FDA Advisory Committee April 26, 2001

5/22/01


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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 3–Keto 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

Author: Michael Worsham