Safety and Efficacy of Gemifloxacin for ABS in Clinical Studies

1
Safety and Efficacy of Gemifloxacin for ABS in
Clinical Studies

• Maureen R. Tierney, MD, MSc.
• Senior Medical Officer
• Division of Special Pathogen and Transplant
  Products
• CDER

Anti-Infective Drugs Advisory Committee
Meeting September 12, 2006
2
Points for Discussion

• Efficacy in ABS
• Cutaneous AEs in ABS Studies
• Cutaneous AEs in NDA 21-158
• QT Issues
• Liver AEs
• Analysis of Risk Benefit

3
ABS Studies
Study Type Drug(s)/duration
009 R, C, DB Sinus puncture Gemi 7 day vs. Cefuroxime 10 day
010 R, C, DB Gemi 7 day vs. Trovofloxacin 10 day
186 R, C, DB Gemi 5 day vs. Gemi 7 day
206 OL, single arm Sinus puncture Gemi 5 day
333 OL, single arm Sinus endoscopy Gemi 5 day
4
Inclusion Criteria

• Symptoms gt7 lt28 days with purulent/mucoid nasal
  discharge plus
• X-Ray (opacification or A/F level)
• 1 Major pain/pressure over sinuses, facial
  congestion, or nasal blockage OR
• 2 Minor tooth pain, earache, non-vascular HA,
  cough, halitosis, fever, change in smell,
  periorbital swelling
• Sinus puncture required in 009 and 206
• 2003 AC recommends sinus puncture in all ABS
  clinical studies

5
Outcome Criteria

• Primary-investigator determination of sustained
  improvement or resolution of signs and symptoms
  as seen at follow-up Days 18-24 such that no
  further antibiotic treatment required.
• Bacteriologic success clinical cure with
  presumed eradication or documented eradication
  with persistent symptoms
• (no f/u sinus puncture required unless
  clinically indicated).

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Clinical Success at Follow up
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Summary of CI ABS Clinical Trials
Study Number PP ITT
009 -6.4, 4.1 -9.4, 1.6
010 -7.1, 5.4 -6.5, 8.1
186 -6.5, 7.6 -8.0, 6.4
206 noncomparative noncomparative
333 noncomparative noncomparative
8
Study 186 at Follow-up
Gemifloxacin 5 days Gemifloxacin 7days
PP Population 178 171
Success 155 (87.1) 148 (86.5)
95 CI -6.51, 7.63 -6.51, 7.63
ITT Population N212 N198
Success 176 (83.0) 166 (83.8)
95 CI -8.02, 6.38 -8.02, 6.38
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Study 186 at End of Therapy
Gemifloxacin 320 mg qd for 5 days Gemifloxacin 320 mg qd for 7 days Gemifloxacin 320 mg qd for 7 days
PP Population N186 N180 N180
Success, n () 173 (93) 173 (96) 173 (96)
95 CI -7.7, 1.5 -7.7, 1.5 -7.7, 1.5
ITT Population N212 N212 N198
Success, n () 188 (88.7) 188 (88.7) 189 (95.5)
95 CI -11.9, -1.6 -11.9, -1.6 -11.9, -1.6

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Microbiological Results for Study 009 at FU
Bacteriological ITT Bacteriological ITT Bacteriological ITT Bacteriological ITT
Gemifloxacin (7 day) Gemifloxacin (7 day) Cefuroxime (10 day) Cefuroxime (10 day)
Follow-Up N165 n/N N165 n/N N156 n/N N156 n/N
All Pathogens 157/185 (84.9) 152/173 (87.9)
S. pneumoniae 58/66 (87.9) 57/64 (89.1)
H. influenzae 29/37 (78.4) 33/36 (91.7)
K. pneumoniae 15/18 (83.3) 18/19 (94.7)
S. aureus 14/17 (82.4) 8/11 (72.7)
M catarrhalis 9/9 (100.0) 6/6 (100.0)
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In vitro Activity of Gemifloxacin
Organism Gemi Cipro Levo Moxi Gati
S. pneumoniae 0.03 2.0 1.0 0.25 0.5
S. aureus 0.06 1.0 0.5 0.12 0.25
H. Influenzae 0.03 0.03 0.03 0.06 lt0.03
H. parainfluenzae 0.06 0.06 0.06 0.25 0.12
M. catarrhalis 0.015 0.06 0.06 0.06 0.03
E. coli 0.25 0.5 0.5 0.06 0.06
K. pneumoniae 0.5 1.0 1.0 1.0 1.0
M. pneumoniae 0.12 -- 0.5 0.12 0.25
L. pneumophila 0.015 0.03 0.015 0.125 0.03

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Comparative PK Data for Quinolones
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Microbiology

• 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

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Efficacy Summary

• 7 Day 2 Non-inferiority DB,R studies
• Clinical outcome _at_FU-82 ITT to 90PP. similar
  trend at end of Rx
• Bacteriologic Outcome in 1 study _at_85 ALL
  Pathogens (88 Pneumo, 79 HI)
• Comparators effect size not determined
• 5 Day 1 Non-inferiority DB, R study
• Clinical Outcome _at_FU-ITT 83
• Comparators effect size not determined
• Results not consistent at end of therapy and
  followup
• No randomized bacteriologic data

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Safety
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Cutaneous Adverse Events in ABS Studies

• 7 day studies
• 009
• 010
• 5 day studies
• 186
• 206
• 333
• Combined 5 vs 7 day

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Study 009 Skin AEs
Gemi 7 D (n 338) Cefurox. (n 337)
Rash 29 2
Erythem.Rash 0 1
Urticaria 5 0
Mac-Pap Rash 1 0
Photosensitivity 2 1
Total (1 overlap) 36 (10.6) 4
Severe Rash 5 0
Withdrawal 8 0

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Study 010 Skin AEs
Gemifloxacin 7day (n 202) Trovafloxacin 10 day (n199)
Rash 11 1
Erythem.Rash 8 1
Urticaria 2 0
Mac-Pap Rash 1 0
Total 22 (10.9) 2
Severe Rash 9 0
Withdrawal 9 0
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Study 009 Rash by Age and Gender Study 009 Rash by Age and Gender Study 009 Rash by Age and Gender Study 009 Rash by Age and Gender
lt40 gt 40 Total
Female 13/104 (12.5) 5/83 (6.0) 18/187 (9.6)
Male 4/78 (5.1) 2/66 (3.0) 6/144 (4.2)
Total 17/182(9.3) 7/149 (4.7) 24/331 (7.3)
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Study 010 Rash by Age and Gender
lt40 gt 40 Total
Female 10/58 (17.2) 4/58 (6.9) 14/116 ( 12.1)
Male 2/48 (4.2) 3/31 (9.7) 5/79 ( 6.3)
Total 12/106 ( 11.3) 7/89 ( 7.9) 19/195 (9.7)
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Study 186 - Incidence of Rash
Gemifloxacin for 5 days Gemifloxacin for 7 days
N 218 N203
Rash 1 (0.5) 1 (0.5)
Rash Maculo-papular 2 (0.9) 4 (2.0)
Rash erythematous 0 7 (3.4)
Urticaria 1 (0.5) 5 (2.5)
Dermatitis 2 (0.9) 1 (0.5)
Total 6 (2.8) 18(8.9)
Withdrawn due to rash 1 0
Severe Rash 0 2
Rash in Women 69 69
Adapted from data in original submission NDA
21-376.
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Study 206 Cutaneous Adverse Events
N461
Patients with Any Cutaneous Adverse Event (5 overlaps) 12 2.6
Rash Maculo-papular 8 1.7
Urticaria 3 0.6
Pruritus 3 0.6
Rash Pustular 1 0.2
Rash 1 0.2
Severe Rash 0
Rash in Women 6/8 75 of rash
Source Adapted from Study Report 206, NDA 21-376
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Study 333-Incidence of Rash
N451
Rash Mac-Pap 12
Rash 5
Urticaria 4
Dermatitis 2
Photosenstivity 2
Rash erythematous 2
Severe Rash 2 (10.5)
Total 23 5.1
Withdrawal 4
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Cutaneous Adverse Events in Combined ABS Studies
Preferred Term Gemi 5 Day N1122 Gemi 7 Day N724 All Comparators N521
Total 35(3.1) 62 (8.6) 5 (1.0)
Urticaria 8 (0.7) 12(1.7) 0
Rash 7 (0.6) 38 (5.2) 3 (0.6)
Rash Mac-pap 22 (2.0) 6 (0.8) 0
Rash erythem 2 (0.2) 18 (2.5) 2 (0.4)
Rash pustular 1 (0.1) 0 0
Severe rash 2 (0.2) 16 (2.2) 0
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Original NDA 21-158 (N6775) Total Clinical
Trial Database (N8119) (6775 CAP studies ABS
333)
Evaluation of Rash
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RASH

• Higher incidence than all comparators
• Higher number of serious AEs and withdrawals than
  all comparators
• Markedly high incidence in an enriched population
  of women under 40 (31.7)
• Higher incidence in any subgroup at any duration
  of therapy

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RASH-Incidence of Events
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Severity of Rash
some rashes categorized twice because of
multiple rash terms
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Number () of Patients With Rash by Gender, Age
Gemifloxacin 320mg qd Gemifloxacin 320mg qd All Comparators All Comparators
Gender
Male 78/3278 (2.4) 20/2511 (0.8)
Female 163/3497 (4.7) 39/2737 (1.4)
Age, yrs
lt40 115/1711 (6.7) 13/1037 (1.3)
gt40 126/5064 (2.5) 46/4211 (1.1)
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Rash Incidence by Decade
Total population Females only
lt 19 7/147 (4.8) 4/92 (4.3)
20-29 54/787 (6.9) 40/455 (8.8)
30-39 54/776 (7.0) 37/445 (8.3)
40-49 40/1124 (3.6) 24/658 (3.6)
50-59 30/1211 (2.5) 22/638 (3.4)
60-69 31/1294 (2.4) 22/591 (3.7)
70-79 18/1110 (1.6) 10/461 (2.2)
80-89 6/292 (2.1) 3/133 (2.3)
gt 90 1/32 (3.1) 1/22 (4.5)
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Day of Rash Onset
Gemifloxacin 320 mg qd Gemifloxacin 320 mg qd All Comparators All Comparators
Patients with Rash N 241 (overall N 6775) N 241 (overall N 6775) N 59 (overall N 5248) N 59 (overall N 5248)
Time to Rash Onset (days) n ( of rash) n ( of rash)
1 9 (3.7) 6 (10.7)
2 19 (7.9) 9 (15.3)
3 14 (5.8) 10 (16.9)
4 10 (4.1) 6 (10.2)
5 12 (5.0) 3 (5.1)
6 (29.4) 7 (2.9) 2 (3.4)
7 6 (2.5) 2 (3.4)
8 36 (14.9) 1 (1.7)
9 46 (19.1) 4 (6.8)
10 38 (15.8) 3 (5.1)
11 19 (7.9) 1 (1.7)
12-14 11 (4.6) 2 (3.4)
15-19 7 (2.9) 5 (8.5)
gt19 7 (2.9) 5 (8.5)
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Number () of Patients With Rash by Therapeutic
Indication
Treatment Group Treatment Group Treatment Group Treatment Group
Gemifloxacin 320mg qd Gemifloxacin 320mg qd All Comparators All Comparators
N6775 N6775 N5248 N5248
Indication n () n ()
AECB 44/2847 (1.5) 21/2591 (0.8)
CAP 55/1160 (4.7) 19/926 (2.1)
ABS 73/1397 (5.2) 5/521 (1.0)
cUTI 48/758 (6.3) 11/729 (1.5)
uUTI 14/430 (3.3) 2/444 (0.5)
uSSSI 5/39 (12.8) 1/37 (2.7)
NGU 2/144 (1.4) 0/0 (0.0)
Data Source Tables 105a, 105b, 105c, 105d, 105e, 105f, 105g. Data Source Tables 105a, 105b, 105c, 105d, 105e, 105f, 105g. Data Source Tables 105a, 105b, 105c, 105d, 105e, 105f, 105g. Data Source Tables 105a, 105b, 105c, 105d, 105e, 105f, 105g. Data Source Tables 105a, 105b, 105c, 105d, 105e, 105f, 105g.
Source Applicants Table 14.20 from NDA 21058 18
month Safety Update
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Study 344 Part A
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Severity of Rash-Part A
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Extent of Gemifloxacin RashPart A (N260)
unknown for 5 cases
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Characteristics of Gemifloxacin Rash-Part A
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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

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Treatment of Gemifloxacin Associated Rash

• Antihistamines
• Topical steroid preparations
• Systemic Steroids
• 12/260 rashes in Study 344 5
• 27/241 rashes in combined clinical population 9

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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

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025-01471
41
025-01471
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Case 2 -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

43
Case 2 - 344-025-01318
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Case 2 - 344-025-01318
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Source of Rash Slides

• Study 344 Report
• Resubmission NDA 21-158

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Preclinical QTc Potential
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Mean Change in QTc

• Clinical Pharmacology Population
• 4.9msec
• Clinical Studies Population
• 2.3msec

48
Hepatic Safety Profile of Gemifloxacin

• Preclinical Findings
• LFT increases with 480 and 640 mg dose
• ALT and/or BR elevations

49
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

50
ALT Elevations

• No patient in range at screening had ALT
  elevation gt8xULN on 320 mg
• 1 patient 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
• Postmarketing Events

51
Safety Conclusions

• Higher incidence of rash and urticaria even at 5
  days (minimum of 2.5 times greater than
  comparators)
• Higher incidence of severe rash
• Higher incidence of withdrawals due to rash
• Low grade liver and QT signal
• No Tendon signal at this time

52
Risk Benefit

• Mild-Moderate Rash
• Labeled Q Allergic
• (2-3)
• ?Sensitization
• Severe Rash
• Meds for Rx of Rash (10)
• ? Serious Rash
• ? QT Prolongation
• ? Liver

• Small and ? Effect size-No demonstrated
  advantage
• No demonstrated randomized bacteriologic benefit
  at 5 days