`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`211192Orig1s000
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
`
`

`

`Application Number NDA 211192
`
`Review Completion Date
`
`Applicant Proposed
`Indication/Population
`
`NDA Multidisciplinary Review and Evaluation
`
`Application Type Original 351(a)
`Priority or Standard Priority Expedited
`Submit Date 12/21/2017
`Received Date 12/21/2017
`PDUFA Goal Date 8/21/2018
`Division/Office DHP/OHOP
`Applicant Agios Pharmaceuticals, Inc.
`Established Name Ivosidenib
`(Proposed) Trade Name Tibsovo
`Pharmacologic Class Isocitrate dehydrogenase-1 inhibitor
`Formulations Tablet (250 mg)
`Dosing Regimen 500 mg taken orally once daily
`For the treatment of adult patients with
`relapsed or refractory acute myeloid
`leukemia (AML) with an isocitrate
`dehydrogenase-1 (IDH1) mutation as
`detected by an FDA-approved test.
`Regulatory Action Regular approval
`For the treatment of adult patients with
`relapsed or refractory acute myeloid
`leukemia (AML) with a susceptible isocitrate
`dehydrogenase-1 (IDH1) mutation as
`detected by an FDA-approved test
`
`Recommendation on
`
`Recommended
`Indication/Population
`
`Reference ID: 4294809
`
`

`

`NDA Multidisciplinary Review and Evaluation
`NDA 211192
`Tibsovo (ivosidenib)
`
`Addendum Clinical Pharmacology
`
`In the Clinical Pharmacology section of the finalized review, the following appears under
`“Outstanding Issues”:
`We have issued one PMR, as presented in the PMR/PMC Section above. There are no other
`outstanding issues.
`
`It should be corrected to:
`We hve issued two PMRs, as presented in the PMR/PMC Section above. There are no other
`outstanding issues.
`
`2
`
`Reference ID: 4294809
`
`

`

`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`WENCHI HSU
`07/20/2018
`
`GENE M WILLIAMS
`07/20/2018
`
`Reference ID: 4294809
`
`

`

`NDA Multidisciplinary Review and Evaluation
`
`Application Number NDA 211192
`
`Applicant Proposed
`
`Application Type Original 351(a)
`Priority or Standard Priority Expedited
`Submit Date 12/21/2017
`Received Date 12/21/2017
`PDUFA Goal Date 8/21/2018
`Division/Office DHP/OHOP
`Review Completion Date 7/19/2018
`Applicant Agios Pharmaceuticals, Inc.
`Established Name Ivosidenib
`(Proposed) Trade Name Tibsovo
`Pharmacologic Class Isocitrate dehydrogenase-1 inhibitor
`Formulations Tablet (250 mg)
`Dosing Regimen 500 mg taken orally once daily
`Indication/Population For the treatment of adult patients with
`relapsed or refractory acute myeloid
`leukemia (AML) with an isocitrate
`dehydrogenase-1 (IDH1) mutation as
`detected by an FDA-approved test.
`Regulatory Action Regular approval
`For the treatment of adult patients with
`relapsed or refractory acute myeloid
`leukemia (AML) with a susceptible isocitrate
`dehydrogenase-1 (IDH1) mutation as
`detected by an FDA-approved test
`
`Recommendation on
`
`Recommended
`Indication/Population
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4293723
`
`

`

`NDA Multidisciplinary Review and Evaluation
`NDA 211192
`Tibsovo (ivosidenib)
`
`
`Table of Contents
`Table of Contents ........................................................................................................................ 2
`Table of Tables ............................................................................................................................ 4
`Table of Figures ........................................................................................................................... 7
`
`1
`
`Executive Summary ............................................................................................................ 14
`
`Reviewers of the Multidisciplinary Review and Evaluation .................................................. 9
`Glossary .................................................................................................................................... 10
`1.1
`Product Introduction ................................................................................................ 14
`1.2
`Conclusions on the Substantial Evidence of Effectiveness .................................... 14
`1.3
`Benefit-Risk Assessment .......................................................................................... 16
`1.4
`Patient Experience Data ........................................................................................... 17
`
`Therapeutic Context ........................................................................................................... 18
`2
`2.1
`Analysis of Condition ................................................................................................... 18
`2.2
`Analysis of Current Treatment Options ...................................................................... 18
`3 Regulatory Background ...................................................................................................... 20
`3.1
`U.S. Regulatory Actions and Marketing History .......................................................... 20
`3.2
`Summary of Presubmission/Submission Regulatory Activity ...................................... 20
`4
`Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on
`Efficacy and Safety ..................................................................................................................... 21
`4.1
`Office of Scientific Investigations (OSI) ...................................................................... 21
`4.2.
`Product Quality ........................................................................................................... 21
`4.3
`Devices and Companion Diagnostic Issues ................................................................. 22
`5 Nonclinical Pharmacology/Toxicology .................................................................................. 23
`5.1
`Executive Summary .................................................................................................... 23
`5.2
`Referenced NDAs, BLAs, DMFs ................................................................................... 25
`5.3
`Pharmacology ............................................................................................................. 25
`5.4
`ADME/PK .................................................................................................................... 35
`5.5
`Toxicology ................................................................................................................... 38
`6 Clinical Pharmacology ........................................................................................................ 49
`6.1
`Executive Summary .................................................................................................... 49
`6.2
`Summary of Clinical Pharmacology Assessment ......................................................... 50
`6.3
`Comprehensive Clinical Pharmacology Review ........................................................... 51
`2
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`Reference ID: 4293723
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`

`

`NDA Multidisciplinary Review and Evaluation
`NDA 211192
`Tibsovo (ivosidenib)
`
`
`7
`Sources of Clinical Data and Review Strategy .................................................................... 65
`7.1
`Table of Clinical Studies .............................................................................................. 65
`7.2
`Review Strategy .......................................................................................................... 66
`8
`Statistical and Clinical Evaluation ...................................................................................... 67
`8.1
`Review of Relevant Individual Trials Used to Support Efficacy ................................... 67
`8.2
`Integrated Review of Effectiveness ........................................................................... 104
`8.3
`Review of Safety ....................................................................................................... 110
`SUMMARY AND CONCLUSIONS ............................................................................................. 158
`8.4
`Statistical Issues ........................................................................................................ 158
`8.5
`Conclusions and Recommendations ......................................................................... 158
`9 Advisory Committee Meeting and Other External Consultations ..................................... 159
`10
`Pediatrics ...................................................................................................................... 159
`11
`Labeling Recommendations .......................................................................................... 159
`11.1
`Prescribing Information ............................................................................................ 159
`11.2
`Patient Labeling ........................................................................................................ 160
`12
`Risk Evaluation and Mitigation Strategies (REMS) ........................................................ 160
`12.1
`Safety Issue(s) that Warrant Consideration of a REMS ............................................. 160
`12.2
`Conditions of Use to Address Safety Issue(s) ............................................................ 160
`12.3
`Recommendations on REMS ..................................................................................... 160
`13
`Postmarketing Requirements and Commitments ........................................................ 160
`14
`Appendices ................................................................................................................... 162
`14.1
`References ................................................................................................................ 162
`14.2
`Financial Disclosure .................................................................................................. 165
`14.3 Nonclinical Pharmacology/Toxicology...................................................................... 165
`14.4 OCP Appendices ........................................................................................................ 166
`14.5 Grouped Preferred Terms ........................................................................................ 217
`15
`Division Director (DHOT) ............................................................................................... 222
`16
`Division Director (OCP) ................................................................................................. 223
`Division Director (OB) ................................................................................................... 224
`Division Director (DHP)................................................................................................. 225
`Office Director (or designee) ........................................................................................ 227
`
`17
`18
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`19
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`Reference ID: 4293723
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`3
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`

`

`NDA Multidisciplinary Review and Evaluation
`NDA 211192
`Tibsovo (ivosidenib)
`
`
`Table of Tables
`
`
`Table 1: Currently Available Treatments for Acute Myeloid Leukemia ........................................ 19
`Table 2: Inhibition of IDH1 Activity by Ivosidenib ......................................................................... 26
`Table 3: Inhibition of 2-HG in IDH Mutant Expressing Cells by Ivosidenib ................................... 27
`Table 4: Ivosidenib and 2-HG Exposure (AUC0-12hr) and Inhibition of 2-HG in Plasma, Bone
`Marrow, and Spleen ...................................................................................................................... 32
`Table 5: Inhibition of Ion Channel Currents .................................................................................. 34
`Table 6: Toxicokinetics in Rats 90-Day Repeat Dose .................................................................... 37
`Table 7: Toxicokinetics in Monkeys 90-Day Repeat Dose ............................................................ 37
`Table 8: Toxicokinetics in Pregnant Rats Following BID Oral Administration - GD6-17 ............... 38
`Table 9: Toxicokinetic in Pregnant Rabbits Following BID Oral Administration - GD7-20 ........... 38
`Table 10. Distribution of and Response Rates by IDH1 R132 Mutation Type in the Primary and R/R
`AML Efficacy Sets ............................................................................................................................ 54
`Table 11. Summary of ivosidenib PK parameters following multiple dosing on Cycle 1, Day 15
`and Cycle 2, Day 1 (dose-escalation) ............................................................................................ 55
`Table 12. Summary of plasma 2-HG percent inhibition at Cycle 2, Day 1 based on average
`concentration following ivosidenib administration (dose-escalation/-expansion combined) .... 56
`Table 13. Number of Responses (CR+CRh) by Number of Co-Occurring Mutations ...................... 59
`Table 14: Summary of ivosidenib PK parameters and LSM analysis in food-effect part of Study
`AG120-C-004 ................................................................................................................................. 61
`Table 15. Summary of ivosidenib PK parameters and LSM analysis in itraconazole DDI Study
`AG120-C-007 ................................................................................................................................. 62
`Table 16. Predicted effect of concomitant fluconazole on ivosidenib exposure ......................... 62
`Table 17. Predicted effect of concomitant rifampin on ivosidenib exposure .............................. 62
`Table 18. Predicted effect of ivosidenib on midazolam exposure ............................................... 63
`Table 19: Listing of Clinical Trials Relevant to this NDA ............................................................... 65
`Table 20: Guidelines on administration of hydroxyurea for leukocytosis .................................... 77
`Table 21: Schedule of Assessments Escalation Phase .................................................................. 79
`Table 22: Schedule of Assessments Expansion Phase .................................................................. 80
`Table 23: PK/Pharmacodynamic Sampling and ECG Schedule – Escalation Phase ...................... 81
`Table 24: PK/Pharmacodynamic Sampling and ECG Schedule – Expansion Phase ...................... 81
`Table 25: Censoring Rules for Time-to-Event Analyses using Response Assessments ................ 85
`Table 26: Reasons for Treatment Discontinuation ....................................................................... 90
`Table 27: Reasons for Study Discontinuation ............................................................................... 90
`Table 28: Protocol Deviations in Subjects in the R/R AML Efficacy Set (N=173) .......................... 91
`Table 29: Demographic Characteristics ........................................................................................ 92
`Table 30: Baseline Disease Characteristics ................................................................................... 93
`Table 31: Ivosidenib Treatment Intensity ..................................................................................... 95
`Table 32: Number of Patients with Dose Intensity <80% or >120% by Treatment Cycle ............ 95
`Table 33: Results of the Efficacy Endpoints .................................................................................. 96
`Table 34: Sensitivity Analysis ........................................................................................................ 97
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`Reference ID: 4293723
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`

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`NDA Multidisciplinary Review and Evaluation
`NDA 211192
`Tibsovo (ivosidenib)
`
`Table 35: IDH1 Mutation ≤ 0.04% R/R AML MRD-Evaluable Subjects (n=111) .......................... 101
`Table 36: Transfusion Dependency Conversion from Baseline to At Least 56 Days Post-Baseline
`..................................................................................................................................................... 102
`Table 37: Transfusion Dependency by Response R/R AML Efficacy Set ..................................... 102
`Table 38: Baseline Demographic and Disease Characteristics Updated R/R AML Efficacy Set .. 107
`Table 39: Efficacy Results in Updated R/R AML Efficacy Set ...................................................... 109
`Table 40: Transfusion Dependency Conversion from Baseline to At Least 56 Days Post-Baseline
`with the Updated R/R AML EFficacy Set ..................................................................................... 109
`Table 41: Duration of Exposure1 to Ivosidenib in the Safety Population ................................... 111
`Table 42: Planned Total Daily Dose of Ivosidenib in the Safety Population ............................... 111
`Table 43: Demographics of the Safety Population ..................................................................... 111
`Table 44: Deaths on Study AG120-C-001 .................................................................................... 114
`Table 45: Causes of Deaths on or Within 30 Days of Treatment in the R/R AML SAS ............... 115
`Table 46: Serious Adverse Events within 28 Days of Follow-Up................................................. 120
`Table 47: Treatment Interruptions, Reductions, or Withdrawals .............................................. 121
`Table 48: TEAE Leading to Dose Interruption ............................................................................. 121
`Table 49: TEAE Leading to Dose Reductions ............................................................................... 122
`Table 50: TEAE Leading to Discontinuations ............................................................................... 122
`Table 51: FDA Criteria for Identifying Cases of Possible DS ........................................................ 124
`Table 52: Possible Cases of DS in the R/R AML SAS .................................................................... 125
`Table 53: Maximum Postbaseline Absolute QTcF Interval ......................................................... 131
`Table 54: Common All-Grade TEAEs (≥ 10%) .............................................................................. 141
`Table 55: Common Grade ≥ 3 TEAEs (≥ 5%) ............................................................................... 142
`Table 56: TEAEs Suspected to Be Possibly or Probably Related to Ivosidenib ........................... 143
`Table 57: Demographics of the Solid Tumor and Healthy Volunteer Studies ............................ 144
`Table 58: Duration of Exposure1 to Ivosidenib in Solid Tumor Patients and Healthy Volunteers
`..................................................................................................................................................... 144
`Table 59: Common (≥ 10%) All-Grade TEAEs Solid Tumors and Healthy Volunteers ................. 145
`Table 60: Post-Baseline Vital Sign Abnormalities ....................................................................... 151
`Table 61: Infections, Bleeding, and Febrile Neutropenia by Response ...................................... 154
`Table 62. Validated bioanalytical methods for ivosidenib in human biological samples ........... 166
`Table 63. Analytical Methods and validation reports for ivosidenib in human plasma (high
`range) .......................................................................................................................................... 167
`Table 64. Tablet formulations used in ivosidenib clinical development .................................... 168
`Table 65. Observed single-dose CL/F of AG-120 obtained with different formulations
`administered to the healthy volunteers (HV) and to patients (AML) ......................................... 174
`Table 66. Mechanistic static model calculations for ivosidenib following oral dosing of 1200 mg
`..................................................................................................................................................... 175
`Table 67: Observed and Predicted Accumulation Ratio (AUC0-tau, ss/AUC0-tau, Day -3) of Ivosidenib
`(300-1200 mg QD) Over a Range of CYP3A4 Induction Parameters (IndC50: 0.125-12.5 μM) .. 176
`Table 68: Observed and Predicted Accumulation Ratio (Cmax,ss/Cmax,Day -3) of Ivosidenib (300-1200
`mg QD) Over a Range of CYP3A4 Induction Parameters (IndC50: 0.125-12.5 μM) ................... 177
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`Reference ID: 4293723
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`

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`NDA Multidisciplinary Review and Evaluation
`NDA 211192
`Tibsovo (ivosidenib)
`
`Table 69. Transporter inhibition parameters determined in vitro ............................................. 177
`Table 70. Mean predicted and observed exposure of ivosidenib following the administration of
`a single dose of 500 mg in the fasted state ................................................................................ 178
`Table 71. Mean predicted and observed AUC0-Tau of ivosidenib in Caucasian subjects receiving
`100 mg to 1200 mg treatment for 19 days in cancer patients ................................................... 178
`Table 72. Mean predicted and observed Cmax of AG-120 in Caucasian subjects receiving 100 mg
`to 1200 mg treatment for 19 days in cancer patients ................................................................ 179
`Table 73. Mean predicted and observed exposure ratios of ivosidenib in the presence and
`absence of itraconazole treatment in Caucasian subjects ......................................................... 179
`Table 74. Mean predicted exposure of CYP substrates in AML subjects receiving a single oral
`dose treatment in the presence and absence of multiple doses of ivosidenib ......................... 180
`Table 75. Mean predicted exposure of transporter substrates in AML subjects receiving a single
`oral dose treatment in the presence and absence of multiple doses of ivosidenib .................. 180
`Table 76. Mean predicted exposure of a single oral dose of 500 mg ivosidenib in the presence
`and absence of CYP enzyme inhibitor/inducer treatment ......................................................... 181
`Table 77. Mean predicted exposure of a multiple daily oral dose of 500 mg ivosidenib in the
`presence and absence of CYP enzyme inhibitor/inducer treatment ......................................... 182
`Table 78. Mean predicted exposure of a multiple daily oral dose of 500 mg ivosidenib in the
`presence and absence of a hypothetical strong CYP3A4 inhibitor treatment ........................... 183
`Table 79. Summary of Baseline Continuous Covariates ............................................................ 191
`Table 80. Summary of Baseline Categorical Covariates ............................................................. 192
`Table 81. Concomitant Medication Summary ........................................................................... 193
`Table 82. Final Population PK Model Parameter Estimates ...................................................... 194
`Table 83. Full and Final Model Development Log ...................................................................... 198
`Table 84. Number of Subjects and Response Rates by Dose Level, Subjects Included in the
`Exposure-Efficacy Analysis. ......................................................................................................... 203
`Table 85. Covariate Distribution Over AUCss Quartiles for all Subjects Included in the Exposure-
`Efficacy Analysis .......................................................................................................................... 204
`Table 86. Incidence of Clinical Response by AUCss Quartile for All Subjects Included in the
`Exposure-Efficacy Analysis. ......................................................................................................... 207
`Table 87. Logistic Regression Results of the AUCss Effect on the Incidence of Efficacy Endpoints
`for Models Including AUCss Only and AUCss + Covariates. ........................................................ 207
`Table 88. Incidence of Selected Safety Endpoints in Study AG120-c-001 Subjects Stratified by
`AUCss Quartiles. .......................................................................................................................... 210
`Table 89. Model-Predicted AE Incidence at the 10th, 50th, and 90th Percentiles of AUCss at AG-
`120 500 mg QD, Based on Logistic Regression Parameter Estimates. ....................................... 212
`Table 90. Analysis Data Sets ....................................................................................................... 213
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`Reference ID: 4293723
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`

`NDA Multidisciplinary Review and Evaluation
`NDA 211192
`Tibsovo (ivosidenib)
`
`
`Table of Figures
`
`
`Figure 1: HBG 1/2 and KLF-1 mRNA Expression in Control and IDH1 (R132H) Mutant Cells After
`Treatment with EPO and Ivosidenib ............................................................................................. 28
`Figure 2: Intracellular 2-HG Protein Concentrations .................................................................... 28
`Figure 3: Effects of Ivosidenib Treatment on 2-HG Concentrations in the Media of Primary Cell
`Cultures ......................................................................................................................................... 29
`Figure 4: Effects of Ivosidenib Treatment on Primary Human Cell Numbers Over Time ............. 30
`Figure 5: FACS Analysis of CD45/CD11b in Primary Human Patient Samples .............................. 30
`Figure 6: FACS Analysis of CD45/CD14 in Primary Human Patient Samples ................................ 31
`Figure 7: Mean Percentage of hCD45+ Cells Over Time ............................................................... 32
`Figure 8: Ivosidenib-Induced Expression of hCD14+ .................................................................... 33
`Figure 9: Ivosidenib-Induced Expression of hCD15+ .................................................................... 33
`Figure 10: Effect on QT Interval .................................................................................................... 57
`Figure 11: Study Diagram .............................................................................................................. 71
`Figure 12: Overall Survival R/R AML Efficacy Set .......................................................................... 96
`Figure 13: Forest Plot of Subgroup Analyses, Part I ..................................................................... 99
`Figure 14: Forest Plot of Subgroup Analyses, Part II .................................................................. 100
`Figure 15: Mean (±SE) Platelets, ANC, and Hemoglobin for R/R AML SAS ................................. 148
`Figure 16. Summary of applicant’s PBPK model building strategy ............................................. 173
`Figure 17: Observed mean (+SD) % increase in 4β-OHC levels as a function of AG-120 dose
`(Study AG120-001) ...................................................................................................................... 176
`Figure 18: Simulated mean plasma concentration-time profiles of itraconazole after multiple
`doses of itraconazole in the presence of multiple oral doses of ivosidenib .............................. 182
`Figure 19: Simulated mean hepatic and intestinal CYP3A4 activity profiles following the
`administration of 300 mg to 1200 mg QD for 19 days. .............................................................. 183
`Figure 20: Simulated (lines) and observed (data points; from Study AG120- C-001) mean plasma
`concentration-time profiles of ivosidenib following the administration of 100 mg BID and 300 -
`1200 mg QD for 19 days. ............................................................................................................ 184
`Figure 21: Goodness of Fit Plots for the Final Population PK Model. ........................................ 195
`Figure 22: Base Model Random Effects versus Continuous Covariates .................................... 196
`Figure 23: Base Model Random Effects versus Categorical Covariates ..................................... 197
`Figure 24: Final Model Random Effects versus Continuous Covariates .................................... 199
`Figure 25: Final Model Random Effects versus Categorical Covariates ..................................... 199
`Figure 26: Sensitivity of AUCss to Covariates and Dose. ........................................................... 200
`Figure 27: Sensitivity of Cmax,ss to Covariates and Dose. ........................................................ 201
`Figure 28: Post Hoc AUCss Distributions for Efficacy Endpoints OR, CR, CR+CRh and Non-CR/CRh
`Response. .................................................................................................................................... 206
`Figure 29: Quartile Plot for Post Hoc AUCss vs Incidence of Clinical Response and Linear Logistic
`Regression for OR, CR, and CR+CRh. ........................................................................................... 208
`Figure 30: AE Incidence versus AUCss, with Incidence grouped by AUCss Quartile and a Linear
`Logistic Regression Fit for ALT – and AST – AEs. ......................................................................... 211
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`Reference ID: 4293723
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`

`

`NDA Multidisciplinary Review and Evaluation
`NDA 211192
`Tibsovo (ivosidenib)
`
`Figure 31: Time Course Of Ivosidenib Concentrations Grouped By Subjects That Received
`Different CYP3A4 Inhibitors. ....................................................................................................... 214
`Figure 32: Time Course Of Ivosidenib Concentrations Grouped By Subjects That Receive
`Different CYP3A4 Inhibitors ........................................................................................................ 215
`Figure 33: Eta(CL) versus baseline creatinine clearance for the data from AG120-C-001. ....... 216
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`Reference ID: 4293723
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`

`NDA Multidisciplinary Review and Evaluation
`NDA 211192
`Tibsovo (ivosidenib)
`
`
`
`Nonclinical Reviewer
`Nonclinical Team Leader
`Office of Clinical Pharmacology Reviewers
`
`Ramadevi Gudi, PhD
`Christopher Sheth, PhD
`Vicky Hsu, PhD; Justin Earp, PhD; Xiling Jiang, PhD;
`Sarah Dorff, PhD
`Gene Williams, PhD; Lian Ma, PhD; Yuching Yang,
`PhD; Rosane Orbach Charlab, PhD
`Clinical Reviewer
`Kelly Norsworthy, MD
`Clinical Team Leader
`Donna Przepiorka, MD, PhD
`Statistical Reviewer
`Lola Luo, PhD
`Statistical Team Leader
`Yuan-Li Shen, DrPH
`Cross‐Disciplinary Team Leader
`Donna Przepiorka, MD, PhD
`Division Director (DHOT)
`John K. Leighton, PhD
`Division Director (OCP)
`Nam Atiqur Rahman, PhD
`Deputy Division Director (OB)
`Thomas E. Gwise, PhD
`Supervisory Associate Division Director (DHP)
`Albert Deisseroth, MD, PhD
`Office Director (or designated signatory authority) Richard Pazdur, PhD
`
`Additional Reviewers of Application
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`Reviewers of the Multidisciplinary Review and Evaluation
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`Office of Clinical Pharmacology Team Leaders
`
`RPM
`CDRH
`ADL (DHP)
`DDS (DHP)
`DMPP
`IRT
`OPDP
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`OPQ
`
`OSE/DMEPA
`OSE/DRISK
`OSI
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`Reference ID: 4293723
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`Laura Wall, MS, APHN
`Aaron J. Schetter, PhD, MPH
`Virginia E. Kwitkowski, MS, ACNP-BC
`Barry Miller, MS, CRNP
`Susan Redwood, MPH, BSN, RN
`Lars Johannesen, PhD; Moh Jee Ng, MS; Dalong Huang, PhD; Mohammad A.
`Rahman, PhD; Jose Vicente Ruiz, MS; Michael Y Li; Christine E. Garnett, PharmD
`Rachael Conklin, MS, RN
`Quality Assessment: Sherita McLamore, PhD
`Drug Substance: Rohit Tiwari, PhD; Charles Jewell, PhD
`Drug Product: Amit Mitra, PhD; Anamitro Banerjee, PhD
`Manufacturing: Ying Zhang; Rakhi Shah
`Facilities: Ying Zhang; Zhihao Qiu, PhD
`Biopharmaceutics: Joan Zhao ; Banu Zolnik, PhD
`Leeza Rahimi, PharmD; Susan Rimmel, PharmD; Hina Mehta, PharmD
`Till Olickal, PhD, PharmD; Elizabeth Everhart, MSN, RN, ACNP
`Anthony Orencia MD, FACP: Jan