Table of Contents
FDA Advisory Committee April 26, 2001
Telithromycin Presentation Agenda
Need for New Antibiotics in Respiratory Tract Infections
Pathogens of Community RTIs in 2001
Recognition of Clinical Relevance of Penicillin Resistance
Recognition of Clinical Relevance of Erythromycin-Resistant S. pneumoniae
Evolution of Resistance of S. pneumoniae to Erythromycin in the US
Therapy of RTI
Telithromycin
Telithromycin Proposed Indications
Telithromycin Presentation Agenda
Telithromycin
Benefits of the 3Keto Function
Benefits of Carbamate Residue and Side Chain at Position C11 C12
Telithromycin: Mode of Action
Inhibition of Protein Synthesis (1)
Inhibition of Protein Synthesis (2)
Ribosomal Depletion
Consequence of Double Binding to 23S rRNA
Telithromycin Activity Against Erythromycin A-Resistant S. pneumoniae
Telithromycin: Antipneumococcal Activity (1)
Telithromycin: Antipneumococcal Activity (2)
Telithromycin: Antipneumococcal Activity Against Resistant Isolates
Telithromycin: Bactericidal Activity
Telithromycin: In Vivo Antipneumococcal Activity
Antipneumococcal Activity in North American Isolates of S. pneumoniae Resistant to Penicillin G and Erythromycin A
PPT Slide
Intracellular Concentration of Telithromycin in Neutrophils
Microbiology of Telithromycin: Summary (1)
Microbiology of Telithromycin: Summary (2)
Telithromycin Presentation Agenda
Clinical Pharmacology Program
Pharmacokinetics of Oral Telithromycin in Healthy Subjects
Tissue and Fluid Penetration of Telithromycin in Patients
Other Key Pharmacokinetic Features
Pathways of Telithromycin Disposition
Effect of CYP3A4 Inhibition
Effect of Hepatic Impairment
Effect of Hepatic Impairment (Multiple Dose)
Effect of Renal Impairment
Exposure in CAP Patients: Elderly and Non-Elderly (Phase III/Study 3000)
Selection of Telithromycin Dose Regimen (Mouse Thigh Infection Model - Craig)
Selection of Telithromycin Dose Regimen Based on PK/PD Model
Dose Selection: H. influenzae
Summary of Human Pharmacology
Telithromycin Presentation Agenda
Clinical Efficacy of Telithromycin
Telithromycin Dosage Regimens in Phase III Studies
Generalized Study Design
Main Analysis Populations
Clinical Efficacy of Telithromycin
CAP: Phase III Controlled Studies
CAP: Other Studies
CAP: Key Subject Background Characteristics, mITT (Western Studies)
CAP: Clinical Cure at TOC, PPc (Controlled Studies, Western Countries)
CAP: Clinical Cure at TOC, PPc (Uncontrolled Studies, Western Countries)
CAP: Clinical Cure by Pathogen (All Western Studies)
CAP: Clinical Cure for Atypical Pneumonia in Telithromycin Subjects (All Western Studies)
CAP: Clinical Cure by Risk Factors for Morbidity (Western Studies)
CAP: Clinical Cure for S. pneumoniae-Resistant Isolates in Subjects Treated with Telithromycin
CAP: Clinical Cure for Subjects with Pneumococcal Bacteremia (Treatment with Telithromycin, All Western Studies)
Summary of Efficacy in CAP
Clinical Efficacy of Telithromycin
AECB: Phase III Studies
AECB: Clinical Cure at TOC, PPc
AECB: Clinical Cure by Pathogen (Both Studies)
AECB: Clinical Cure for Atypical Pathogens (Both Studies)
AECB: Clinical Cure by Baseline Characteristics (Both Studies)
Summary of Efficacy in AECB
Clinical Efficacy of Telithromycin
Acute Sinusitis: Phase III Studies
Acute Sinusitis: Clinical Cure at TOC, PPc
Acute Sinusitis: Clinical Cure by Pathogen (All Studies)
Acute Sinusitis: Clinical Cure for S. pneumoniae-Resistant Isolates in Subjects Treated with Telithromycin (All Studies)
Summary of Efficacy in Acute Sinusitis
Clinical Efficacy of Telithromycin
Tonsillitis/Pharyngitis: Phase III Studies
Tonsillitis/Pharyngitis: Bacterial Eradication by Subject at TOC, PPb (Both Studies)
Summary of Efficacy in Tonsillitis/Pharyngitis
Summary of Efficacy in RTIs (1)
Summary of Efficacy in RTIs (2)
Safety Results
Subjects (%) in Phase III Safety Population
Subjects (%) with Treatment-Related Adverse Events (? 2%) (Controlled Phase III Studies)
Subjects (%) with Discontinuations Due to Adverse Events (Controlled Phase III Studies)
Prevalence of Diarrhea for Telithromycin vs Comparator Drugs (Controlled Phase III Studies)
Treatment-Related Adverse Events by Age (Controlled Phase III Studies)
Summary of Mortality (All Phase III Studies)
Serious Adverse Events (Controlled Phase III Studies)
Subject 0502/1069
Hepatic Adverse Events (Controlled Phase III Studies)
Frequency of Subjects with ALT ?3x ULN During Treatment (Controlled Phase III Studies)
Distribution of ALT Values During Treatment in Subjects with Normal ALT at Baseline (Controlled Phase III Studies)
Summary of Phase III Safety
Telithromycin Presentation Agenda
Background
Telithromycin: Preclinical Studies
Plasma Levels and HERG Affinity of Selected Antibiotics
ECG Phase III Analysis
QTc Values at Baseline and On-Therapy for Telithromycin-treated Subjects
?QTc from Baseline and QT Dispersion
?QTc vs Telithromycin Plasma Concentration
?QTc vs Telithromycin Plasma Concentration
Frequency of QTc Outliers (Telithromycin vs Clarithromycin)
Frequency of QTc Outliers (Telithromycin vs Non-macrolides)
Clinical Risk Factors for QTc Prolongation (1)
Clinical Risk Factors for QTc Prolongation (2)
Association Between Baseline QTc and ?QTc
Incidence of Treatment-Related Adverse Events of Special Interest in QT Interval Assessment
Further Characterization of Telithromycin Effect on Cardiac Repolarization
Comparison between Correction Formulas for Heart Rate Effects Using Data Obtained at Baseline (Phase I Data)
Relationship Between ?QTn and Concentration for Telithromycin Doses from 800 to 3200 mg (Phase I Data)
Drug Interactions of Special Interest
Effect of Telithromycin and Ketoconazole on ?QTn
Drug Interaction Between Telithromycin and Cisapride
Effect of Telithromycin on Sotalol-Induced Prolongation of QTn
Study in Subjects with CV Disease: Design/Population
Subjects with CV Disease: Mean Changes in ?QTn and ?QTc
Subjects with CV Disease: ?QTn vs Telithromycin Plasma Concentration
?QTc vs Telithromycin Plasma Concentration in RTI Patients with Cardiovascular Disease (Phase III)
Summary of ECG Analysis (1)
Summary of ECG Analysis (2)
Telithromycin Presentation Agenda
Medical Need for New Antibiotics
Microbiological and PK Features
Summary of Efficacy in Respiratory Tract Infections
Summary of Safety
The Advantages that Telithromycin Brings
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