Pre-Approval Efficacy and Safety Data

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Pre-Approval Efficacy and Safety Data

• John Alexander M.D., M.P.H.
• Medical Team Leader
• Division of Anti-Infective Ophthalmology
  Products, CDER/FDA

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Overview

• Efficacy Data
• Acute Exacerbation of Chronic Bronchitis (AECB)
• Acute Bacterial Sinusitis (ABS)
• Community-Acquired Pneumonia (CAP)
• Multi-Drug Resistant Streptococcus pneumoniae
  (MDRSP)
• Safety Data
• Controlled Clinical Trials
• Foreign Post-Marketing

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Acute Exacerbation of Chronic Bronchitis

• Two Studies with the Original NDA
• Study 3003
• Telithromycin 800 mg QD for 5 days
• Amox/Clav 500mg/125mg TID for 10 days
• Study 3007
• Telithromycin 800 mg QD for 5 days
• Cefuroxime Axetil 500 mg BID for 10 days
• One Study in the Resubmission
• Study 3013
• Telithromycin 800 mg QD for 5 days
• Clarithromycin 500 mg BID for 10 days

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Acute Exacerbation of Chronic Bronchitis
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Acute Exacerbation of Chronic Bronchitis

• Pathogen Analyses in Briefing Package
• Bacteriological Success for H. influenzae
• Original NDA
• Telithromycin 15/25 (60.0)
• Comparators 15/17 (88.2)
• Resubmission
• Telithromycin 27/35 (77.1)
• Clarithromycin 30/36 (83.3)

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Acute Bacterial Sinusitis

• Three Studies with 1st Review Cycle
• Study 3002
• Telithromycin for 5 or 10 days, uncontrolled
• Study 3005
• Telithromycin for 5 days or 10 days
• Amox/Clav 500mg/125mg TID for 10 days
• Study 3011
• Telithromycin 800 mg QD for 5 days
• Cefuroxime Axetil 250 mg BID for 10 days
• No New ABS Studies in the Resubmission

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Acute Bacterial Sinusitis
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Acute Bacterial Sinusitis

• Pathogen Analyses in Briefing Package
• Comparable H. influenzae Cure Rates for
  Telithromycin and Cefuroxime (82-86)
• Outcomes for Penicillin- and Erythromycin-Resistan
  t S. pneumoniae
• No Specific Claim for ABS due to MDRSP

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Community-Acquired Pneumonia

• Original NDA Studies
• Study 3001
• Telithromycin 800 mg QD for 10 days
• Amoxicillin 1g TID for 10 days
• Study 3006
• Telithromycin 800 mg QD for 10 days
• Clarithromycin 500 mg BID for 10 days
• Study 3009
• Telithromycin 800 mg QD for 7-10 days
• Trovafloxacin 200 mg QD for 7-10 days
• Open-Label Studies 3000, 3009OL, 3010

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Community-Acquired Pneumonia
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Community-Acquired Pneumonia
Subgroup Telithromycin (cure/N)
Per Protocol 92.4 (1046/1132)
S. pneumoniae Bacteremia 91.5 (43/47)
Fine Score Class I Class II Class III 93.3 (517/554) 91.3 (368/403) 92.0 (161/175)
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MDRSP in CAP

• Two New CAP Studies in Resubmission
• Study 4003
• Telithromycin for 5 days or 7 days
• Clarithromycin 500 mg BID for 10 days
• Study 3012
• Open-label, Telithromycin for 7 days
• Resubmission Analyses Focused on Resistant
  Pathogens

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MDRSP in CAPTelithromycin Cure Rates CAP due
to MDRSP
Antimicrobial MITT (Cure/N) PPc (Cure/N)
Penicillin 74.2 (23/31) 86.9 (20/23)
Cefuroxime 76.7 (23/30) 90.9 (20/22)
Erythromycin 81.8 (36/44) 88.9 (32/36)
Tetracycline 75.0 (15/20) 84.6 (11/13)
TMP/SMX 77.1 (27/35) 88.9 (24/27)
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Pre-Approval Safety

• Ketolide (Related to Macrolide Class)
• Animal Toxicology Studies
• Hepatic, Cardiac (QT Prolongation)
• Clinical Pharmacology
• CYP3A4 and CYP2D6 Substrate
• Strong CYP3A4 Inhibitor
• Phase 1 Studies
• Liver Function Test Increases

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Safety Data in Phase 3 Trials
AE Telithromycin N2702 Comparator N2130
Diarrhea 10.8 8.6
Nausea 7.9 4.6
Headache 5.5 5.8
Dizziness 3.7 2.7
Vomiting 2.9 2.2
Loose Stools 2.3 1.5
Dysgeusia 1.6 3.6
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Visual Adverse Effects

• Recognized in Phase 3 Study Results
• Ketek/Comp 1.1/0.28
• FemalesgtMales, Younger Age (lt40)
• CYP3A4 Inhibitor 1.9/0.4
• First or Second Dose (65)
• Mechanistic Studies (Dose-Response)
• Appendix D of Briefing Document

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Cardiac Adverse Effects

• QT Prolongation
• On-therapy increase in QTc
• QTc (Bazetts) 1.5 msec Increase
• QTc (Fridericias) 3.8 msec Increase
• Careful Review of Cardiac Adverse Events in Phase
  3 Trials
• Additional Phase 1 Study of QTc
• Elderly, Renal Impairment, CYP3A4 Inhibitor

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Hepatic Adverse Effects

• LFT Increases in Phase 3 Trials
• Appendix B of Briefing Document
• Serious Hepatic AE
• 76 y/o Female with CAP
• 50 y/o Finnish Man with CAP
• Led to Design of Study 3014

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Foreign Post-Marketing

• Approximately 3.7M Exposures Ex-US as of January
  2003
• France, Germany, Italy, Spain, Mexico, Brazil
• Other EU, Latin American, International
• Total 2345 Reports in 932 Patients
• Focus on Visual, Hepatic, Myasthenia Gravis
• Appendix C of Briefing Package

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Foreign Post-Marketing

• Visual AE 415 AE in 315 Patients
• 33.8 of All Patients in Post-Marketing
• Serious Visual AE 101 Reports in 66 Patients
• Counts FgtM, Age (lt40, 40-55, gt55)
• Severe Visual Effects ADL
• Most (gt75) Recovered
• Limited Information in Passive Reports

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Foreign Post-Marketing

• Hepatic AE - 90 Reports in 43 Patients
• 24 Female 16 Male
• Patterns of Liver Injury
• Most Unclear (24/43)
• Cholestatic (12) and Cytolytic (5)
• Limited Data for Causality
• 1 Death Multiple Confounding Factors
• Hep. A, Q Fever, High-Dose Acetaminophen

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Foreign Post-Marketing

• Exacerbations of Myasthenia Gravis
• 13 Patients Likely Cases
• 6 Patients Probable Cases
• Sx Varied from Ptosis/Weakness to Respiratory
  Failure

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US Approval

• Approved on April 1, 2004 (400 mg Tabs)
• Indications for mild to moderate CAP (including
  MDRSP), ABS and AECB
• Warnings QT Effects, Myasthenia Gravis
  Exacerbation, and C. difficile Colitis
• Precautions Hepatic Dysfunction, Visual AE
  (Driving Precautions), Drug Interactions

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US Post-Marketing

• Continued Monitoring
• 300 mg Tablets for Patients with Severe Renal
  Impairment
• Labeling Supplement Appendix E
• Precautions Syncope Usually with Vagal Syndrome
  (Driving)
• 56 Reports in Syncope/LOC Preferred Terms as of
  July 1, 2004
• Reduced to 11 Cases after Review

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Back-Up Slides
Return to meeting agenda.
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QT Prolongation Study (1063)

• Elderly Patients with Renal Impairment
• A Ketoconazole 400 mg QD alone
• B Ketoconazole Telithromcyin 800 mg QD
• C Ketoconazole Clarithromycin 500 mg BID
• 1.6 Fold Increase in Cmax of Telithromycin
• 2.7 Fold Increase in AUC of Telithromycin
• Change in QTc(N) from Day -1 to Day 5
• A -4.5 msec
• B 6.5 msec
• C 11.7 msec

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Acute Sinusitis
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Return

• Return to meeting agenda.

Anti-Infective Drugs Advisory Committee in Joint
Session with the Drug Safety and Risk Management
Advisory Committee. December 14 15, 2006