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Shionogi Briefing Document ANTIMICROBIAL DRUGS ADVISORY COMMITTEE CEFIDEROCOL BRIEFING DOCUMENT NDA # 209445 Advisory Committee Meeting October 16, 2019 300 Campus Drive Florham Park, NJ 07932 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Shionogi Inc. NDA # 209445 Cefiderocol Advisory Committee Briefing Document TABLE OF CONTENTS TABLE OF CONTENTS .....................................................................................................2 LIST OF TABLES ...............................................................................................................6 LIST OF FIGURES .............................................................................................................9 LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................11 1 EXECUTIVE OVERVIEW .......................................................................................15 2 INTRODUCTION .....................................................................................................20 3 MEDICAL NEED ......................................................................................................22 3.1 Complicated Urinary Tract Infections ...........................................................22 3.2 Carbapenem-Resistant cUTI ..........................................................................23 3.3 Mechanisms of Carbapenem Resistance ........................................................24 3.4 Recent Antibiotic Development .....................................................................25 3.5 Medical Need Conclusions ............................................................................26 4 CEFIDEROCOL MECHANISM OF ACTION ........................................................28 5 MICROBIOLOGY AND SURVEILLANCE ............................................................30 5.1 Susceptibility Analyses from Surveillance Studies .......................................30 5.2 Molecular Analysis of Carbapenem Resistance-Related Genes ....................34 5.3 Investigations of the Potential Development of Resistance ...........................34 5.4 Microbiology and Surveillance Conclusions .................................................35 6 NONCLINICAL EFFICACY AND PHARMACOKINETIC/ PHARMACODYNAMIC ASSESSMENTS .............................................................36 6.1 PK/PD Parameter for Therapeutic Efficacy ...................................................36 6.2 Rat Lung Infection Model Based on Human Exposure Profile .....................37 6.3 Murine Thigh Infection Model Based on Human Exposure Profile ..............39 6.4 Human PK Profiles and Recommendation for Extended Infusion ................41 6.5 Probability of Target Attainment ...................................................................42 6.6 Conclusions of Nonclinical Efficacy and Pharmacokinetic/Pharmacodynamic Assessments ........................................44 7 NONCLINICAL SAFETY AND TOXICOLOGY ...................................................45 7.1 Effect on the Central Nervous System ...........................................................45 7.2 Effect on the Cardiovascular System .............................................................46 7.3 Toxicology Studies ........................................................................................48 7.4 Nonclinical Safety Conclusions .....................................................................50 8 CLINICAL PHARMACOLOGY ..............................................................................51 8.1 Key Findings for the Clinical Pharmacology of Cefiderocol ........................52 8.2 Population Pharmacokinetics with Patients in the Phase 1 Studies, the Phase 2 cUTI Study, and the Phase 3 CREDIBLE-CR Study .......................55 8.2.1 Population PK Model .............................................................................55 Page 2 of 375 Shionogi Inc. NDA # 209445 Cefiderocol Advisory Committee Briefing Document 8.2.2 Comparison of Exposure of Cefiderocol among Patients with Various Levels of Renal Function .......................................................................57 8.3 Proposed Dosing Regimens for Cefiderocol ..................................................57 8.4 Clinical Pharmacology Conclusions ..............................................................58 9 CUTI STUDY ............................................................................................................60 9.1 cUTI Study Design ........................................................................................60 9.2 Efficacy Endpoints .........................................................................................61 9.3 Study Disposition ...........................................................................................62 9.4 Demographic and Baseline Characteristics ...................................................63 9.5 cUTI Efficacy Results ....................................................................................66 9.5.1 Primary Endpoint Analysis ....................................................................66 9.5.2 Secondary Endpoint Outcome Analyses ................................................67 9.5.2.1 Response Rate in the ME Population ............................................67 9.5.2.2 Response Rate in Sensitivity Analyses and Subgroups .................67 9.5.2.3 Response Rate by Time Point ........................................................69 9.5.2.4 Per-Pathogen Analyses ..................................................................71 9.5.2.5 Analysis of Clinical Outcome by Patient-Reported Symptoms ....71 9.5.3 Efficacy Conclusions of the cUTI Study ...............................................71 9.6 cUTI Safety Findings .....................................................................................72 9.6.1 Exposure ................................................................................................72 9.6.2 Patient Disposition .................................................................................72 9.6.3 Baseline Characteristics and Demographics in the Safety Population ..73 9.6.4 Adverse Events ......................................................................................75 9.6.4.1 Overall Adverse Events .................................................................75 9.6.4.2 Common Adverse Events ..............................................................76 9.6.4.3 Treatment-Related Adverse Events ...............................................77 9.6.4.4 Serious Adverse Events .................................................................79 9.6.4.5 Safety in Subgroups .......................................................................81 9.6.4.6 Adverse Events of Interest .............................................................81 9.6.5 Resistance to Cefiderocol ......................................................................83 9.6.6 Safety Conclusions of the cUTI Study ..................................................83 10 CREDIBLE-CR STUDY ...........................................................................................84 10.1 Study Design ..................................................................................................84 10.2 CREDIBLE-CR Analysis Population and Disposition ..................................87 10.3 CREDIBLE-CR Baseline Characteristics and Demographics .......................88 10.3.1 Demographics ........................................................................................88 10.3.2 Baseline Study Drug Regimen for Gram-negative Pathogens ...............89 10.3.3 Baseline Pathogens ................................................................................91 Page 3 of 375 Shionogi Inc. NDA # 209445 Cefiderocol Advisory Committee Briefing Document 10.4 Duration of Study Drug Treatment ................................................................92 10.5 CREDIBLE-CR Efficacy ...............................................................................93 10.5.1 Study Efficacy Outcome – Clinical Definition ......................................93 10.5.2 Study Efficacy Outcome – Microbiological Definition .........................93 10.5.3 Outcomes by Time point ........................................................................94 10.5.4 Outcomes by Baseline Pathogen ............................................................96 10.5.5 Outcomes by Treatment Regimen .........................................................96 10.6 CREDIBLE-CR Safety ..................................................................................97 10.6.1 Overview of Adverse Events .................................................................97 10.6.2 Adverse Events by Preferred Term Classification .................................98 10.6.3 Treatment-related Treatment-emergent Adverse Events .....................100 10.6.4 Serious Adverse Events .......................................................................101 10.6.5 Treatment-related Serious Adverse Events ..........................................103 10.6.6 Liver-related Adverse Events ..............................................................105 10.6.7 Renal Toxicity According to RIFLE Criteria ......................................106 10.7 CREDIBLE-CR Mortality ...........................................................................106 10.7.1 Adverse Events Leading to Death .......................................................109 10.7.2 External
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