`
`
`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
` APPLICATION NUMBER:
`
`761169Orig1s000
`
`
` MULTI-DISCIPLINE REVIEW
`
`Summary Review
`
`Clinical Review
`
`Non-Clinical Review
`
`Statistical Review
`
`Clinical Pharmacology Review
`
`
`
`

`

`BLA-761169
`
` Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Applicant
`
`
` Dose form/formulation(s)
`
` Dosing regimen
`
`
`
`
`
` Integrated Review
`
` Table 1. Administrative Application Information
` Application Information
`
` Category
`
`
` Application type
`
` BLA
`
` Application number(s)
`
` BLA 761169
` Priority or standard
`
`
`
` Priority
` Submit date(s)
`
`
`
` 2/25/2020
`
` Received date(s)
`
`
` 2/25/2020
` PDUFA goal date
`
`
` 10/28/2020
` Division/office
`
`
` Division of Antivirals (DAV)
`
` Review completion date
`
` 10/14/2020
`
`
` Established name
` Atoltivimab, maftivimab, and odesivimab-ebgn
` (Proposed) trade name
`
`
` Inmazeb
` Pharmacologic class
`
`
` Antiviral/Ebolavirus (7030249)
`
`
` Code name
` Atoltivimab (REGN3470), odesivimab (REGN3471), maftivimab
`
`
` (REGN3479); REGN3470-3471-3479; REGN-EB3
`
` Regeneron Pharmaceuticals, Inc.
`
` Solution for injection
`
`
` The recommended dosage of INMAZEB is 50 mg of atoltivimab,
`
` 50 mg of maftivimab, and 50 mg of odesivimab per kg (3 mL/kg)
`
`
`
`
` diluted and administered as a single intravenous infusion.
`
`
`
`
`
`
`Throughout the review we refer to INMAZEB dosing as
` 150 mg/kg as a single intravenous infusion
`
`
`
` Treatment of infection caused by Zaire ebolavirus
`
`
`
`
`
` Approved SNOMED
`
` indication
`
`
`
`
`
`
`
`
` Integrated Review Template, version date 2019/10/16
`
`
`
`Reference ID: 4685606
`
`
`
` Applicant proposed
`
` indication(s)/population(s)
`
` Proposed SNOMED
`
` indication
` Regulatory action
`Approved
` indication(s)/population(s)
`
` (if applicable)
`
`
`
`
`
`
`
`
`
` 37109004 | Ebola virus disease (disorder)
`
`
`
` Approval
`
` INMAZEB is indicated for the treatment of infection caused by
`
` Zaire ebolavirus in adult and pediatric patients, including neonates
`
`
` born to a mother who is RT-PCR positive for Zaire ebolavirus
`
` infection.
`
`Limitations of Use
`
`
`The efficacy of INMAZEB has not been established for other
`
`
`species of the Ebolavirus and Marburgvirus genera.
`
`
`
`
`
`Zaire ebolavirus can change over time, and factors such as
`
`
`
`emergence of resistance, or changes in viral virulence could
`
`
`diminish the clinical benefit of antiviral drugs. Consider available
`
`information on drug susceptibility patterns for circulating Zaire
`
`
`
` ebolavirus strains when deciding whether to use INMAZEB.
` 37109004 | Ebola virus disease (disorder)
`
`
`

`

`
`BLA-761169
`
`
`
`Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
` Table of Contents
`
` Table of Tables ........................................................................................................ vi
`
`
`
`
`
` Table of Figures ....................................................................................................... xi
`
`
`
` Glossary .............................................................................................................. 14
`
`
`
`
` I. Executive Summary .......................................................................................... 16
`
`
`
`
`
` 1. Summary of Regulatory Action........................................................................ 16
`
`
`
`
` 2. Benefit-Risk Assessment ................................................................................. 19
`
`
`
`
` II. Interdisciplinary Assessment .............................................................................. 25
`
`
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`
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` 3. Introduction ..................................................................................................... 25
`
`
`
`
`3.1. Approach to the Review ............................................................................ 25
`
`
`
`
`4. Patient Experience Data................................................................................... 28
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`
`
`
`5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology .......... 29
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`
`
`
`5.1. Nonclinical Assessment of Potential Effectiveness .................................... 31
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`
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`
`
`6. Evidence of Benefit (Assessment of Efficacy).................................................. 36
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`
`
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`
`
`6.1. Assessment of Dose and Potential Effectiveness........................................ 36
`
`
`6.2. Design of Clinical Trials Intended to Demonstrate Benefit to Patients ....... 36
`
`
`
`
`6.2.1. Trial Design ........................................................................................ 36
`
`
`
`
`
`
`
`6.2.2. Eligibility Criteria ............................................................................... 37
`
`
`
`
`
`6.2.3. Statistical Analysis Plan ...................................................................... 38
`
`
`6.3. Results of Analyses of Clinical Trials/Studies Intended to Demonstrate
`
`Benefit to Patients ...................................................................................... 38
`
`
`
`
`6.3.1. Disposition, Baseline Demographics, and Baseline Clinical
`
`Characteristics ........................................................................................ 38
`
`
`
`
`6.3.2. Primary and Key Secondary Efficacy Results...................................... 42
`
`
`
`
`
`6.3.3. Subgroup Analyses for the Primary Efficacy Endpoint........................ 44
`
`
`
`
`
`
`
`
`
`
`6.4. Review Issues Relevant to the Evaluation of Benefit ................................. 44
`
`
`6.4.1. Use of an Investigational Drug, ZMapp, as an Active Control Versus
`
`
`
`
`
`Optimized Standard of Care Alone.......................................................... 45
`
`
`
`
`6.4.2. Lower Efficacy in Subjects With a Baseline CtNP of 22 or Lower ...... 46
`
`
`
`
`
`
`
`
`6.4.3. Demonstration of the Contribution of Each Component of the
`
`
`Combination ........................................................................................... 50
`
`
`
`
`6.4.4. Adequacy of Clinical Experience With Pediatric Subjects and
`
`
`Inclusion of Labeling for Low-Birth-Weight Neonates Born to EBOV-
`
`Infected Mothers..................................................................................... 52
`
`
`
`
`6.4.5. Lack of Clinical Experience With REGN-EB3 for Treatment of
`
`
`EBOV Infection Acquired by Routes Other Than Natural Transmission.. 53
`
`
`
`
`
`7. Risk and Risk Management.............................................................................. 55
`
`
`
`
`
`
` Integrated Review Template, version date 2019/10/16
`
`ii
`
`
`
`Reference ID: 4685606
`
`

`

`
`BLA-761169
`
`
`
`Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
`
`
`
` 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data.................. 55
`
`
`
`7.2. Potential Risks or Safety Concerns Based on Drug Class or Other Drug-
`
`Specific Factors.......................................................................................... 55
`
`
`
`
`7.3. Potential Safety Concerns Identified Through Postmarketing Experience .. 56
`
`
`
`7.4. FDA Approach to the Safety Review......................................................... 56
`
`
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`
`
`7.5. Adequacy of the Clinical Safety Database ................................................. 58
`
`
`
`
`7.6. Safety Findings and Safety Concerns Based on Review of the Clinical
`
`
`
`Safety Database.......................................................................................... 59
`
`
`
`
`7.6.1. Overall Adverse Event Summary ........................................................ 59
`
`
`
`
`
`7.6.2. Deaths................................................................................................. 61
`
`
`
`
`7.6.3. Serious Adverse Events....................................................................... 61
`
`
`
`
`7.6.4. Dropouts and/or Discontinuations Due to Adverse Events................... 63
`
`
`
`
`
`7.6.5. Treatment-Emergent Adverse Events .................................................. 64
`
`
`
`
`7.6.6. Laboratory Findings............................................................................ 69
`
`
`
`
`
`
`
`
`7.7. Review Issues Relevant to the Evaluation of Risk...................................... 70
`
`
`7.7.1. Development of Resistance Against REGN-EB3 Has Not Been
`
`
`Adequately Characterized ....................................................................... 71
`
`
`
`
`7.7.2. Potential Risks of Immunogenicity...................................................... 74
`
`
`
`
`
`7.7.3. Risks Associated With the Proposed Total Infusion Volumes and
`
`
`Infusion Times for Neonates ................................................................... 75
`
`
`
`
`
`8. Therapeutic Individualization........................................................................... 77
`
`
`
`8.1. Intrinsic Factors......................................................................................... 77
`
`
`
`
`8.2. Drug Interactions....................................................................................... 77
`
`
`
`
`
`8.3. Pediatric Labeling/Plans for Pediatric Drug Development.......................... 78
`
`
`
`
`8.4. Pregnancy and Lactation............................................................................ 78
`
`
`
`
`
`9. Product Quality................................................................................................ 82
`
`
`
`
`
`
`9.1. Device or Combination Product Considerations......................................... 82
`
`
`10. Human Subjects Protections/Clinical Site and Other GCP
`
`
`
`Inspections/Financial ..................................................................................... 83
`
`
`
`
`11. Advisory Committee Summary...................................................................... 84
`
`
`
`
`III. Appendices........................................................................................................ 85
`
`
`
`12. Summary of Regulatory History..................................................................... 85
`
`
`
`13. Pharmacology Toxicology Assessments and Additional Information ............. 86
`
`
`
`
`
`13.1. Summary Review of Studies Submitted Under IND................................. 86
`
`
`
`
`
`13.1.1. Pharmacology (Primary and Secondary)............................................ 86
`
`
`
`
`
`13.1.2. Safety Pharmacology......................................................................... 88
`
`
`
` 13.1.3. Pharmacokinetics .............................................................................. 88
`
`
`
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`
`
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` Integrated Review Template, version date 2019/10/16
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`
`
` iii
`
`
`Reference ID: 4685606
`
`

`

`BLA-761169
`
`
`Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
`
`
`
` 13.1.4. Toxicology.......................................................................................100
`
`
`
`
` 13.1.4.1. General Toxicology ...................................................................100
`
`
`
` 13.1.4.2. Genetic Toxicology, Carcinogenicity, Reproductive Toxicology108
`
`
` 13.1.4.3. Other Toxicology/Specialized Studies........................................109
`
`
`
` 13.1.5. Excipients/Impurities/Degradants.....................................................109
`
`
`
`13.1.6. Extractables/Leachables ...................................................................112
`
`
`
`13.1.7. Referenced NDAs, BLAs, DMFs .....................................................112
`
`
`
`13.1.8. Individual Reviews of Studies Submitted to the NDA ......................113
`
`
`
`14. Clinical Pharmacology Assessment: Additional Information .........................113
`
`
`
`14.1. In Vitro Studies ......................................................................................113
`
`
`
`
`14.2. In Vivo Studies.......................................................................................113
`
`
`
`14.3. Comparison of PK in NHP and Humans .................................................114
`
`
`
`
`14.4. Bioanalytical ..........................................................................................118
`
`
`
`15. Trial Design: Additional Information and Assessment ..................................119
`
`
`
`
`
`16. Efficacy Assessment Additional Information and Assessment.......................130
`
`
`
`
`16.1. Additional Analyses of Demographics....................................................130
`
`
`
`
`16.2. Additional Analyses for the Primary Efficacy Endpoint..........................131
`
`
`
`
`
`
`16.2.1. Subjects Excluded From the ITT Concurrent Population for the
`
`
`
`
`Primary Efficacy Analysis......................................................................131
`
`
`16.2.2. Sensitivity Analysis Populations for Primary Efficacy Endpoint
`
`
`
`
`Analyses ................................................................................................132
`
`
`
`
`
`
`16.3. Additional Analyses for Secondary Analyses..........................................133
`
`
`16.4. Additional Subgroup Analyses for the Primary Efficacy Endpoint..........135
`
`
`
`
`
`
`16.5. Twenty-Eight-Day Mortality Rates of ZMapp in PREVAIL II and
`
`
`PALM Trials .............................................................................................142
`
`
`17. Clinical Safety Assessment Additional Information and Assessment.............143
`
`
`
`
`
`
`18. Mechanism of Action/Drug Resistance Additional Information and
`
`
`Assessment ...................................................................................................150
`
`
`18.1. Virology: Additional Information and Assessment..................................150
`
`
`18.1.1. Introduction and Background ...........................................................150
`
`
`
`18.1.1.1. Methodology .............................................................................152
`
`
`
`18.1.1.2. Prior FDA Virology Reviews.....................................................152
`
`
`
`18.1.1.3. State of Antivirals Used for the Indication Sought......................153
`
`
`
`
`
`18.1.2. Nonclinical Virology........................................................................153
`
`
`
`18.1.2.1. Mechanism of Action.................................................................153
`
`
`
`18.1.2.2. Cell Culture Studies ...................................................................162
`
`
`
`
` 18.1.2.3. Resistance and Cross-Resistance Assessments in Cell Culture ...168
`
`
`
`
`
`
` Integrated Review Template, version date 2019/10/16
`
`
`
` iv
`
`
`Reference ID: 4685606
`
`

`

`BLA-761169
`
`
`Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
`
`
`
`
` 18.1.2.4. Animal Studies ..........................................................................172
`
`
` 18.1.2.5. Resistance Studies in Animals and Bioinformatics Assessment
`
`
`
`
`
` of Epitope Conservation .....................................................................218
`
`
`
`19. Other Drug Development Considerations Additional Information .................225
`
`
`
`
`20. Data Integrity-Related Consults (OSI, Other Inspections) .............................226
`
`
`
`21. Labeling Summary of Considerations and Key Additional Information.........234
`
`
`
`
`22. Postmarketing Requirements and Commitments ...........................................237
`
`
`
`23. Financial Disclosure......................................................................................239
`
`
`24. References ....................................................................................................239
`
`
`
`25. Review Team Acknowledgments..................................................................244
`
`
`
`
`
`
`
` Integrated Review Template, version date 2019/10/16
`
`v
`
`
`Reference ID: 4685606
`
`
`

`

`BLA-761169
`
`
`Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
`
`
`
`
`
`
` Table of Tables
`
` Table 1. Administrative Application Information ............................................................. i
`
`
` Table 2. Benefit-Risk Framework.................................................................................. 19
`
`
`
` Table 3. Clinical Trials Submitted in Support of Efficacy and/or Safety
`
`
`
`Determinations1 for INMAZEB (atoltivimab, maftivimab and odesivimab-ebgn;
`
`
`
`
`
`REGN-EB3)............................................................................................................ 27
`
`
` Table 4. Patient Experience Data Submitted or Considered ........................................... 28
`
`
`
`
` Table 5. Summary of General Clinical Pharmacology and Pharmacokinetics ................ 29
`
`
`
`
` Table 6. Summary of REGN-EB3 Mechanism of Action Data....................................... 31
`
`
`
`
` Table 7. Summary of Antiviral Activity Data for REGBN-EB3..................................... 32
`
`
`
` Table 8. Summary of Data From Guinea Pig Lethal Challenge Studies ......................... 33
`
`
`
`
`
` Table 9. Subject Screening and Randomization, PALM Trial ........................................ 39
`
`
`
`
` Table 10. Disposition, ITT Amendment 3 Population, PALM Trial............................... 39
`
`
`
`
` Table 11. Baseline Demographic and Clinical Characteristics, ITT Concurrent
`
`
` Population, PALM Trial .......................................................................................... 40
`
`
`
` Table 12. Summary of 28-Day Mortality in the Primary Efficacy Analysis, ITT
`
`
`
`
`
` Concurrent Population, PALM Trial* ...................................................................... 42
`
`
`
` Table 13. Summary of 28-Day Mortality in Different Analysis Populations, PALM
`
`
` Trial ........................................................................................................................ 42
`
`
`
`Table 14. Number of Deaths by Study Day, ITT Concurrent population, PALM Trial... 43
`
`
`
`
`Table 15. PREVAIL II Summary of Results.................................................................. 46
`
`
`
`
`
`Table 16. Twenty-Eight-Day Mortality Rate by Baseline Viral Load, PALM Trial,
`
`
`
`
`ITT Concurrent Population...................................................................................... 47
`
`
`
`
`
`Table 17. Subjects Treated With REGN-EB3 by Age Group, PALM Trial and EAP
`
`
`
`
`1846........................................................................................................................ 52
`
`
`
`Table 18. PALM Trial Mortality Rate ........................................................................... 53
`
`
`
`
`
`Table 19. Overview of Clinical Safety Data................................................................... 58
`
`
`
`Table 20. Duration of Exposure, Safety Population, PALM RCT .................................. 58
`
`
`
`
`Table 21. Summary of Study Duration, Safety Population, PALM RCT........................ 59
`
`
`
`
`Table 22. Summary of Disposition, Safety Population, EAP 1846................................. 59
`
`
`
`
`Table 23. Overview of Adverse Events, Safety Population, PALM Trial ....................... 60
`
`
`
`
`Table 24. Serious Adverse Events, Safety Population, PALM Trial............................... 62
`
`
`
`
`Table 25. Adverse Events Occurring With an Incidence of ≥1% in the REGN-EB3
`
`
`
`Arm, Safety Population, PALM Trial ...................................................................... 65
`
`
`
`
`Table 26. Prespecified Symptoms Experienced Postbaseline, Safety Population,
`
`
`PALM Trial............................................................................................................. 68
`
`
`
`Table 27. Adult and Pediatric Subjects Meeting Laboratory Abnormality Criteria,
`
`
`
`
`Cumulative Worsened Grade From Baseline, Safety Population, PALM Trial......... 70
`
`
`
`
`
`
`
`
`
` Integrated Review Template, version date 2019/10/16
`
`vi
`
`
`
`Reference ID: 4685606
`
`

`

`BLA-761169
`
`
`Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
`
`
`
`
`
`
`
`
` Table 28. EC50 Values for Cell Culture Neutralization of EBOV VLPs With REGN­
`
` EB3 mAbs............................................................................................................... 74
`
`
`Table 29. Theoretical Infusion Volumes and Infusion Rates of INMAZEB for Patients
`
`
`
`
`Weighing Less Than 2 kg ........................................................................................ 76
`
`
`
`
`Table 30. INMAZEB Infusion Volumes and Times by Body Weight ............................ 76
`
`
`
`
`
`Table 31. Pregnancy Outcomes Following Exposure to RGN-EB3 During PALM
`
`
`
`
`RCT ........................................................................................................................ 79
`
`
`
`
`Table 32. Pregnancy Outcomes Following Exposure to REGN-EB3 During the
`
`
`
`
`PALM-Extension .................................................................................................... 79
`
`
`
`
`Table 33. Pregnancy Outcomes Following Exposure to REGN-EB3 Through EAP
`
`
`
`
`
`1846........................................................................................................................ 81
`
`
`
`Table 34: Chemistry, Manufacturing, and Controls Postmarketing Commitments ......... 82
`
`
`
`
`Table 35. Study Sites Requested for Inspection ............................................................. 83
`
`
`
`
`
`Table 36. Summary of Nonhuman Primate Studies Evaluating the Activity of REGN­
`
`
`EB3......................................................................................................................... 87
`
`
`Table 37. PK in Uninfected Cynomolgus Macaque Study Design.................................. 88
`
`
`
`
`
`Table 38. Experimental Design of PK Study in Uninfected Cynomolgus Macaque........ 89
`
`
`
`
`
`Table 39. Mean Pharmacokinetic Parameters of REGN3479, REGN3471, and
`
`REGN3470 Individually or in Combination in the Cynomolgus Macaque ............... 90
`
`
`
`
`
`Table 40. PK in Uninfected Rhesus Macaque Study Design .......................................... 90
`
`
`
`
`
`
`
`Table 41. Experimental Design of PK in Uninfected Rhesus Macaque .......................... 91
`
`
`
`
`
`Table 42. Mean Pharmacokinetic Parameters of REGN3470, REGN3471, and
`
`REGN3479 in Serum Following Single Sequential Intravenous Administration of
`
`
`30 mg/kg REGN-EB3 in Rhesus Macaque .............................................................. 92
`
`
`
`
`
`
`Table 43. Mean Pharmacokinetic Parameters of REGN3470, REGN3471, and
`REGN3479 in Serum Following Single Sequential Intravenous Administration of
`
`
`100 mg/kg REGN-EB3 in Rhesus Macaque............................................................. 93
`
`
`
`
`
`Table 44. Mean Pharmacokinetic Parameters of REGN3470, REGN3471, and
`
`
`REGN3479 in Serum Following Single Sequential Intravenous Administration of
`
`
`150 mg/kg REGN-EB3 in Rhesus Macaque............................................................. 94
`
`
`Table 45. Mean Pharmacokinetic Parameters of REGN3470, REGN3471, and
`REGN3479 in Serum Following Single Sequential Intravenous Administration of
`
`
`300 mg/kg REGN-EB3 in Rhesus Macaque............................................................. 95
`
`
`
`
`Table 46. PK in EBOV-Infected Rhesus Macaque Study Design................................... 96
`
`
`
`
`
`Table 47. PK in EBOV-Infected Rhesus Macaque—Experimental Design .................... 97
`
`
`
`
`
`Table 48. Clinical Observation Scoring System in EBOV-Infected Rhesus Macaque .... 97
`
`
`
`
`Table 49. EBOV-Infected Rhesus Macaque Study Review Findings ............................. 98
`
`
`
`
`Table 50. Mean Pharmacokinetic Parameters of REGN3470, REGN3471, and
`
`REGN3479 in Serum Following Single Intravenous Administration of REGN­
`
`EB3 in EBOV-Infected Rhesus Macaque ................................................................ 99
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`
`
`
`
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`
`
` Integrated Review Template, version date 2019/10/16
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`vii
`
`
`
`Reference ID: 4685606
`
`

`

`
`BLA-761169
`
`
`
`Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
`
` Table 51. Three-Week Rat IV Toxicity Study Design.................................................. 100
`
`
`
`
`
`
` Table 52. Experimental Design of 3-Week Rat IV Toxicity Study............................... 101
`
`
`
`
` Table 53. Three-Week Rat IV Toxicity Study Findings ............................................... 101
`
`
`
`
`
`
` Table 54. Toxicokinetic Data ...................................................................................... 102
`
`
`
`
`Table 55. TCR in Adult Tissue Study Design.............................................................. 102
`
`
`
`
`Table 56. TCR Findings in Adult Tissue ..................................................................... 103
`
`
`
`
`
`
`
`Table 57. TCR in Fetal Tissue Study Design ............................................................... 104
`
`
`
`
`Table 58. TCR Findings in Fetal Tissue ...................................................................... 105
`
`
`
`
`
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`Table 59. Competition/TCR in Adult and Fetal Tissue Study Design........................... 106
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`Table 60. TCR Findings in Fetal Tissue ...................................................................... 107
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`Table 61. REGN-EB3 Drug Product Formulations for Nonclinical and Clinical
`
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`
`Studies .................................................................................................................. 110
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`Table 62. Potential Process-Related Impurities............................................................ 111
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`Table 63. Potential REGN-EB3 Drug Product-Related Impurities ............................... 112
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`Table 64. PK Parameters in Uninfected Adults Administered a Single IV Dose of
`
`
`REGN-EB3 ........................................................................................................... 114
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`Table 65. Baseline Predefined Symptoms, ITT Concurrent Population, PALM Trial... 130
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`Table 66. Drug Shortage Periods in the PALM Trial ................................................... 132
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`
`Table 67. Subjects Who Differed Between Analysis Populations................................. 132
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`
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`Table 68. Eleven Subjects Who Were Rerandomized After Cessation of the PALM
`
`
`Trial ...................................................................................................................... 133
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`
`Table 69. Subjects Who Received ZMapp But Were Rerandomized After the Interim
`
`
`
`Analysis, PALM Trial ........................................................................................... 133
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`Table 70. Summary of Death and Discharge From ETU by Study Day, ITT
`
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`Concurrent Population, PALM Trial...................................................................... 134
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`Table 71. Summary of 28-Day Mortality by Selected Baseline Factors, ITT
`
`
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`Concurrent Population, PALM Trial...................................................................... 136
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`Table 72. Twenty-Eight-Day Mortality Rates by Age Groups, ITT Concurrent,
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`
`PALM Trail........................................................................................................... 138
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`Table 73. Summary of 28-Day Mortality by CtNP Baseline Category Across Analysis
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`
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`Populations, PALM Trial ...................................................................................... 138
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`Table 74. Summary of 28-Day Mortality by Site Across Analysis Populations, PALM
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`
`Trial ...................................................................................................................... 139
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`Table 75. Subject Counts by Baseline CtNP value and the Number of days From
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`Symptom Onset to Randomization, ITT Concurrent Population, PALM Trial........ 139
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`Table 76. Sub-Subgroup Analyses of Viral Load and the Number of Days From
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`
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`Symptom Onset to Randomization on the Primary Efficacy Endpoint (28-Day
`
`
`Mortality), ITT Concurrent, PALM Trial............................................................... 140
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` Integrated Review Template, version date 2019/10/16
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`viii
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`Reference ID: 4685606
`
`

`

`
`BLA-761169
`
`
`
`Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
`
`
`
`
`
`
`
`
`
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`
`
` Table 77. Subject Counts by Baseline Viral Load and Baseline ALT Category (≤5
`
` ULN vs. >5 ULN), ITT Concurrent, PALM Trial .................................................. 140
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`
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`Table 78. Subject Counts by Baseline Viral Load and Baseline ALT Category (≤10
`
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`
`
`ULN vs. >10 ULN), ITT Concurrent, PALM Trial ................................................ 140
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`Table 79. Subject Counts by Baseline Viral Load and Baseline AST Category (≤5
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`
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`ULN vs. >5 ULN), ITT Concurrent, PALM Trial .................................................. 141
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`Table 80. Subject Counts by Baseline Viral Load and Baseline AST Category (≤10
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`ULN vs. >10 ULN), ITT Concurrent, PALM Trial ................................................ 141
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`Table 81. Subject Counts by Baseline Viral Load and Baseline Creatinine Category
`
`
`(≤3 mg/dL vs. >3 mg/dL), ITT Concurrent, PALM Trial ....................................... 141
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`Table 82. Summary of Regression Analyses Between Baseline Viral Load and
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`
`Baseline Laboratory Measures, ITT Concurrent, PALM Trial ............................... 141
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`Table 83. Sub-Subgroup Analyses of Viral Load and Laboratory Measures on the
`
`Primary Efficacy Endpoint (28-Day Mortality), ITT Concurrent, PALM Trial....... 142
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`
`Table 84. Subgroup Analysis of Primary Endpoint by Baseline Viral Load in the
`
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`
`
`PREVAIL II Trial ................................................................................................. 143
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`Table 85. Subgroup Analysis of Primary Endpoint by Baseline Viral Load in the
`
`
`
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`PALM Trial........................................................................................................... 143
`
`
`Table 86. Adverse Events Occurring at ≥1% in the REGN-EB3 Arm, Safety
`Population, PALM Trial ........................................................................................ 144
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`
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`Table 87. Summary of Adverse Reactions During or After Infusion Reported by
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`≥10% of Subjects in the REGN-EB3 Arm, Safety Population, Subjects Under 18
`
`
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`
`
`Years of Age, PALM Trial .................................................................................... 145
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`Table 88. Subjects Meeting Laboratory Abnormality Criteria, Cumulative Worsened
`
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`Grade From Baseline, PALM Trial, Safety Population, Subjects Under 18 Years
`
`
`of Age, PALM Trial .............................................................................................. 145
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`Table 89. Subgroup Analysis by Gender for AEs Occuring During or Post-Infusion,
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`
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`Safety Population, Trial RCT-19-I-0003................................................................ 146
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`Table 90. Subgroup Analysis by Age Groups for AEs Occuring During or Post-
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`
`Infusion, Safety Population, Trial RCT-19-I-0003................................................. 146
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`Table 91. Efficacy of Individual and Combined Monoclonal Antibody Treatments in
`
`
`Guinea Pigs and Nonhuman Primates .................................................................... 151
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`
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`Table 92. Summary of Kinetic Binding Parameters for the Interaction of Atoltivimab
`
`(REGN3470), Odesivimab (REGN3471), and Maftivimab (REGN3479) With
`
`Recombinant EBOV GP.10xhis at 25°C ................................................................ 154
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`
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`Table 93. Dissociation Rate Constant and Dissociative Half-Life of Atoltivimab
`
`
`(REGN3470), Odesivimab (REGN3471), or Maftivimab (REGN3479) From
`
`
`EBOV GP at pH 5.0, 6.0 and 7.4 ........................................................................... 154
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`Table 94. Cross-Competition of Atoltivimab (REGN3470), Odesivimab
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`(REGN3471), and Maftivimab (REGN3479) for Binding to EBOV GP.10xhis at
`
`
`25°C...................................................................................................................... 156
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`
` Integrated Review Template, version date 2019/10/16
`
`ix
`
`
`Reference ID: 4685606
`
`

`

`BLA-761169
`
`
` Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn)
`
`
`
`
`
`
`
`
`
`
` Table 95. EBOV GP Peptides Protected by REGN-EB3 mAbs.................................... 159
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` Table 96. REGN-EB3 Mechanism of Action Data (DAV Analyses)............................ 161
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` Table 97. Neutralization Titers of Anti-EBOV GP Antibodies in a Replication-
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`
`
` Competent EBOV Infection Assay ........................................................................ 163
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`