AVELOX? (moxifloxacin HCl)NDA # 21-085

3/6/00

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Agenda

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FDA Advisory Committee

Overview

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Rationale for Development

Decreasing Penicillin/Macrolide Susceptibility of S. pneumoniae in the US

Rationale for the Design of Moxifloxacin

Chemical Structure of Moxifloxacin

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In Vitro Activity of Moxifloxacin Against Key RTI Pathogens

In Vitro Activity of Moxifloxacin Against Other RTI Pathogens

In Vitro Activity of Moxifloxacin Against Other Pathogens

Moxifloxacin MIC90 for S. pneumoniae is Unaffected by Resistance to Penicillin

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Mechanisms of Resistance and Quinolones

Differential Emergence of Resistance Between Levofloxacin and Moxifloxacin (S. pneumoniae 4241)

Differential Emergence of Resistance Between Levofloxacin and Moxifloxacin(S. aureus 133)

No Development of Moxifloxacin Resistance in Rat Granuloma Pouch Model

Moxifloxacin: Minimization of the Emergence of Resistance Summary

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Pharmacokinetics of Moxifloxacin Support Once Daily Oral Dosing of 400 mg

Moxifloxacin and Levofloxacin Concentrations in Plasma and Respiratory Tissue

Moxifloxacin Pharmacokinetics/Pharmacodynamics

Cmax/MIC90* Data for Selected Quinolones^

AUC/MIC90* Data for Selected Quinolones^

Summary of Moxifloxacin PK/PD Attributes

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Phase II/Phase III Clinical Development Program

Phase II/Phase III Clinical Development Program (continued)

Phase II/III Studies* of Moxifloxacin in Patients with Infectious Diseases

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Acute Sinusitis (Ex-North America)

Acute Sinusitis: Pathogen Eradication Rates at Test-of-Cure Visit*

Conclusions for Acute Sinusitis

Moxifloxacin NDAPhase IIIAcute Exacerbation ofChronic Bronchitis (AECB)Clinical Program

AECB: (North America and Ex-North America)

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Conclusions for Acute Exacerbation of Chronic Bronchitis

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Community-Acquired Pneumonia: Pathogen Eradication Rates* by Culture at Test-of-Cure

Summary and Conclusions for CAP

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Uncomplicated Skin and SkinStructure Infections

Uncomplicated SSSI: Pathogen Eradication Rates* in Microbiologically Evaluable Patients:

Summary and Conclusions for Skin and Skin Structure Infections

Proposed Indications and Durations Dose: Moxifloxacin 400 Mg QD

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Penicillin intermediate and resistant isolates of S. pneumoniae from pivotal trials (400 mg moxifloxacin and control)

Activity of Moxifloxacin Against Drug-Resistant S. pneumoniae

Outcome Analysis: Acute Exacerbation Chronic Bronchitis/Community Acquired Pneumonia

Outcome Analysis: Worsening of Respiratory Conditions Resulting In Hospitalization (AECB and CAP Studies)

Efficacy Conclusions

Review ofMoxifloxacin Safety Profile

Moxifloxacin Safety and Tolerability: Dosing and Metabolism

Moxifloxacin Safety and Tolerability: Drug Interactions

Moxifloxacin Safety Profile

Safety Procedures

Moxifloxacin Safety Profile

Patient Exposure to Moxifloxacin and Comparators

Incidence of Adverse Events of Body System: Controlled Studies with 400 mg Moxifloxacin and Control: All Indications (Worldwide)*

Premature Discontinuations Due to Adverse Events: Moxifloxacin 400 mg and Controlled Studies (Worldwide)*

Incidence of Serious Adverse Events in Patients Valid for Safety Analysis*

Adverse Event Profile: Controlled Trials

Mortality Rates* Moxifloxacin 400 mg Controlled Studies (Worldwide)

Selected Events Associated with Some Quinolones

Preclinical/Phase I Hepatic Safety

Incidence Rates of Lab Abnormalities: (LFTs) 400mg Moxifloxacin vs Control Pool: Controlled Studies (Worldwide)

Moxifloxacin: Summary of Safety

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Conclusions

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MOXIFLOXACIN AND THE QT INTERVAL

Introduction

Why is QTc Prolongation an Issue?

Moxifloxacin and the QTc Interval: Presentation

ECG Complexes and Intervals

QT Interval and Heart Rate Correction

Action Potential and Potassium Currents

Moxifloxacin Preclinical Studies

Preclinical StudiesArrhythmia Models

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Moxifloxacin Effects on QTc: Clinical Studies

Mean + S.D. QTc Change from Baseline (msec): All Comparative Studies

Antibiotics with QTc Prolongation:Clinical Studies

QTc versus Moxifloxacin Concentration Phase I Data at Cmax

Committee for Proprietary Medicinal Products (CPMP) Criteria

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Effects of Moxifloxacin on QTc Dispersion (Phase I)

Reverse Rate Dependency

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Summary of ECG Risk Factors for QT Prolongation in Moxifloxacin Studies

QT Prolongation-Associated Clinical Risk Factors

Clinical Risk Factors

Clinical Risk Factors: Drug Interactions

Moxifloxacin Drug Interaction Studies

Clinical Risk Factors

Summary: Clinical Risk Factors for QT Prolongation in Moxifloxacin Studies

Is There an Increased Risk for Cardiovascular AEs in Patients Who Are QTc Outliers?

Incidence of Treatment-Emergent Clinical AEs Considered Surrogates for QTc Prolongation

Deaths in Moxifloxacin Clinical Development Program in Relation to Therapy

Moxifloxacin and the QTc Interval: Conclusions

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Proposed QT Labeling

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Author: Steve Turner

AVELOX? (moxifloxacin HCl) NDA # 21-085

3/6/00

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Table of Contents

AVELOX? (moxifloxacin HCl)NDA # 21-085