophila; Staphylococcus aureus Proposed Dose: One 320 mg tablet daily for 7 days

21. 21 Overview Efficacy in relation to Duration of Treatment Severity of disease Streptococcus pneumoniae Penicillin-resistant Macrolide-resistant Cefuroxime-resistant Quinolone-resistant

22. 22 Clinical Studies

23. 23 FDA Analyses - Duration of Treatment Statistical issues with the combining of all 7 day patients because 1 controlled study (011) and 2 uncontrolled were of 7 days duration a priori in studies 061, 049, and 185, the duration of treatment was determined at the on-therapy visit and was investigator-driven FDA performed additional analyses based on a stricter division of studies into those with a priori duration of 7 days and those where duration could vary

24. 24 Patient Disposition- CAP

25. 25 FDA Analysis of Clinical Response by Duration of Treatment

26. 26 Severity Severity was determined by retrospective application of Fine criteria with the exception of study 287 where the Fine criteria were applied prospectively Patients assigned to a risk class (I - V) according to demographic, clinical and laboratory characteristics that stratified them by risk of mortality within 30 days Based on assigned risk class, patients were classified as having mild (I, II), moderate (III) or severe (IV, V) disease Patients in risk classes I, II and III can often be managed as outpatients, whereas those in classes IV and V are at higher risk of death and often require hospitalization* *mortality risk class IV = 9 - 12%, class V = 30%

27. 27 Severity Demographics Gemifloxacin ITT

28. 28 FDA Analysis of Clinical Response by Severity

29. 29 Clinical Response in Hospitalized Patients Hospitalization used as a criterion to assess the effectiveness of gemifloxacin in severe cases CAP Questions regarding appropriateness of using hospitalization as a sole determinant of severity Decision to hospitalize was investigator-driven and may have varied according to geographic location Only in study 185 were all patients hospitalized as per protocol for at least 24 hours Comparable efficacy between treatment arms

30. 30 FDA Analysis of Clinical Response in Bacteremic Patients

31. 31 Severity and Mortality

32. 32 Severity and Precedents Two quinolones, levofloxacin and moxifloxacin have a severe disease claim; both with PO and IV formulations Criteria for determining severity differed but were applied at the time of randomization in both applications that received an approval. Criteria were used to determine mode of treatment as well as duration. Most of the severe patients in the levofloxacin NDA received IV treatment. Moxifloxacin claim was granted after FDA review of the IV formulation.

33. 33 Streptococcus pneumoniae Sponsor is requesting approval for penicillin, macrolide, and cefuroxime resistant S. pneumoniae Data also submitted on quinolone-resistant S. pneumoniae Levofloxacin and moxifloxacin have the indication of PRSP No antimicrobial currently has an MRSP indication PRSP and MRSP discussed at January 2003 AIDAC No previous claims for cefuroxime-resistant PRSP What is the clinical relevance of Macrolide- and Cefuroxime-resistant S. pneumoniae in the setting of penicillin resistance?

34. 34 Penicillin Resistant Streptococcus pneumoniae Agency and sponsor in agreement that: 12 BPP gemifloxacin-treated patients had Streptococcus pneumoniae isolates with penicillin MICs of  2mcg/mL (3 of these had MICs of 4 mcg/mL) Clinical success and bacteriological eradication rates in the PP patients with PRSP were 100% Four (4) comparator arm patients had PRSP with 100% clinical success and bacteriological eradication rates

35. 35 Macrolide Resistant Streptococcus pneumoniae 25 gemifloxacin-treated PP patients with Streptococcus pneumoniae had macrolide resistant isolates (clarithromycin MIC  1mcg/mL) Clinical success and bacteriologic eradication rates were 22/25 (88%) PP 10 isolates (40%) were also penicillin-resistant 12 comparator-treated PP patients had macrolide resistant Streptococcus pneumoniae Clinical success and bacteriologic eradication rates were 11/12 (91.6%) PP 3 isolates (25%) were also penicillin-resistant

36. 36 Cefuroxime-resistant Streptococcus pneumoniae 18 patients had cefuroxime -resistant Streptococcus pneumoniae isolates (MIC  4 mcg/mL) Clinical success and bacteriological eradication rates at follow-up were 17/18 (94.4%) 12 out of the 18 cefuroxime-resistant isolates were also PRSP (67%) 15 of the 18 cefuroxime-resistant isolates were also clarithromycin resistant (83%) On the comparators arm there were 7 patients with Streptococcus pneumoniae isolates (PP) resistant to cefuroxime that were all successfully treated (ITT 8)

37. 37 Quinolone-resistant Streptococcus pneumoniae In the gemifloxacin group of the combined studies population, there were no pathogens resistant to ofloxacin and levofloxacin 1 resistant isolate on the all comparators arm (failure) In the gemifloxacin group there were 4 isolates of Streptococcus pneumoniae with an MIC against ciprofloxacin of 4 mcg/mL (clinical success and bacteriological eradication rate: 100%)

38. 38 Acute Bacterial Exacerbation of Chronic Bronchitis Factive (gemifloxacin) NDA 21-158 Eileen Navarro, MD

39. 39 ABECB Applicant’s Proposed Label Indication and Claim “ FACTIVE is effective for the treatment of acute exacerbations of chronic bronchitis due to H. influenzae, M. catarrhalis, S. pneumoniae, H. parainfluenzae and S. aureus.” “ earlier eradication of H. influenzae from the sputum”

40. 40 Issues in Applicant’s Additional Findings : “Superior clinical efficacy” “Prolonged exacerbation-free intervals” “Efficacy in hospitalized severe ABECB” - “no requirement for an IV to oral switch” -results in earlier time to hospital discharge -reduces RTI related hospitalization LIMITATIONS: Study design issues Adjustments for multiple comparisons Clinical relevance

41. 41 Efficacy in Principal Studies

42. 42 Early Bacterial Eradication in ABECB Patients with H. influenzae represent only a small proportion of patients with ABECB in the clinical studies In patients with H. influenzae, no clear correlation of early eradication with clinical benefit Early eradication related to pharmacokinetics Eradication favored comparators in some pivotal studies

43. 43 Clinical Success - ITT Analysis Supportive Studies

44. 44 Applicant’s Finding: Superiority over Comparators ITT - Considerations A finding limited to the ITT population of Supportive Studies 069 and 207 –Primary analysis of clinical efficacy (PP) - non- inferiority –Similar response rates in the secondary analyses of Bacterial Efficacy in the BPP and BITT Pivotal ABECB studies do not show superiority for Clinical Efficacy in ITT and PP population.

45. 45 Efficacy in Severe ABECB Study 207- Considerations Non-inferior to parenteral therapy in hospitalized ABECB –open label, non-US study –hospitalized patients able to tolerate oral therapy limits applicability to ALL hospitalised patients requiring parenteral therapy Earlier time to discharge (mean difference of 0.5 days) –clinical significance of a 0.5 day difference –multiple secondary endpoints –no difference in primary outcome –no difference in other related outcomes (time to resolution, indirect costs)

46. 46 Prolonged Time to Next Exacerbation & Reduced Respiratory Tract Related Hospitalization - Considerations Prolonged Time to Next Exacerbation 3 studies - contradictory outcomes one showed a trend favoring FACTIVE (Study 139), one favored the comparator (Study 105) Study 112 -primary analysis showed no difference Reduced Respiratory Tract Related Hospitalization Analyses not adjusted for multiple comparisons No difference in other related outcomes (e.g. indirect costs)

47. 47 Partial List of Approved Products for ABECB Quinolone: levofloxacin ofloxacin moxifloxacin ciprofloxacin gatifloxacin Macrolide: clarithromycin azithromycin Beta lactam: amoxicillin/clavulanate cefaclor ceftibuten cefuroxime axetil cefdinir cefditoren pivoxil cefixime cefpodoxime loracarbef

48. 48 Anti-infective Use in ABECB- Considerations

49. 49 Summary FACTIVE clinical efficacy non-inferior to comparators in ABECB Unresolved questions regarding clinical relevance or applicability of other findings Limited evidence supporting other findings Potential impact of broader use in the community

50. 50 Safety of Factive (gemifloxacin) NDA 21-158 Maureen R. Tierney, MD, MSc. Medical Officer FDA

51. 51 Safety Population Phase II and III clinical trials –Gemifloxacin 320 mg po=6775 –All Comparators (beta lactams, macrolides, and quinolones)=5248 ABECB~45% CAP~17.5% ABS, uUTI, cUTI, SSSI, NGU Study 344 & other special Clin. Pharm.

52. 52 Demographics of Safety Population

53. 53 Demographics of Safety Population

54. 54 Demographics of Safety Population

55. 55 Adverse Events of Special Interest Withdrawals and Serious Adverse Events QT Prolongation Hepatic Safety Profile Rash

56. 56 Withdrawals Due to Adverse Events

57. 57 Serious Adverse Events with Suspected Relationship

58. 58 QT Effects Known side effect for quinolone class Some mild prolongation noted in database Serious event if occurred

59. 59 QT Effects

60. 60 Mean Change in QTc Clinical Pharmacology 4.9 msec Combined Clinical Population 2.6 msec

61. 61 Changes in QTc

62. 62 Gemifloxacin Dose and QTc

63. 63 Drug Interactions and QTc No inhibition or induction of CYP450 enzymes Not dependent upon metabolism by CYP450 enzymes Dual route of elimination

64. 64 Hepatic Safety Profile of Gemifloxacin Pre-clinical Findings LFT increases with 480 and 640 mg doses LFT increases in those with hepatic impairment or more comorbidity ALT and/or BR elevations

65. 65 Pre-clinical Hepatic Findings in Dogs Cholangitis/pericholangitis with hepatocellular degeneration and single cell necrosis at high doses crystalline deposits of drug in bile canaliculi elevated ALT and Alk Phos

66. 66 LFT Elevations at Higher Doses Uncomplicated UTI Study –gemifloxacin 640 mg x 1 –ciprofloxacin 250 mg BID x 3 days 9/592 (1.6%) of gemifloxacin group ALT>2xULN with 4 >6xULN No ALT elevations >2xULN for comparator No bilirubin elevations >2xULN in either group Similar results seen in 480mg and 640mg dose clinical pharmacology studies Study 005 4/16 elderly withdrawn with high LFTs (ALT 121-333)

67. 67 AEs of the Liver and Biliary System in Patients with Baseline Liver Disease* * history of liver disease and elevated LFTs at screening Source: Sponsor Safety Table 17.35

68. 68 LFT Elevations in Patients with Higher Comorbidity Study 185 –6 with LFT elevations to >3xULN with 4 withdrawals from Gemifloxacin arm – 3 with LFT elevations >3xULN but no withdrawals from comparator arm Study 287 –2 with ALT>3xULN + BR>1.5mg/dl

69. 69 Combined ALT and Bilirubin Elevations ALT>3xULN + BR >1.5 mg/dl 2 patients in Study 287 Non comparative CAP 1 in comparator in combined clin pop ALT>2xULN + BR>1.5 mg/dl in range additional 3 for gemifloxacin from comparative clinical trials none for comparator

70. 70 Bilirubin Elevations One healthy male BR 0.8 to 7.5 mg/dl during clin pharm study (previously had an elevation of BR to 1.7mg/dl on oflox) 3 BR elevations >2xULN <4xULN in patients in range at screening (none for comparator) in the combined clinical population (all in comparative studies)

71. 71 ALT Elevations No patient in range at screening had ALT elevation >8xULN on 320 mg 1 patient in total safety population had treatment emergent ALT elevations to >8xULN on therapy-ALT 110 to 501 IU 2 patients on 640 mg dose who were in range at screening had ALT elevations >8xULN

72. 72 RASH Higher incidence than all comparators Higher number of serious AEs and withdrawals than all comparators Markedly high incidence in an enriched population (31.7% Study 344) –Large % BSA, more urticaria, 6% mucus membrane involvement Issues affecting clinical practice

73. 73 RASH-Incidence of Events

74. 74 Severity of Rash *some rashes categorized twice because of multiple rash terms

75. 75 Time and Rash Two-thirds of rash in gemifloxacin patients began after day 7 of therapy Two-thirds of rash in comparator patients began Day 7 or before days 8,9,10 most likely for gemifloxacin rash

76. 76 Risk Factors for Rash Development Gender (female) Age (<40) Planned duration of treatment (>7 days) Indication HRT in Women >40 years of age

77. 77 Rash by Age, Gender, and Duration of Therapy - Combined Population gemifloxacincomparators

78. 78 Rash by Indication

79. 79 Rash in ABECB by Gender, Age and Duration

80. 80 Rash in CAP by Age, Gender, and Duration

81. 81 HRT use and Risk of Rash

82. 82 Prior or Subsequent Quinolone Usage 3/181 (1.7%) patients who had received a prior quinolone developed a rash –selection bias - no rash on prior exposure 0/12 patients developed a rash upon receiving a subsequent quinolone after experiencing a rash on gemifloxacin –selection bias (?) - rash probably not severe

83. 83 Study 344

84. 84 Demographics Study 344

85. 85 Study 344 Part A

86. 86 Withdrawals and SAEs Due to Rash Study 344 Part A Withdrawals –26/819 from Gemifloxacin –0/164 from Ciprofloxacin Serious AEs –No rash related serious AEs in either arm Severe cutaneous AE’s –20/260 for gemifloxacin –0/7 for ciprofloxacin

87. 87 Time and Rash-Part A

88. 88 Severity of Rash-Part A

89. 89 Extent of Gemifloxacin Rash Part A (N=260) *unknown for 5 cases

90. 90 Characteristics of Gemifloxacin Rash-Part A

91. 91 Mucus Membrane Involvement Part A None in Ciprofloxacin rash (n=7) Gemifloxacin - 16/260 (6.2% of rash) –Eyes 3/260 –Genitalia 1/260 –Mouth 12/260

92. 92 Mouth Mucus Membrane Lesions in Gemifloxacin Rash Part A 5 with one to a few ulcerations, erosions, papules, or vesicles inside mouth or on lips 2 with erythema on lips or inside mouth 2 with petechiae on lips 3 unavailable description of mouth lesions no pictures taken

93. 93 Treatment of Gemifloxacin Associated Rash Antihistamines Topical steroid preparations Systemic Steroids –12/260 rashes in Study 344 –27/241 rashes in combined clinical population

94. 94 Case 1 344-025-1471 24yo WF with no PMH Onset day 8 with fever Pruritic rash with erythematous macules and papules >60%BSA Lesions in mouth (?type) Treatment with Zyrtec and Medrol pack Duration of rash 6 days Quality of Life - very much affected

95. 95 025-01471

96. 96 Case 2 344-020-00844 20 yo WF no PMH Onset day 8 Pruritic rash with erythematous macules and papules >60%BSA with plaques and mild facial edema Erythematous macules on lips Treatment Benadryl and oral Prednisone Duration of rash 12 days Quality of Life - moderately affected

97. 97 020-00844

98. 98 Case 3 -344-025-01318 21 yo WF with h/o child asthma Onset Day 6 Pruritic urticarial rash with erythematous macules and papules >60% BSA Treatment Benadryl and oral Solumedrol Duration of rash 6 days Quality of Life - some aspects very much affected

99. 99 025-01318

100. 100 Case 4 344-030-1420 21 yo WF no PMH Onset day 8 Non pruritic rash with erythematous macules and papules >60%BSA with ulcers in mouth and pharyngitis Not withdrawn No systemic therapy Duration of rash 7 days Quality of Life-minimally affected

101. 101 030-01420

102. 102 Case 5 344-028-1374 39 yo WF with a h/o hives to sulfa Onset day 9 Morbilliform urticarial eruption 40-60% BSA with erythema on labial mucosa Acetaminophen only Duration of rash 30 days Quality of Life-no assessment made

103. 103 028-01374

104. 104 Case 6 344-029-01399 20 yo WF no PMH Onset Day 6 Pruritic rash with erythematous macules 20- 40% BSA Duration of rash 4 days No photographs of rash taken Biopsy - Linear deposition of IgM along dermal basement membrane Quality of Life-moderately affected

105. 105

106. 106 Histopatholgy of Gemifloxacin Rash Most-mild superficial perivascular infiltrate Moderate or deep perivasular infiltrate in 10 specimens Eosinophils noted in 10 cases No pattern for CD-4 or CD-8 cells IF faint deposits of IgM and/or C3 in dermal vessel lumina with 1 along BM No evidence of vasculitis, bulla or necrosis

107. 107 Study 344 Part B

108. 108 Study 344 Part B Excluding Center 027

109. 109 Summary Study 344 - Part B Suggestion of minor cross-sensitization with ciprofloxacin (not conclusive) Cannot extrapolate about cross sensitization with other quinolones No evidence of subclinical sensitization with gemifloxacin

110. 110 Quinolones and Severe Cutaneous Reactions Roujeau et al NEJM 1995;333:1600-7. –Multivariate Crude RR for SJS/TEN quinolones 10 (2.6-38) aminopenicillins 6.7 (2.5-18) sulfonamides 173 (75-396) Literature Review –13 case reports SJS/TEN with a variety of fluoroquinolones

111. 111 Summary of Safety Minor increase in Mean QTc Some LFT elevations particularly in those with liver disease or more comorbidity Rash –Increased overall incidence –Large %BSA involved –Some severe rashes with mucus membrane involvement in Study 344

112. 112 Risk Benefit

113. 113 Risk Benefit Considerations - ABECB Efficacy Length of therapy Chronic condition often requiring recurrent therapy Rash rates in population prescribed drug Possible limitation of future quinolone availabilty in those who experience rash Small increases in LFTs Minor increase in mean QTC

114. 114 Risk Benefit Considerations - CAP Efficacy Oral therapy Prescriber compliance with 7 day regimens Possible limitation of future quinolone availability in those who experience rash Possibly more hepatic effects in those with more comorbidity Minor increase in mean QTc

115. 115

116. 116 Summary - 1 Microbiology –in vitro and animal model data –pharmacokinetic parameters Community Acquired Pneumonia –duration of treatment –severity of disease –Streptococcus pneumoniae Acute Bacterial Exacerbation of Chronic Bronchitis –principal studies support efficacy –statistical and clinical considerations for other findings –population differences clinical trial vs. usage data

117. 117 Summary - 2 Safety –rash - rates, risk factors, remaining questions risk for more serious dermatologic manifestations? likelihood of cross-sensitization to other fluoroquinolones? practical considerations? –hepatic safety - findings at daily doses >320 mg –cardiac repolarization –risk benefit considerations for the proposed indications CAP ABECB