Factive

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
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
MICROBIOLOGY OF FACTIVE

• GEMIFLOXACIN MESYLATE
• NDA 21-158
• Peter A. Dionne
• Microbiologist DSPIDP

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
In vitro Activity of Gemifloxacin and
Comparators MIC90s
6
Comparative PK Data for Quinolones
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
Activity Against PEN-R S. pneumoniae
9
Activity Against Quinolone-RS. pneumoniae
10
MICs of Selected S. pneumoniaeMutants
11
Susceptibility of Cipro-RS. pneumoniae
12
Activity Against 44 S. pneumoniaeSecond Step
Mutants at each MIC
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
Efficacy of Gemifloxacin Compared to Levofloxacin
in RTI in Rats (Gemi MIC lt 0.03 mcg/mL

15
Efficacy of Gemifloxacin Compared to Levofloxacin
in RTI in Rats Gemi MICs gt 0.125 mcg/mL
16
Efficacy of Gemifloxacin Compared to Moxifloxacin
and Gatifloxacin in RTI in Rats
17
In rat S. pneumoniae RTI infection model

• Isolates with Gemi MICs lt 0.03 mcg/mL once daily
  dosing is effective and CFU/lung reaches close to
  level of detection (lt 1.7 CFU/lung
• Isolates with Gemi MICs gt 0.125 mcg/mL must be
  dosed BID for efficacy and CFU/lung is gt level of
  detection
• Gemi better than Levo Gemi about same as Moxi
  and Gati

18
Summary

• GEMI MOXI gt LEVO

19
Community Acquired PneumoniaFactive
(gemifloxacin)NDA 21-158

• Regina Alivisatos, MD

20
Sponsors 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
Overview

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

22
Clinical Studies
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
Patient Disposition- CAP
25
FDA Analysis of Clinical Response by Duration of
Treatment
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
Severity DemographicsGemifloxacin ITT
28
FDA Analysis of Clinical Response by Severity
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
FDA Analysis of Clinical Response in Bacteremic
Patients
31
Severity and Mortality
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
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
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
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
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
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
Acute Bacterial Exacerbation of Chronic
BronchitisFactive (gemifloxacin) NDA 21-158

• Eileen Navarro, MD

39
ABECBApplicants 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
Issues in Applicants 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
Efficacy in Principal Studies
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
Clinical Success - ITT AnalysisSupportive Studies
44
Applicants 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
Efficacy in Severe ABECBStudy 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
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
Partial List of Approved Products for ABECB

• Beta lactam
• amoxicillin/clavulanate
• cefaclor
• ceftibuten
• cefuroxime axetil
• cefdinir
• cefditoren pivoxil
• cefixime
• cefpodoxime
• loracarbef

• Quinolone
• levofloxacin
• ofloxacin
• moxifloxacin
• ciprofloxacin
• gatifloxacin
• Macrolide
• clarithromycin
• azithromycin

48
Anti-infective Use in ABECB- Considerations
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
Safety of Factive(gemifloxacin)NDA 21-158

• Maureen R. Tierney, MD, MSc.
• Medical Officer
• FDA

51
Safety Population

• Phase II and III clinical trials
• Gemifloxacin 320 mg po6775
• All Comparators (beta lactams, macrolides, and
  quinolones)5248
• ABECB45
• CAP17.5
• ABS, uUTI, cUTI, SSSI, NGU
• Study 344 other special Clin. Pharm.

52
Demographics of Safety Population
53
Demographics of Safety Population
54
Demographics of Safety Population
55
Adverse Events of Special Interest

• Withdrawals and Serious Adverse Events
• QT Prolongation
• Hepatic Safety Profile
• Rash

56
Withdrawals Due to Adverse Events
57
Serious Adverse Events with Suspected Relationship
58
QT Effects

• Known side effect for quinolone class
• Some mild prolongation noted in database
• Serious event if occurred

59
QT Effects
60
Mean Change in QTc

• Clinical Pharmacology 4.9 msec
• Combined Clinical Population 2.6 msec

61
Changes in QTc
62
Gemifloxacin Dose and QTc
63
Drug Interactions and QTc

• No inhibition or induction of CYP450 enzymes
• Not dependent upon metabolism by CYP450 enzymes
• Dual route of elimination

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
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
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 ALTgt2xULN
  with 4 gt6xULN
• No ALT elevations gt2xULN for comparator
• No bilirubin elevations gt2xULN 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
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
LFT Elevations in Patients with Higher Comorbidity

• Study 185
• 6 with LFT elevations to gt3xULN with 4
  withdrawals from Gemifloxacin arm
• 3 with LFT elevations gt3xULN but no withdrawals
  from comparator arm
• Study 287
• 2 with ALTgt3xULN BRgt1.5mg/dl

69
Combined ALT and Bilirubin Elevations

• ALTgt3xULN BR gt1.5 mg/dl
• 2 patients in Study 287 Non comparative CAP
• 1 in comparator in combined clin pop
• ALTgt2xULN BRgt1.5 mg/dl in range
• additional 3 for gemifloxacin from comparative
  clinical trials
• none for comparator

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 gt2xULN lt4xULN in patients in
  range at screening (none for comparator) in the
  combined clinical population (all in comparative
  studies)

71
ALT Elevations

• No patient in range at screening had ALT
  elevation gt8xULN on 320 mg
• 1 patient in total safety population had
  treatment emergent ALT elevations to gt8xULN on
  therapy-ALT 110 to 501 IU
• 2 patients on 640 mg dose who were in range at
  screening had ALT elevations gt8xULN
  
  
  

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
RASH-Incidence of Events
74
Severity of Rash
some rashes categorized twice because of
multiple rash terms
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
Risk Factors for Rash Development

• Gender (female)
• Age (lt40)
• Planned duration of treatment (gt7 days)
• Indication
• HRT in Women gt40 years of age

77
Rash by Age, Gender, and Duration of Therapy -
Combined Population
gemifloxacin
comparators
78
Rash by Indication
79
Rash in ABECB by Gender, Age and Duration
80
Rash in CAP by Age, Gender, and Duration
81
HRT use and Risk of Rash
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
Study 344
84
Demographics Study 344
85
Study 344 Part A
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 AEs
• 20/260 for gemifloxacin
• 0/7 for ciprofloxacin

87
Time and Rash-Part A
88
Severity of Rash-Part A
89
Extent of Gemifloxacin RashPart A (N260)
unknown for 5 cases
90
Characteristics of Gemifloxacin Rash-Part A
91
Mucus Membrane InvolvementPart A

• None in Ciprofloxacin rash (n7)
• Gemifloxacin - 16/260 (6.2 of rash)
• Eyes 3/260
• Genitalia 1/260
• Mouth 12/260

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
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
Case 1 344-025-1471

• 24yo WF with no PMH
• Onset day 8 with fever
• Pruritic rash with erythematous macules and
  papules gt60BSA
• Lesions in mouth (?type)
• Treatment with Zyrtec and Medrol pack
• Duration of rash 6 days
• Quality of Life - very much affected

95
025-01471
96
Case 2 344-020-00844

• 20 yo WF no PMH
• Onset day 8
• Pruritic rash with erythematous macules and
  papules gt60BSA 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
020-00844
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 gt60 BSA
• Treatment Benadryl and oral Solumedrol
• Duration of rash 6 days
• Quality of Life - some aspects very much affected

99
025-01318
100
Case 4 344-030-1420

• 21 yo WF no PMH
• Onset day 8
• Non pruritic rash with erythematous macules and
  papules gt60BSA with ulcers in mouth and
  pharyngitis
• Not withdrawn
• No systemic therapy
• Duration of rash 7 days
• Quality of Life-minimally affected

101
030-01420
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
028-01374
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
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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
Study 344 Part B
108
Study 344 Part B Excluding Center 027
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
Quinolones and Severe Cutaneous Reactions

• Roujeau et al NEJM 19953331600-7.
• 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
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
Risk Benefit
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
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
(No Transcript)
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
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 gt320 mg
• cardiac repolarization
• risk benefit considerations for the proposed
  indications
• CAP
• ABECB