Omadacycline Paratek Pharmaceuticals Antimicrobial Drugs Advisory Committee (AMDAC) Briefing Book 01-July-2018 Omadacycline p-Toluenesulfonate Tablets and Injection For the Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) and Community-Acquired Bacterial Pneumonia (CABP) Briefing Document for: Antimicrobial Drugs Advisory Committee (AMDAC) Meeting Date: 08-Aug-2018 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Page 1 of 124 Omadacycline Paratek Pharmaceuticals Antimicrobial Drugs Advisory Committee (AMDAC) Briefing Book 01-July-2018 TABLE OF CONTENTS TABLE OF CONTENTS .................................................................................................................2 LIST OF TABLES ...........................................................................................................................4 LIST OF FIGURES .........................................................................................................................7 LIST OF ABBREVIATIONS ..........................................................................................................8 1 INTRODUCTION ..................................................................................................................11 1.1 Unmet Need .......................................................................................................................11 1.1.1 Acute Bacterial Skin and Skin Structure Infections ....................................................12 1.1.2 Community-Acquired Bacterial Pneumonia ................................................................13 1.2 Pharmacokinetics ...............................................................................................................14 1.2.1 Distribution, Metabolism, Excretion............................................................................16 1.2.2 Effect of Hepatic and Renal Dysfunction on Pharmacokinetics ..................................16 1.2.3 Effect of Age and Gender on Pharmacokinetics ..........................................................17 1.2.4 Effect of Food on Oral Absorption ..............................................................................17 1.2.5 Drug-Drug and Other Interactions ...............................................................................17 1.3 Microbiology......................................................................................................................18 1.4 Pharmacokinetics/Pharmacodynamics ...............................................................................19 1.4.1 Population Pharmacokinetics .......................................................................................19 1.4.2 Pharmacokinetics-Pharmacodynamics and Dose Justification ....................................19 1.5 Nonclinical Studies ............................................................................................................23 1.6 Clinical Development Program ..........................................................................................23 2 EFFICACY IN ABSSSI .........................................................................................................24 2.1 Study Designs ....................................................................................................................24 2.1.1 Selection of Patients .....................................................................................................26 2.1.1.1 OASIS-1 (iv Followed by Oral) .............................................................................26 2.1.1.2 OASIS-2 (Oral Only) .............................................................................................27 2.2 Efficacy Analysis ...............................................................................................................27 2.3 Study Populations in the Pivotal Phase 3 Studies in ABSSSI ...........................................28 2.4 Efficacy Results in the Pivotal Phase 3 ABSSSI Studies ..................................................28 2.4.1 Primary Efficacy Analysis ...........................................................................................28 2.4.2 Secondary and Additional Analyses ............................................................................30 2.4.2.1 Investigator Assessment of Clinical Response ......................................................30 2.4.2.2 Clinical Response in Microbiologic Populations ...................................................31 2.4.2.3 Clinical Response by Pathogen ..............................................................................32 2.4.2.4 Microbiological Outcomes.....................................................................................34 2.5 Subpopulation Analyses.....................................................................................................35 2.6 Efficacy Conclusions in ABSSSI.......................................................................................36 3 EFFICACY IN CABP ............................................................................................................37 3.1 Study Design ......................................................................................................................37 3.1.1 Selection of Patients .....................................................................................................38 Page 2 of 124 Omadacycline Paratek Pharmaceuticals Antimicrobial Drugs Advisory Committee (AMDAC) Briefing Book 01-July-2018 3.1.1.1 Key Inclusion Criteria ............................................................................................38 3.1.1.2 Key Exclusion Criteria ...........................................................................................39 3.2 Efficacy Analysis ...............................................................................................................40 3.3 Study Population ................................................................................................................42 3.4 Microbiology......................................................................................................................46 3.5 Efficacy Results in the Pivotal Phase 3 Study in CABP ....................................................46 3.5.1 Primary Efficacy Analysis ...........................................................................................46 3.5.2 Secondary and Additional Analyses ............................................................................47 3.5.2.1 Investigator Assessment of Clinical Response ......................................................47 3.5.2.2 Clinical Response by Pathogen ..............................................................................49 3.5.2.3 Microbiological Outcomes.....................................................................................53 3.5.2.4 Clinical Response in Microbiologic Populations ...................................................54 3.5.2.5 CABP Signs and Symptoms ..................................................................................56 3.5.2.6 Subgroup Analyses ................................................................................................58 3.6 Efficacy Conclusions in the Pivotal Phase 3 Study in CABP ............................................62 4 SAFETY IN THE PIVOTAL PHASE 3 STUDIES ...............................................................62 4.1 Extent of Exposure .............................................................................................................62 4.2 Adverse Events ..................................................................................................................65 4.2.1 Overall Summary of TEAEs ........................................................................................65 4.2.2 Frequent TEAEs...........................................................................................................67 4.3 Serious Adverse Events .....................................................................................................69 4.4 Cardiac Safety ....................................................................................................................70 4.5 Liver Safety ........................................................................................................................75 4.6 Mortality ............................................................................................................................75 4.6.1 Mortality Across the Clinical Development Program .................................................75 4.6.1.1 Mortality in ABSSSI ..............................................................................................76 4.6.1.2 Mortality in CABP .................................................................................................77 4.6.1.3 Causes of Death in CABP ......................................................................................78 4.6.1.4 Mortality-Associated Safety Analyses ...................................................................79 4.6.1.5 Mortality in OPTIC - Discussion ...........................................................................80 4.7 Safety Conclusions.............................................................................................................82 5 BENEFIT RISK DISCUSSION .............................................................................................83 5.1 Benefits ..............................................................................................................................83