Anti-Infective Advisory Committee March 24, 2000

3/28/00


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Table of Contents

Anti-Infective Advisory Committee March 24, 2000

Pharmacia & Upjohn is Seeking Approval of Linezolid for:

Linezolid - Presentation Agenda

Most Common Nosocomial Blood Culture Isolates (US Hospitals)

Increasing Incidence of Resistance in the US MRSE, MRSA, VRE, PRSP, GISA 1980-1999

Limitations of Current Antibiotics for Serious Gm+ Infections

New Antibacterials are Required to Treat Gm+ Bacterial Infections

Linezolid: First Antibacterial from a New Structural Class

Linezolid Profile

Linezolid : Unique Site of Action

Linezolid Profile (cont.)

Efficacy - Phase III Studies in Adults

In Vitro Susceptibility Database

Streptococci: Preclinical Summary

S. pneumoniae Sentry and Phase III Data

Staphylococci: Preclinical Summary

S. aureus Sentry and Phase III Data

Enterococci: Preclinical Summary

Enterococcus spp Sentry and Phase III Data

Laboratory Prediction of Resistance Mechanism

Characterization of Lab-derived Mutants

Linezolid Efficacious in Key Animal Models

Summary

Linezolid - Presentation Agenda

Steady-State Plasma Concentrations Linezolid PO 600 mg BID (Mean ? SD, N=16)

Linezolid Absolute Bioavailability After a Single IV or Oral 375 mg Dose (Mean ? SD, N = 12)

Clinical Pharmacology

Linezolid Metabolism

Linezolid Elimination

Clinical Pharmacology Summary

PPT Slide

Efficacy - Phase III Studies in Adults

Complicated SST (55)

Clinical Cure Complicated SST (55)

Pathogen Eradication Rates Complicated SST (55)

Uncomplicated SST (39A)

Clinical Cure Uncomplicated SST (39A)

Pathogen Eradication Rates Uncomplicated SST (39A)

Conclusions: SST

Efficacy - Phase III Studies in Adults

Patients Hospitalized with CAP (33)

Clinical Cure Patients Hospitalized with CAP (33)

Pathogen Eradication Rates Hospitalized CAP (33)

Outpatients with CAP (51)

Clinical Cure Outpatients with CAP (51)

Pathogen Eradication Rates Outpatient CAP (51)

Nosocomial Pneumonia (48A)

Clinical Cure Nosocomial Pneumonia (48A)

Pathogen Eradication Rates Nosocomial Pneumonia (48A)

Conclusions: Pneumonia

Efficacy - Phase III Studies in Adults

Methicillin-Resistant Staphylococcus (31)

Primary Source of Infection (31)

Clinical Cure - All Patients (31)

Clinical Cure - Complicated SST (31)

Clinical Cure - Nosocomial Pneumonia (31)

MRSA Pathogen Eradication (31)

VRE Study Design Considerations

VRE (54A, 54)

VRE - Primary Infection Source

Clinical Cure VRE (54A)

Clinical Cure - Interim Results VRE (54)

Clinical Cure (CE) by Diagnosis VRE (54A)

Clinical Cure (CE) by Diagnosis - Interim Results VRE (54)

Microbiologic Outcome (ME) in VRE (54A)

Compassionate Use (25)

Clinical Cure (CE) Compassionate Use (25)

Conclusions: VRE

Efficacy Conclusions

Resistance Surveillance

Resistance Development

PPT Slide

Early Development Issues

Drug Interactions with MAOIs

Phase I MAOI Studies

Linezolid - Phenylpropanolamine Systolic BP Effects

Phase II Analysis of Potential MAOI-Related Drug Interactions

Phase II MAOI Experience

Phase III Analysis of Potential MAOI-Related Drug Interactions

Phase III MAOI Experience

Blood Pressure Measurements in Phase III Patients with Concomitant MAOI Potentiators

MAOI Conclusions

Safety - Phase III Comparator-Controlled Studies

All AEs ? 2% (1 of 2) Phase III Comparator-Controlled Studies

All AEs ? 2% (2 of 2) Phase III Comparator-Controlled Studies

Drug-Related AEs ? 1% Phase III Comparator-Controlled Studies

Most Common Serious AEs Phase III Comparator-Controlled Studies

Laboratory Assessments

Percent of Patients with Chemistry Assays ? 2 Times Upper Limit of Normal

Cumulative Percentage Over Time - Patients With at Least One Substantially High ALT Value

ALT Values for Linezolid-Treated Patients with Substantially High Values

ALT Values for Comparator-Treated Patients with Substantially High Values

Percent of Patients with Hematology Assays < 75% of Lower Limit of Normal*

Cumulative Percentage Over Time - Patients With at Least One Substantially Low Platelet Count

Platelet Counts for Linezolid-Treated Patients with Substantially Low Values

Platelet Counts for Comparator-Treated Patients with Substantially Low Values

Platelet Conclusions

Safety Conclusions

Linezolid - Presentation Agenda

Linezolid Pediatric Drug Development

Linezolid - Pediatric Use Development Program

Linezolid - Pediatric Use Clinical Pharmacokinetics

Linezolid - Pediatric Use Phase II Study Design

Linezolid - Pediatric Use Most Common Drug-Related Adverse Events

Linezolid - Pediatric Use All Reported Serious Adverse Events

Linezolid - Pediatric Use Conclusions

Linezolid - Presentation Agenda

Linezolid Conclusions

Pharmacia & Upjohn is Seeking Approval of Linezolid for:

Author: W Gary Tarpley