`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209606Orig1s000
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
`
`

`

`NDA Multidisciplinary Review and Evaluation
`
`
`Application Number(s) NDA 209606
`Application Type Original 505(b)(1)
`Priority or Standard Priority
`Submit Date(s) December 30, 2016
`Received Date(s) December 30, 2016
`PDUFA Goal Date August 30, 2017
`Division/Office DHP/OHOP
`Review Completion Date
`July 28, 2017
`Applicant Celgene Corporation
`Established Name Enasidenib
`IDHIFA®
`(Proposed) Trade Name
`Pharmacologic Class
`Isocitrate dehydrogenase 2 inhibitor
`Formulation(s) Tablets, 50mg and 100mg
`Dosing Regimen 100 mg once daily
`Applicant Proposed
`IDHIFA is indicated for the treatment of patients with relapsed or
`Indication(s)/Population(s)
`refractory acute myeloid leukemia with an IDH2 mutation
`Recommendation on
`Regular approval
`Regulatory Action
`Recommended
`Indication(s)/Population(s)
`
`IDHIFA is an isocitrate dehydrogenase-2 inhibitor indicated for the
`treatment of adult patients with relapsed or refractory acute
`myeloid leukemia with an isocitrate dehydrogenase-2 mutation as
`detected by an FDA-approved test.
`
`Reference ID: 4131433
`
`

`

`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`
`Table of Contents
`
`Table of Contents ........................................................................................................................... 2
`
`Table of Tables ............................................................................................................................... 6
`
`Table of Figures .............................................................................................................................. 9
`
`Reviewers of Multidisciplinary Review and Evaluation ................................................................ 10
`
`Additional Reviewers of Application ............................................................................................. 10
`
`Glossary ......................................................................................................................................... 11
`
`1
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`2
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`3
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`4
`
`Executive Summary ............................................................................................................... 14
`1.1.
` Product Introduction ...................................................................................................... 14
` Conclusions on the Substantial Evidence of Effectiveness ............................................ 14
`1.2.
` Benefit-Risk Assessment ................................................................................................ 16
`1.3.
`
`Therapeutic Context .............................................................................................................. 18
`2.1.
` Analysis of Condition ...................................................................................................... 18
` Analysis of Current Treatment Options ......................................................................... 18
`2.2.
`
`Regulatory Background ......................................................................................................... 20
`3.1.
` U.S. Regulatory Actions and Marketing History ............................................................. 20
`Summary of Presubmission/Submission Regulatory Activity ........................................ 20
`3.2.
`
`
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ................................................................................................................. 21
`4.1.
` Office of Scientific Investigations ................................................................................... 21
` Product Quality .............................................................................................................. 21
`4.2.
` Devices and Companion Diagnostic Issues .................................................................... 22
`4.3.
`
`5 Nonclinical Pharmacology/Toxicology................................................................................... 23
`5.1.
` Executive Summary ........................................................................................................ 23
` Referenced NDAs, BLAs, DMFs ....................................................................................... 27
`5.2.
` Pharmacology ................................................................................................................. 27
`5.3.
` ADME/PK ........................................................................................................................ 40
`5.4.
` Toxicology ....................................................................................................................... 44
`5.5.
`
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`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`
`5.5.1.
`5.5.2.
`5.5.3.
`5.5.4.
`
` General Toxicology .................................................................................................. 44
` Genetic Toxicology .................................................................................................. 50
` Carcinogenicity ........................................................................................................ 51
` Reproductive and Developmental Toxicology ........................................................ 51
`
`Clinical Pharmacology ............................................................................................................ 58
`6.1.
` Executive Summary ........................................................................................................ 58
`Summary of Clinical Pharmacology Assessment ............................................................ 59
`6.2.
`
` Pharmacology and Clinical Pharmacokinetics ........................................................ 59
`6.2.1.
` General Dosing and Therapeutic Individualization ................................................. 59
`6.2.2.
` Comprehensive Clinical Pharmacology Review ............................................................. 60
` General Pharmacology and Pharmacokinetic Characteristics ................................ 60
`6.3.1.
` Clinical Pharmacology Questions ............................................................................ 61
`6.3.2.
`
`6.3.
`
`6
`
`7
`
`7.2.
`
`Statistical and Clinical Evaluation .......................................................................................... 69
`7.1.
`Sources of Clinical Data and Review Strategy ................................................................ 69
`
` Table of Clinical Studies .......................................................................................... 69
`7.1.1.
` Review Strategy ...................................................................................................... 69
`7.1.2.
` Review of Relevant Individual Trials Used to Support Efficacy ...................................... 71
` AG221-C-001 ........................................................................................................... 71
`7.2.1.
` Study Results ........................................................................................................... 81
`7.2.2.
` Study Results Addendum ........................................................................................ 99
`7.2.3.
`Integrated Review of Effectiveness .............................................................................. 105
` Assessment of Efficacy Across Trials ..................................................................... 105
`7.3.1.
` Integrated Assessment of Effectiveness ................................................................ 108
`7.3.2.
` Review of Safety ........................................................................................................... 108
` Safety Review Approach ....................................................................................... 108
`7.4.1.
` Review of the Safety Database ............................................................................. 109
`7.4.2.
` Adequacy of Applicant’s Clinical Safety Assessments .......................................... 111
`7.4.3.
` Safety Results ........................................................................................................ 112
`7.4.4.
` Analysis of Submission-Specific Safety Issues ....................................................... 134
`7.4.5.
` Safety Analyses by Demographic Subgroups ........................................................ 134
`7.4.6.
` Specific Safety Studies/Clinical Trials .................................................................... 134
`7.4.7.
`
`7.3.
`
`
`
`7.4.
`
`
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`Reference ID: 4131433
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`

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`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`
`7.4.8.
` Additional Safety Explorations .............................................................................. 135
`7.4.9.
` Safety in the Postmarket Setting .......................................................................... 135
`7.4.10.
`Integrated Assessment of Safety ................................................................... 136
`
`
`SUMMARY AND CONCLUSIONS .................................................................................................. 137
`7.5.
`Statistical Issues ........................................................................................................... 137
`
` Conclusions and Recommendations ............................................................................ 138
`7.6.
`
`8 Advisory Committee Meeting and Other External Consultations ....................................... 139
`
`9
`
`Pediatrics ............................................................................................................................. 140
`
`10 Labeling Recommendations ................................................................................................ 141
`10.1.
`Prescribing Information ............................................................................................ 141
`
`Patient Labeling ........................................................................................................ 143
`10.2.
`
`Container Labeling .................................................................................................... 143
`10.3.
`
`
`11 Risk Evaluation and Mitigation Strategies (REMS) .............................................................. 144
`
`12 Post-marketing Requirements and Commitments .............................................................. 145
`
`13 Appendices .......................................................................................................................... 146
`13.1.
`References ................................................................................................................ 146
`
`Financial Disclosure .................................................................................................. 147
`13.2.
`
`Nonclinical Pharmacology/Toxicology...................................................................... 147
`13.3.
`
`OCP Appendices (Technical documents supporting OCP recommendations) ......... 147
`13.4.
`
`13.4.1.
`Summary of Bioanalytical Method Validation and Performance .................. 147
`
`Clinical PK ....................................................................................................... 150
`13.4.2.
`
`Pharmacometrics Assessments ..................................................................... 157
`13.4.3.
`
`Grouped Preferred Terms ........................................................................................ 171
`13.5.
`
`
`14 Division Director (DHOT) ..................................................................................................... 173
`
`15 Division Director (OCP) ........................................................................................................ 174
`
`16 Division Director (OB) .......................................................................................................... 175
`
`17 Division Director (Clinical) ................................................................................................... 176
`
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`Reference ID: 4131433
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`

`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`18 Office Director (or designated signatory authority) ............................................................ 177
`
`
`
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`Reference ID: 4131433
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`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`
`Table of Tables
`
`
`Table 1: Benefit-Risk Framework .................................................................................................. 16
`Table 2: Currently Available Treatments for Acute Myeloid Leukemia ........................................ 19
`Table 3: Inhibition of IDH2 Activity by Enasidenib and its Metabolites ....................................... 27
`Table 4: Enasidenib Inhibition of Isocitrate Dehydrogenase 2 Mutants ...................................... 28
`Table 5: Inhibition of Adenosine Receptor Functions by Enasidenib and AGI-16903 .................. 37
`Table 6: IC50s at Adenosine Receptors versus Steady-State Free Cmax in Patients.................... 38
`Table 7: Inhibition of Ion Channel Currents .................................................................................. 38
`Table 8: TK Parameters for Oral Enasidenib in Female Dogs ....................................................... 39
`Table 9: Monkey PK Parameters Following Administration of Enasidenib .................................. 41
`Table 10: Percent Plasma Protein Binding of AG-221 in Various Species .................................... 42
`Table 11: Comparative Metabolic Profile in Animals ................................................................... 43
`Table 12: Monkey PK Parameters Following Administration of Enasidenib ................................ 43
`Table 13: Excretion of Enasidenib and Metabolites Following a Single 10 mg/kg Oral
`Administration .............................................................................................................................. 44
`Table 14: Toxicokinetics in Rats following 90-Day Repeat Dosing with Enasidenib ..................... 46
`Table 15: Toxicokinetics in Monkeys following 88-Day Repeat Dosing with Enasidenib ............. 48
`Table 16: Uterine and Ovarian Examinations In Rats ................................................................... 53
`Table 17: Rat Fetal Evaluations ..................................................................................................... 53
`Table 18: Summary of Toxicokinetics Parameters in Rats ........................................................... 54
`Table 19: Uterine and Ovarian Examinations In Rabbits .............................................................. 56
`Table 20: Enasidenib: Summary of Mean Toxicokinetic Parameters in Rabbits .......................... 56
`Table 21: Distribution of IDH2 Mutations as Detected by the Proposed Companion Diagnostic
`Test (Final FDA Efficacy Analysis Set) ............................................................................................ 62
`Table 22: Best Response by IDH2 R140 or R172 Mutation (Efficacy Evaluable Population) ........ 63
`Table 23: Number of Patients Achieving CR/CRh by Number of Co-Occurring Mutations .......... 66
`Table 24: Effect of a High-Fat Meal on the Bioavailability of Enasidenib ..................................... 67
`Table 25: Relative Bioavailability of Enasidenib Following the Administration of Two
`Formulations ................................................................................................................................. 68
`Table 26: Listing of Clinical Trials Relevant to this NDA ............................................................... 69
`Table 27: Reasons for Treatment Discontinuation ....................................................................... 83
`Table 28: Reasons for Study Discontinuation ............................................................................... 84
`Table 29: Protocol Deviations ....................................................................................................... 84
`Table 30: Demographic Characteristics ........................................................................................ 85
`Table 31: Baseline Disease Characteristics ................................................................................... 86
`Table 32: Number of Patients with Dose Intensity <80% or >120% by Treatment Cycle ............ 88
`Table 33: Summary of Efficacy Endpoint-Investigator’s Assessment ........................................... 90
`Table 34: Summary of Efficacy Endpoint-Sponsor’s Assessment ................................................. 91
`Table 35: Summary of Time to Response Analysis –Investigator’s Assessment .......................... 92
`Table 36: Summary of Time to Response Analysis –Sponsor’s Assessment ................................ 93
`Table 37: Summary of Sponsor's Assessed CR/CRh by Cycle ....................................................... 94
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`Reference ID: 4131433
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`

`

`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`Table 38: Summary of RBC Transfusion Status ............................................................................. 95
`Table 39: Summary of Platelet Transfusion Status ....................................................................... 95
`Table 40: Summary of Analysis Results for Overall Survival ......................................................... 95
`Table 41: Subgroup Analyses by Age, Gender, Race and Region for CR-Investigator Assessment
`....................................................................................................................................................... 97
`Table 42: Subgroup Analyses by Baseline Disease Characteristic for CR-Investigator Assessment
`....................................................................................................................................................... 97
`Table 43: Subgroup Analyses by Age, Gender, Race and Region for CR-Sponsor’s Assessment . 98
`Table 44: Subgroup Analyses by Bassline Disease Characteristic for CR-Sponsor’s Assessment . 98
`Table 45: FDA Adjudication of Discordant Determinations of CR .............................................. 100
`Table 46: Final FDA Analysis of Response ................................................................................... 103
`Table 47: Subgroup Analyses by Age, Gender, Race and Region –Complete Response ............ 103
`Table 48: Subgroup Analyses by Baseline Disease Characteristic –Complete Response ........... 104
`Table 49: Transfusion Dependence in Final Efficacy Pool .......................................................... 104
`Table 50: Assessment for Consistency Between Response and Clinical Outcomes ................... 107
`Table 51: Duration of Exposure1 to Enasidenib in the Safety Population .................................. 109
`Table 52: Planned Total Daily Dose of Enasidenib in the Safety Population .............................. 110
`Table 53: Demographics of the Safety Population ..................................................................... 110
`Table 54: Deaths on Study AG-221-C-001 .................................................................................. 112
`Table 55: Causes of Deaths Occurring On or Within 30 Days of Treatment in Phase 1 ............. 113
`Table 56: Serious Adverse Events within 28 Days of Follow-Up................................................. 118
`Table 57: Treatment Interruptions, Reductions, or Withdrawals .............................................. 119
`Table 58: TEAE Leading to Dose Interruption ............................................................................. 119
`Table 59: TEAE Leading to Dose Reductions ............................................................................... 120
`Table 60: TEAE Leading to Discontinuations ............................................................................... 120
`Table 61: Post-baseline Changes in Bilirubin and Transaminases .............................................. 121
`Table 62: FDA Analysis of Maximum Bilirubin Level ................................................................... 122
`Table 63: FDA Analysis of Maximum ALT/AST Level ................................................................... 122
`Table 64: FDA Criteria for Identifying Cases of Possible DS ........................................................ 124
`Table 65: Common TEAE (All Grades) ......................................................................................... 127
`Table 66: Common Grade ≥ 3 TEAE ............................................................................................ 128
`Table 67: TEAE Suspected to Be Possibly or Probably Related to Enasidenib ............................ 129
`Table 68: Vital Sign Abnormalities .............................................................................................. 132
`Table 69: Maximum Postbaseline Absolute QTcF Interval ......................................................... 133
`Table 70: Enasidenib Metabolite Profile in Human Plasma and Excreta in Study AG-221-CP-002
`..................................................................................................................................................... 148
`Table 71: Protein Binding for Enasidenib (AG-221) and its Metabolite ..................................... 149
`Table 72: Summary of Bioanalytical Methods ............................................................................ 150
`Table 73: Summary of Enasidenib Pharmacokinetics in Healthy Japanese and Caucasian Subjects
`..................................................................................................................................................... 151
`Table 74: Summary of Enasidenib Pharmacokinetics in Healthy Subjects ................................. 152
`Table 75: Summary of Enasidenib Pharmacokinetics in Healthy Subjects ................................. 152
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`Reference ID: 4131433
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`

`

`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`Table 76: Summary of Enasidenib Pharmacokinetics in Patients with Advanced Hematologic
`Malignancies ............................................................................................................................... 153
`Table 77: Summary of AGI-16903 Pharmacokinetics in Patients with Advanced Hematological
`Malignancies ............................................................................................................................... 155
`Table 78: Summary of Studies included in PPK Analysis ............................................................ 157
`Table 79: Summary of Populations in Different Dose Regimens in Population Pharmacokinetic
`Analysis ....................................................................................................................................... 158
`Table 80: Parameter Estimates (95% CI) for Enasidenib Final Population Pharmacokinetic Model
`..................................................................................................................................................... 159
`Table 81: Estimated Parameters for the Linear Mixed Effect Modeling .................................... 163
`Table 82: Probability of ORR in Relapsed Refractory AML Stratified by IDH2 Mutation Type ... 168
`Table 83: Results from the Logistic Regression of E-R of Grade 3 or Grade 4 Adverse Reactions
`for Patients with R/R AML .......................................................................................................... 169
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`Reference ID: 4131433
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`APPEARS THIS WAY ON ORIGINAL
`
`

`

`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`
`Table of Figures
`
`
`Figure 1: Enasidenib Effect on [2-HG] in TF-1 IDH2 R140Q Mutant Cells ..................................... 29
`Figure 2: Enasidenib Reduces Histone Methylation in R140Q Mutant and Control Cells ............ 29
`Figure 3: Hemoglobin G1/2 and Kruppel-like Factor-1 in TF-1 IDH2 R140Q Mutant Cells ........... 30
`Figure 4: Hematopoietic Progenitor and Stem Cells Respond to Treatment with Enasidenib .... 31
`Figure 5: Enasidenib Decreases 2-HG in Primary Human IDH2 (R140Q) Mutant Cells ................ 32
`Figure 6: Maturation of Primary Human Patient IDH2 R140Q Mutant Cells ................................ 32
`Figure 7: Effects of Enasidenib on Maturation of Human AML Bone Marrow Cell Types ........... 33
`Figure 8: Human IDH2 (R140Q) Leukemic Blasts in Mouse Peripheral Blood .............................. 34
`Figure 9: Enasidenib Increased Bone Marrow Leukemic Blast Cell Differentiation ..................... 34
`Figure 10: Enasidenib Prolonged Mouse Survival Dose-Dependently ......................................... 35
`Figure 11: 2-HG Blood Concentrations and Percent Reduction in Inducible IDH2 (R140Q) AML 36
`Figure 12: Kaplan-Meyer survival plot of the secondary recipients ............................................. 36
`Figure 13: Kaplan-Meyer survival plot of the secondary recipients ............................................. 36
`Figure 14: Exposure-efficacy Relationships for Objective Response Rate ................................... 64
`Figure 15: Exposure-Safety Relationship for Grade 3 and Grade 4 Total Bilirubin Elevation
`(N=242) ......................................................................................................................................... 65
`Figure 16: Study Diagram .............................................................................................................. 72
`Figure 17: Kaplan-Meier Plot for Overall Survival ........................................................................ 96
`Figure 18: Mean (±SD) of Hemoglobin (g/L), ANC (109/L), and Platelets (109/L) by Visit for All
`Subjects on AG-221-C-001 .......................................................................................................... 131
`Figure 19: Enasidenib Pharmacokinetic Profile in Patients Following Once Daily Dosing ......... 156
`Figure 20: No Apparent Effect of Renal Impairment and Mild Hepatic Impairment on Apparent
`Oral Clearance ............................................................................................................................. 160
`Figure 21: Goodness-of-Fit Plots of the Final Model – Population or Individual Predicted
`Concentrations versus Observed Concentrations ...................................................................... 161
`Figure 22: Visual Predictive Checks for the Time Profiles of Enasidenib Concentrations in Healthy
`Subjects ( Left Panel ) and Patients (Right Panel) ....................................................................... 161
`Figure 23: Boxplots of Trough Observations Stratified by Cycles ............................................... 163
`Figure 24: Correlation between Dose vs. Steady State Exposure (A) and Mutation Type vs.
`Steady State Exposure (B) ........................................................................................................... 165
`Figure 25: Percent Suppression of 2-HG vs. Steady State Exposure .......................................... 166
`Figure 26: Relationship between Steady State Exposure and Investigator-assessed Best
`Responses in Data from Phase 1 and 2 Portions of Study AG221-C-001 ................................... 166
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`Reference ID: 4131433
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`

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`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`Reviewers of Multidisciplinary Review and Evaluation
`
`Regulatory Project Manager
`Nonclinical Reviewer
`Nonclinical Team Leader
`Office of Clinical Pharmacology Reviewer(s)
`
`Office of Clinical Pharmacology Team Leader(s)
`
`Jennifer Lee, PharmD
`Ramadevi Gudi, PhD
`Christopher M. Sheth, PhD
`Sarah Dorff, PhD
`Xianhua Cao, PhD
`Stacy S. Shord, PhD
`Nitin Mehrotra, PhD
`Rosane Charlab Orbach, PhD
`Ashley Ward, MD
`Donna Przepiorka, MD, PhD
`Qing Xu, PhD
`Yuan Li Shen, PhD
`Donna Przepiorka, MD, PhD
`John K. Leighton, PhD
`NAM Atiqur Rahman, PhD
`Rajeshwari Sridhara, PhD
`Albert Deisseroth, MD, PhD
`Richard Pazdur, MD
`
`Clinical Reviewer
`Clinical Team Leader
`Statistical Reviewer
`Statistical Team Leader
`Cross-Disciplinary Team Leader
`Division Director (DHOT)
`Division Director (OCP)
`Division Director (OB)
`Supervisory Associate Division Director (DHP)
`Office Director
`
`
`Additional Reviewers of the Application
`
`OPQ
`
`OPDP
`OSI
`
`OSE/DMEPA
`OSE/DRISK
`DMPP
`
`DHP DDS
`QT/IRT
`
`Drug Substance: Rohit Tiwari, PhD; Benjamin Stevens, PhD, MPH
`Drug Product: Nina Ni, PhD; Anamitro Banerjee, PhD
`Manufacturing, Process and Controls: David Anderson, PhD; Ying Zhang
`Facilities: Zhihao Peter Qiu, PhD; Zhong Li, PhD
`Biopharmaceutics: Banu Zolnik, PhD; Okponanabofa Eradiri, PhD
`Quality Assessment: Sherita McLamore-Hines, PhD
`Rachael Conklin, MS, RN; Kathleen Davis, RN
`Anthony Orencia MD, FACP; Cynthia Kleppinger, MD); Janice Pohlman, MD, MPH;
`Kassa Ayalew, MD, MPH
`Leeza Rahimi, PharmD; Susan Rimmel, PharmD; Hina Mehta, PharmD
`Till Olickal, PhD, PharmD; Elizabeth Everhart, MSN, RN, ACNP
`Susan Redwood, MPH, BSN, RN; Shawna Hutchins, MPH, BSN, RN; LaShawn Griffiths,
`MSHS-PH, BSN, RN
`Barry Miller, MS, CRNP
`Nan Zheng, PhD; Dhananjay D. Marathe, PhD; Dalong Huang, PhD; Qianyu Dang;
`Michael Y. Li, MS; Christine E. Garnett, PharmD
`OPQ=Office of Pharmaceutical Quality
`OPDP=Office of Prescription Drug Promotion
`OSI=Office of Scientific Investigations
`OSE= Office of Surveillance and Epidemiology
`DEPI= Division of Epidemiology
`DHP DDS=Division of Hematology Products Deputy Director for Safety
`DMEPA=Division of Medication Error Prevention and Analysis
`DMPP=Division of Medical Policy Programs
`DRISK=Division of Risk Management
`
`
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`Reference ID: 4131433
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`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
`Glossary
`
`
`2-HG
`ADaM
`ADME
`AE
`
`ALT
`
`AML
`
`ANC
`
`AST
`
`AUC
`
`BID
`
`BW
`
`CBC
`
`CDER
`
`CDRH
`
`CDTL
`
`CDx
`
`CFR
`
`CMC
`
`CMP
`
`CI
`
`CR
`
`CRh
`
`CRi
`
`CRp
`
`CSR
`
`CV
`
`DDS
`
`DEPI
`
`DHOT
`DHP
`
`DMEPA
`DMPP
`DOR
`
`DRISK
`DS
`
`DSRC
`
`ECG
`
`eCTD
`
`ECOG
`
`
`
`
`2-hydroxyglutarate
`Analysis Data Model
`absorption, distribution, metabolism, excretion
`adverse event
`alanine aminotransferase
`acute myeloid leukemia
`absolute neutrophil count
`aspartate aminotransferase
`area under the curve
`twice daily
`body weight
`complete blood counts
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`Cross-Discipline Team Leader
`companion diagnostic
`Code of Federal Regulations
`chemistry, manufacturing, and controls
`comprehensive metabolic panel
`confidence interval
`complete remission
`complete remission with partial hematologic recovery
`complete remission with incomplete neutrophil recovery
`complete remission without platelet recovery
`clinical study report
`cardiovascular
`Deputy Director for Safety
`Division of Epidemiology
`Division of Hematology Oncology Toxicology
`Division of Hematology Products
`Division of Medication Error Prevention and Analysis
`Division of Medical Policy Programs
`duration of response
`Division of Risk Management
`Differentiation syndrome
`data safety review committee
`electrocardiogram
`electronic common technical document
`Eastern Cooperative Oncology Group
`
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`Reference ID: 4131433
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`

`Multidisciplinary Review and Evaluation
`NDA 209606
`IDHIFA® (enasidenib)
`
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`EFS
`
`EFT
`
`E-R
`
`FACS
`
`FAS
`
`FDA
`
`GCP
`
`GFR
`
`GLP
`GVHD
`HCP
`
`hERG
`
`HSCT
`
`ICH
`
`IDH2
`
`IND
`
`IWG
`
`MAD
`
`MAED
`MDS
`
`MedDRA
`MLFS
`
`MRD
`
`MTD
`
`NDA
`
`OB
`
`OCP
`
`OPDP
`
`OPQ
`
`ORR
`
`OS
`
`OSE
`
`OSI
`
`PD
`
`PD
`
`PK
`
`PLLR
`
`PMA
`
`PMC
`
`PMR
`
`PO
`
`PR
`
`
`event-free survival
`embryo-fetal toxicity
`exposure-response
`fluorescence-activated cell sorting
`full analysis set
`Food and Drug Administration
`good clinical practice
`glomerular filtration rate
`good laboratory practice
`graft-versus-host disease
`healthcare provider
`human ether-a-go-go-related gene
`hematopoietic stem cell transplantation
`International Conference on Harmonization
`Is