CENTER FOR DRUG EVALUATION AND
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` RESEARCH
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`APPLICATION NUMBER:
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`211672Orig1s000
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`211673Orig1s000
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` MULTI-DISCIPLINE REVIEW
`Summary Review
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`Office Director
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`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
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`

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` NDA/BLA Multi-disciplinary Review and Evaluation {NDA 211672 and NDA 211673}
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` {XENLETA / lefamulin injection and tablets}
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` Community-Acquired Bacterial Pneumonia (CABP) in adults
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` 53084003 |Bacterial pneumonia (disorder)|
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` Approval
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` Community-Acquired Bacterial Pneumonia (CABP) in adults
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` 53084003 |Bacterial pneumonia (disorder)|
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` NDA/BLA Multi-Disciplinary Review and Evaluation
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` Application Type NDA
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` Application Number(s) 211672, 211673
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` Priority or Standard Priority
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` Submit Date(s) 19 December 2018
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` Received Date(s) 19 December 2018
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` PDUFA Goal Date 19 August 2019
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` Division/Office DAIP/OAP
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` Review Completion Date 12 August 2019
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` Established/Proper Name Lefamulin
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` (Proposed) Trade Name XENLETA
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` Pharmacologic Class Pleuromutilin
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` Code name BC-3781
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` Applicant Nabriva Therapeutics
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` Dosage form 150 mg for injection and 600 mg oral tablet
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` Applicant proposed Dosing
` 150 mg IV every 12 hours; 600 mg PO every 12 hours
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` Regimen
`Applicant Proposed
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` Indication(s)/Population(s)
`Applicant Proposed
` SNOMED CT Indication
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` Disease Term for each
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` Proposed Indication
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` Recommendation on
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` Regulatory Action
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` Recommended
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` Indication(s)/Population(s)
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` (if applicable)
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` Recommended SNOMED
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` CT Indication Disease
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` Term for each Indication
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`(if applicable)
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` Recommended Dosing
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` Regimen
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` 150 mg IV every 12 hours; 600 mg PO every 12 hours
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`Version date: October 12, 2018
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`i
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`Reference ID: 4478662Reference ID: 4480095
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`

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` NDA/BLA Multi-disciplinary Review and Evaluation {NDA 211672 and NDA 211673}
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` {XENLETA / lefamulin injection and tablets}
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` Table of Contents
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` Table of Contents.............................................................................................................................ii
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` Table of Tables ................................................................................................................................vi
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` Table of Figures.............................................................................................................................xiii
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`Reviewers of Multi-Disciplinary Review and Evaluation ................................................................ 1
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`Glossary........................................................................................................................................... 6
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`Executive Summary ................................................................................................................. 8
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`Product Introduction........................................................................................................ 8
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`Conclusions on the Substantial Evidence of Effectiveness .............................................. 8
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`Benefit-Risk Assessment .................................................................................................. 9
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`Patient Experience Data................................................................................................. 14
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`Therapeutic Context .............................................................................................................. 15
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`Analysis of Condition...................................................................................................... 15
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`Analysis of Current Treatment Options ......................................................................... 16
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`Regulatory Background ......................................................................................................... 17
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` U.S. Regulatory Actions and Marketing History............................................................. 17
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` Summary of Presubmission/Submission Regulatory Activity ........................................ 17
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` Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
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` Efficacy and Safety................................................................................................................. 18
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` Office of Scientific Investigations (OSI) .......................................................................... 18
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` Product Quality .............................................................................................................. 18
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`Clinical Microbiology ...................................................................................................... 19
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`Final Clinical Microbiology Recommendations....................................................... 24
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`Nonclinical Pharmacology/Toxicology................................................................................... 26
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`Executive Summary........................................................................................................ 26
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`Referenced INDs, NDAs, BLAs, DMFs ............................................................................. 30
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`Pharmacology................................................................................................................. 30
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`ADME/PK........................................................................................................................ 34
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`Toxicology....................................................................................................................... 40
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`General Toxicology.................................................................................................. 40
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`Genetic Toxicology.................................................................................................. 70
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`Carcinogenicity........................................................................................................ 71
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`Version date: October 12, 2018
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`ii
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`Reference ID: 4478662Reference ID: 4480095
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`

`

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` NDA/BLA Multi-disciplinary Review and Evaluation {NDA 211672 and NDA 211673}
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`
` {XENLETA / lefamulin injection and tablets}
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` Reproductive and Developmental Toxicology........................................................ 71
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` Other Toxicology Studies ........................................................................................ 86
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` Clinical Pharmacology............................................................................................................ 96
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`Executive Summary........................................................................................................ 96
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`Summary of Clinical Pharmacology Assessment............................................................ 97
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`Pharmacology and Clinical Pharmacokinetics ........................................................ 97
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`General Dosing and Therapeutic Individualization................................................. 98
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`Comprehensive Clinical Pharmacology Review ............................................................. 99
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`General Pharmacology and Pharmacokinetic Characteristics................................ 99
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`Clinical Pharmacology Questions.......................................................................... 101
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`Sources of Clinical Data and Review Strategy ..................................................................... 116
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`Table of Clinical Studies................................................................................................ 116
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`Review Strategy............................................................................................................ 118
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`Statistical and Clinical Evaluation ........................................................................................ 118
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`Review of Relevant Individual Trials Used to Support Efficacy.................................... 118
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`Trial 3101 – Study Design...................................................................................... 118
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`Trial 3101 - Study Results...................................................................................... 124
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`Trial 3102 – Study Design...................................................................................... 138
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`Trial 3102 - Study Results...................................................................................... 142
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`Assessment of Efficacy Across Trials..................................................................... 154
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`Integrated Assessment of Effectiveness............................................................... 155
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`Review of Safety........................................................................................................... 156
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`Safety Review Approach ....................................................................................... 156
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`Review of the Safety Database ............................................................................. 156
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`Adequacy of Applicant’s Clinical Safety Assessments .......................................... 159
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`Safety Results........................................................................................................ 160
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`Analysis of Submission-Specific Safety Issues....................................................... 191
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`Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability...... 193
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`Safety Analyses by Demographic Subgroups........................................................ 193
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`Specific Safety Studies/Clinical Trials.................................................................... 195
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`Additional Safety Explorations.............................................................................. 195
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`Safety in the Postmarket Setting ............................................................... 196
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`Version date: October 12, 2018
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`iii
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`Reference ID: 4478662Reference ID: 4480095
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`

`

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`
`
` NDA/BLA Multi-disciplinary Review and Evaluation {NDA 211672 and NDA 211673}
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` {XENLETA / lefamulin injection and tablets}
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` Integrated Assessment of Safety ............................................................... 196
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`Statistical Issues ........................................................................................................... 198
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`Conclusions and Recommendations ............................................................................ 199
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`Advisory Committee Meeting and Other External Consultations....................................... 199
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`Pediatrics ............................................................................................................................. 199
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`Labeling Recommendations ................................................................................................ 201
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`Prescription Drug Labeling ....................................................................................... 201
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`Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 205
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`Postmarketing Requirements and Commitment ................................................................ 205
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`Division Director (DAIP) Comments .................................................................................... 207
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`Office Director Comments................................................................................................... 207
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`Appendices .......................................................................................................................... 208
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`References ................................................................................................................ 208
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`Financial Disclosure .................................................................................................. 209
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`OCP Appendices (Technical Documents Supporting OCP Recommendations)........ 210
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`Nonclinical Studies..................................................................................... 210
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`Clinical Studies ........................................................................................... 215
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`Clinical Appendices................................................................................................... 270
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`Treatment-Emergent Adverse Events Occurring in <1% of Subjects ........ 270
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` Treatment-Emergent Adverse Events Occurring in >2% of Subjects in Study
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`3101 and Study 3102 ...................................................................................................... 274
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` Review of Respiratory Treatment-Emergent Adverse Events from Study
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`2001………….. ................................................................................................................... 274
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` Investigator Assessment of Clinical Response at Test of Cure in Subjects in
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`the Micro-ITT-2 Population with a Baseline Pathogen of S. Pneumoniae...................... 275
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`Clinical Success in Subjects with a Baseline Pathogen of S. pneumoniae
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`Without a Positive Nasopharyngeal (NP) Swab.............................................................. 277
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`Clinical Success in Subjects with Bacteremia............................................. 278
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`Clinical Microbiology Review............................................................................................... 281
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`Activity In Vitro ......................................................................................................... 281
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`Mechanism of Action................................................................................................ 290
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`Resistance................................................................................................................. 292
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`Susceptibility Test Methods and Interpretive Criteria ............................................. 297
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`Animal Models of Infection ...................................................................................... 302
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`Version date: October 12, 2018
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`Reference ID: 4478662Reference ID: 4480095
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`

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`
` NDA/BLA Multi-disciplinary Review and Evaluation {NDA 211672 and NDA 211673}
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` {XENLETA / lefamulin injection and tablets}
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` Pharmacokinetics and Pharmacodynamics.............................................................. 306
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` Human Clinical Trials ................................................................................................ 306
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` Interpretive Criteria.................................................................................................. 315
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` Final Clinical Microbiology Recommendations ........................................................ 317
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`Version date: October 12, 2018
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`v
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`Reference ID: 4478662
`Reference ID: 4480095
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`
`

`

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`
`
` NDA/BLA Multi-disciplinary Review and Evaluation {NDA 211672 and NDA 211673}
`
`
` {XENLETA / lefamulin injection and tablets}
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` Table of Tables
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` Table 1. PSI/PORT Score for CABP Risk Stratification ................................................................... 15
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` Table 2. Summary of Available Antibacterial Drugs for Treatment of CABP................................ 17
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` Table 3. Agency’s MIC Breakpoints for Lefamulin ........................................................................ 22
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`Table 4. CLSI Guideline Acceptable Discrepancy Rate (Without Intermediate Range)................ 22
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`Table 5. Agency’s Disk Interpretive Criteria for Lefamulin........................................................... 24
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`Table 6. Agency’s Interpretive Criteria for Lefamulin................................................................... 26
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`Table 7. Summary of Studies and Major Findings ........................................................................ 34
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`Table 8. Study No. AA97305: Methods......................................................................................... 41
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`Table 9. Study No. AA97305: Observations and Results: Changes From Control ........................ 42
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`Table 10. Study No. AA97305: Toxicokinetic Parameters ............................................................ 43
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`Table 11. Study No. AB21053: Methods....................................................................................... 44
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`Table 12. Study No. AB21053: Observations and Results: Changes From Control ...................... 44
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`Table 13. Study No. AB21053: Toxicokinetic Parameters............................................................. 48
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`Table 14. Study No.
`.289.15: Methods ................................................................................. 49
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`.289.15: Observations and Results: Changes From Control ................ 50
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` Table 15. Study No.
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`.289.15: Group Mean Toxicokinetic Parameters ................................. 52
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` Table 16. Study No.
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`.289.15: Group Mean Toxicokinetic Parameters (Day 1 vs. Day 28) ... 53
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` Table 17. Study No.
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`.289.19: Methods ................................................................................. 54
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` Table 18. Study No.
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`.289.19: Observations and Results: Change From Control .................. 55
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` Table 19. Study No.
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`.289.19: Toxicokinetic Parameters....................................................... 59
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` Table 20. Study No.
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` Table 21. Study No. AB16227: Methods....................................................................................... 60
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` Table 22. Study No. AB16227: Observations and Results: Change From Control........................ 60
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`Table 23. Study No. AB16227: Test Article Toxicokinetic Parameters ......................................... 64
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`Table 24. Study No. AB16227: Metabolite Toxicokinetic Parameters.......................................... 65
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`Table 25. Study No. 8275686: Methods ....................................................................................... 66
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`Table 26. Study No. 8275686: Observations and Results: Changes From Control....................... 66
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`Table 27. Study No. 8275686: Mean Toxicokinetic Parameters of BC-3781 on Day 1................. 68
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`Table 28. Study No. 8275686: Mean Toxicokinetic Parameters of BC-3781 on Day 28............... 68
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`Table 29. Study No. 8275686: Mean Toxicokinetic Parameters of BC-8041 on Day 1................. 68
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`Table 30. Study No. 8275686: Mean Toxicokinetic Parameters of BC-8041 on Day 28............... 69
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`Table 31. Study No. AA97303: Methods....................................................................................... 72
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`Table 32. Study No. AA97303: Observations and Results ............................................................ 72
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`Table 33. Study No. AA97304: Methods....................................................................................... 74
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`Table 34. Study No. AA97304: Observations and Results ............................................................ 74
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`Table 35. Study No. AA97308: Methods....................................................................................... 76
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`Table 36. Study No. AA97308: Observations and Results ............................................................ 76
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`Table 37. Study No. AA97308: Toxicokinetic Parameters ............................................................ 78
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`Table 38. Study No. 82750: Methods ........................................................................................... 79
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`Table 39. Study No. 82750: Observations and Results................................................................. 79
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`Table 40. Study No. AB21312: Methods....................................................................................... 81
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`vi
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`Version date: October 12, 2018
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`Reference ID: 4478662Reference ID: 4480095
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`(b) (4)
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`

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` NDA/BLA Multi-disciplinary Review and Evaluation {NDA 211672 and NDA 211673}
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` {XENLETA / lefamulin injection and tablets}
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`Table 41. Study No. AB21312: Observations and Results ............................................................ 83
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` Table 42. Study No. AB21312: Plasma Concentrations for Dams................................................. 85
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` Table 43. Study No. AB21312: Plasma Concentrations for Pups.................................................. 86
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` Table 44. Study No. AB03683: Methods....................................................................................... 89
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`Table 45. Study No. AB03683: Observations and Results ............................................................ 89
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`Table 46. Study No. AB03683: Toxicokinetic Parameters............................................................. 91
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`Table 47. Potentially Genotoxic Impurities for Lefamulin............................................................ 93
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`Table 48. Recommended Dosages of Lefamulin for Patients With Hepatic Impairment............. 96
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`Table 49. Summary of the Clinical Pharmacokinetics of Lefamulin (LEF)..................................... 97
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`Table 50. Summary of Pharmacologic Activity and Clinical Pharmacology.................................. 99
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`Table 51. Lefamulin Exposure Across Hepatic Stages................................................................. 107
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`Table 52. LEF Plasma Protein Binding as a Function of Time After the Beginning of Infusion... 107
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`Table 53. Composition Comparison Between Phase 3 LEF Tablets and To-Be-Marketed LEF
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`Tablets ......................................................................................................................... 114
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`Table 54. Listing of Clinical Trials ................................................................................................ 116
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`Table 55. Trial 3101: Composition of Intention-to-Treat Analysis Sets...................................... 125
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`Table 56. Trial 3101: Study Withdrawals and Treatment Discontinuations in the ITT Analysis Set
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`Table 57. Trial 3101: Significant Protocol Deviations in ITT Analysis Set ................................... 126
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`Table 58. Trial 3101: Demographic Characteristics of the ITT Analysis Set................................ 127
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`Table 59. Trial 3101: Baseline Health Status of the ITT Analysis Set.......................................... 128
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`Table 60. Trial 3101: Study Drug Treatment Non-Compliance in the mITT Analysis Set ........... 129
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`Table 61. Trial 3101: Post Study Entry Concomitant Medication Use in the ITT Analysis Set.... 129
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`Table 62. Trial 3101: Post-Study Entry Concomitant Systemic Antibacterial Medication Use in
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`the ITT Analysis Set...................................................................................................... 130
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`Table 63. Trial 3101: Results of Analyses of Early Clinical Response (ECR) in ITT Analysis Set .. 131
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`Table 64. Trial 3101: Indeterminate Data Values in Secondary Efficacy Endpoints................... 132
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`Table 65. Trial 3101: Results of Analyses of Secondary Efficacy Endpoints ............................... 133
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`Table 66. Trial 3101: By-Pathogen IACR at TOC in the MicroITT Analysis Set............................ 134
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`Table 67. Trial 3101: Patterns of Treatment Success at ECA, TOC, and LFU Visits in the ITT
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`Analysis Set.................................................................................................................. 135
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`Table 68. Trial 3101: Early Clinical Response (ECR) Rates in Demographic Subgroups of the ITT
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`Analysis Set.................................................................................................................. 136
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`Table 69. Trial 3101: Early Clinical Response (ECR) Rates in Baseline Health Status Subgroups of
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`the ITT Analysis Set...................................................................................................... 136
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`Table 70. Trial 3102: Composition of Intention-to-Treat Analysis Sets...................................... 142
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`Table 71. Trial 3102: Study Withdrawals and Treatment Discontinuations in the ITT Analysis Set
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`..................................................................................................................................... 143
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`Table 72. Trial 3102: Significant Protocol Deviations in ITT Analysis Set ................................... 144
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`Table 73. Trial 3102: Demographic Characteristics of the ITT Analysis Set................................ 144
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`Table 74. Trial 3102: Baseline Health Status of the ITT Analysis Set.......................................... 145
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`Table 75. Trial 3102: Post Study Entry Concomitant Medication Use in the ITT Analysis Set.... 146
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`Version date: October 12, 2018
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`vii
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`Reference ID: 4478662Reference ID: 4480095
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`

`

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`
` NDA/BLA Multi-disciplinary Review and Evaluation {NDA 211672 and NDA 211673}
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`Table 76. Trial 3102: Post Study Entry Concomitant Systemic Antibacterial Medication Use in
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`the ITT Analysis Set...................................................................................................... 147
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` Table 77. Trial 3102: Results of Analyses of Early Clinical Response (ECR) on ITT Analysis Set . 148
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` Table 78. Trial 3102: Indeterminate Data Values in Secondary Efficacy Endpoints................... 149
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`Table 79. Trial 3102: Results of Analyses of Secondary Efficacy Endpoints ............................... 149
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`Table 80. Trial 3102: By-pathogen IACR by TOC Results in the MicroITT Analysis Set............... 150
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`Table 81. Trial 3102: Patterns of Treatment Success at ECA, TOC, and LFU Visits in the ITT
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`Analysis Set.................................................................................................................. 151
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`Table 82. Trial 3102: Early Clinical Response (ECR) Rates in Demographic Subgroups of the ITT
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`Analysis Set.................................................................................................................. 152
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`Table 83. Trial 3102: Early Clinical Response (ECR) Rates in Baseline Health Status Subgroups of
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`the ITT Analysis Set...................................................................................................... 153
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`Table 84. Investigator-Assessed Clinical Response Rates at TOC by Baseline Pathogen in Trial
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`3101 and Trial 3102 (MicroITT Analysis Set)............................................................... 155
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`Table 85. Safety Database for the Lefamulin Development Program........................................ 157
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`Table 86. Demographic and Other Baseline Patient Characteristics of Pool 3 (Phase 3 Safety
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`Population) by Actual Arm .......................................................................................... 158
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`Table 87. Summary of Deaths in the Phase 3 Safety Population ............................................... 160
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`Table 88. Treatment-Emergent Serious Adverse Events in the Phase 3 Safety Population by
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`System Organ Class and Preferred Term .................................................................... 168
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`Table 89. Dropouts and Discontinuations Due to Treatment-Emergent Adverse Events in the
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`Phase 3 Safety Population by System Organ Class and Preferred Term..................... 178
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`Table 90. Treatment-Emergent Adverse Events in the Phase 3 Safety Population by Study,
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`Treatment Group, and System Organ Class ................................................................ 181
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`Table 91. Treatment-Emergent Adverse Events Occurring in >1% of Subjects by Preferred Term
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`in the Phase 3 safety population................................................................................. 182
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`Table 92. Treatment-Emergent Adverse Events in the Gastrointestinal Disorders SOC Occurring
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`in >3 Subjects Overall by Preferred Term in the Phase 3 Safety Population.............. 183
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`Table 93. Treatment-Emergent Adverse Events in the Infections and Infestations SOC Occurring
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`in >3 Subjects Overall by Preferred Term in the Phase 3 Safety Population.............. 183
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`Table 94. Clinical Data on 12 Subjects With TEAEs of Pneumonia in the Phase 3 Safety
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`Population ................................................................................................................... 185
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`Table 95. Microbiological Data on 12 Subjects With TEAEs of Pneumonia in the Phase 3 Safety
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`Population ................................................................................................................... 187
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`Table 96. Treatment-Emergent Adverse Events in the Investigations SOC Occurring in >3
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`Subjects Overall by Preferred Term in the Phase 3 Safety Population....................... 188
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`Table 97. Subjects With Potentially Clinically Significant (PCS) Laboratory Parameters of Interest
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`by Treatment Arm in the Phase 3 Safety Population.................................................. 189
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`Table 98. Measures of Post-Baseline QTcF Prolongation in the Phase 3 Safety Population...... 192
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`Table 99. Measures of Post-Baseline QTcF Prolongation in Phase 2 Study in ABSSSI (2001) .... 193
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`Table 100. Proportion of Subjects with at least one TEAE by Demographic Subgroups in the
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`Phase 3 Safety Population........................................................................................... 194
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`Table 101. Significant High-Level Labeling Changes (Not Direct Quotations)............................ 201
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`viii
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`Version date: October 12, 2018
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`Reference ID: 4478662Reference ID: 4480095
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` NDA/BLA Multi-disciplinary Review and Evaluation {NDA 211672 and NDA 211673}
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` {XENLETA / lefamulin injection and tablets}
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`Table 102. Human In Vitro LEF Plasma Protein Binding Comparison Between Studies............. 211
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` Table 103. In Vitro Assessment of Lefamulin as a Substrate, Inhibitor, or Inducer of Metabolism
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`..................................................................................................................................... 212
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` Table 104. In Vitro Assessment of Lefamulin as a Substrate or Inhibitor of Human Uptake and
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`Efflux Transporters ...................................................................................................... 213
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` Table 105. Observed Free-Druga AUCb/MIC Targets in Neutropenic Lung-Infected Mice......... 215
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` Table 106. LEF PK Parameters Following Single IV Dose ............................................................ 217
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` Table 107. Summary of Dose Proportionality; Statistical Analyses (One-Way ANOVA) ............ 217
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` Table 108. LEF PK Parameters in Various Body Compartments Following Single IV 1-hr Infusion
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` of 150 mg LEF .............................................................................................................. 217
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` Table 109. LEF PK Parameters Following Single Oral Dose........