`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209607Orig1s000
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`Clinical Review
`Non-Clinical Review
`Statistical Review
`Clinical Pharmacology Review
`
`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`NDA/BLA Multi-Disciplinary Review and Evaluation
`Application Type NDA
`Application Number 209607
`Priority or Standard Priority
`Submit Date 10-31-2017
`Received Date 10-31-2017
`PDUFA Goal Date 7-30-2018
`Division/Office DOP2/OHOP
`Review Completion Date 7-24-2018
`Established Name 131I Iobenguane
`(Proposed) Trade Name AZEDRA
`Pharmacologic Class Radiopharmaceutical
`Code name
`Applicant Progenics Pharmaceuticals Inc.
`Formulation Solution
`Dosing Regimen Dosimetric dose: 5 – 6 mCi (0.1 mCi/kg for patients ≤ 50 kg)
`Therapeutic dose: 500 mCi (8 mCi/kg for patients ≤ 62.5 kg)
`every 12 weeks for two doses
`Treatment of patients age
` years and older with iobenguane
`avid malignant and/or recurrent pheochromocytoma or
`paraganglioma
`Approval
`
`Recommendation on
`Regulatory Action
`Recommended Indication Treatment of patients age 12 years and older with iobenguane
`scan positive, unresectable, locally advanced or metastatic
`pheochromocytoma or paraganglioma who require systemic
`anticancer therapy
`
`Applicant Proposed
`Indication
`
`1
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4297867
`
`(b)
`(4)
`
`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`Table of Contents
`
`Reviewers of Multi-Disciplinary Review and Evaluation.................................................................9
`
`Additional Reviewers of Application ..............................................................................................9
`
`Glossary ........................................................................................................................................10
`
`1
`
`Executive Summary...............................................................................................................12
`1.1 Product Introduction ..........................................................................................................12
`1.2 Conclusions on the Substantial Evidence of Effectiveness .................................................14
`1.3 Benefit-Risk.........................................................................................................................16
`1.4 Patient Experience Data .....................................................................................................22
`
`2 Therapeutic Context ..................................................................................................................24
`2.1 Analysis of Condition ..........................................................................................................24
`2.2 Analysis of Current Treatment Options ..............................................................................25
`
`3 Regulatory Background .............................................................................................................27
`3.1 U.S. Regulatory Actions and Marketing History..................................................................27
`3.2 Summary of Presubmission/Submission Regulatory Activity .............................................27
`
`4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy
`and Safety .............................................................................................................................31
`4.1 Office of Scientific Investigations (OSI)...............................................................................31
`4.2 Product Quality...................................................................................................................31
`4.3 Clinical Microbiology ..........................................................................................................31
`4.4 Devices and Companion Diagnostic Issues .........................................................................31
`4.5 Division of Medical Imaging Products.................................................................................32
`
`5 Nonclinical Pharmacology/Toxicology.......................................................................................33
`5.1 Executive Summary ............................................................................................................33
`5.2 Referenced NDAs, BLAs, DMFs ...........................................................................................35
`5.3 Pharmacology .....................................................................................................................35
`5.4 ADME/PK ............................................................................................................................44
`5.5 Toxicology...........................................................................................................................46
`5.5.1 General Toxicology ..................................................................................................46
`5.5.2 Genetic Toxicology...................................................................................................48
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`Reference ID: 4297867
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`5.5.3 Carcinogenicity ........................................................................................................49
`5.5.4 Reproductive and Developmental Toxicology .........................................................49
`5.5.5 Other Toxicology Studies .........................................................................................50
`
`6 Clinical Pharmacology................................................................................................................51
`6.1 Executive Summary ............................................................................................................51
`6.2 Recommendations..............................................................................................................51
`6.3 Postmarketing Requirements and Commitments .............................................................52
`6.4 Summary of Clinical Pharmacology Assessment ................................................................52
`6.5 Pharmacology and Clinical Pharmacokinetics ....................................................................52
`6.6 General Dosing and Therapeutic Individualization.............................................................53
`6.6.1 General Dosing ........................................................................................................53
`6.6.2 Therapeutic Individualization ..................................................................................53
`6.6.3 Outstanding Issues...................................................................................................54
`6.6.4 Summary of Labeling Recommendations ...............................................................55
`Comprehensive Clinical Pharmacology Review..............................................................55
`6.7.1 General Pharmacology and Pharmacokinetic Characteristics .................................55
`6.7.2 Clinical Pharmacology Questions............................................................................57
`[Source: NDA 209607/SDN 2 – FDA’s IRT-QTc Review, PP 2] ...........................................63
`
`6.7
`
`7 Sources of Clinical Data and Review Strategy............................................................................71
`7.1 Table of Clinical Studies ......................................................................................................71
`7.2 Review Strategy ..................................................................................................................73
`
`8 Statistical and Clinical and Evaluation .......................................................................................74
`8.1 Review of Relevant Individual Trials Used to Support Efficacy...........................................74
`8.1.1 MIP-IB12B: A Phase II Study Evaluating the Efficacy and Safety of 131I-MIBG in
`Patients with Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma.......74
`8.1.2 MIP-IB12B Study Results..........................................................................................81
`8.1.3 Study MIP-IB12: A Phase I Study Evaluating the Maximum Tolerated Dose,
`Dosimetry, Safety and Efficacy of Ultratrace Iobenguane I 131 in Patients with Malignant
`Pheochromocytoma/ Paraganglioma...............................................................................97
`8.1.4 Assessment of Efficacy Across Trials......................................................................100
`8.1.5 Integrated Assessment of Effectiveness................................................................101
`8.2 Review of Safety ..............................................................................................................101
`
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4297867
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`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`8.2.1 Safety Review Approach........................................................................................102
`8.2.2 Review of the Safety Database ..............................................................................103
`8.2.3 Adequacy of Applicant’s Clinical Safety Assessments............................................104
`8.2.4 Safety Results.........................................................................................................106
`8.2.5 Analysis of Submission-Specific Safety Issues........................................................127
`8.2.6 Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability .......129
`8.2.7 Safety Analyses by Demographic Subgroups.........................................................130
`8.2.8 Specific Safety Studies/Clinical Trials.....................................................................131
`8.2.9 Additional Safety Explorations...............................................................................131
`8.2.10 Safety in the Postmarket Setting .........................................................................133
`8.2.11 Integrated Assessment of Safety .........................................................................133
`
`10 SUMMARY AND CONCLUSIONS.............................................................................................135
`10.1 Statistical Issues..............................................................................................................135
`10.2 Conclusions and Recommendations...............................................................................135
`
`11 Advisory Committee Meeting and Other External Consultations .........................................137
`
`12 Pediatrics ...............................................................................................................................138
`
`13 Labeling Recommendations ..................................................................................................138
`13.1 Prescription Drug Labeling..............................................................................................138
`
`14 Risk Evaluation and Mitigation Strategies (REMS).................................................................140
`
`15 Postmarketing Requirements and Commitments .................................................................141
`
`16 Division Director (DHOT) .......................................................................................................142
`
`17 Division Director (OCP) ..........................................................................................................143
`
`18 Division Director (OB) ............................................................................................................144
`
`19 Division Director (Clinical) .....................................................................................................145
`
`21 Appendices ............................................................................................................................150
`21.1 References ......................................................................................................................150
`21.2 Financial Disclosure ........................................................................................................153
`21.3 Nonclinical Pharmacology/Toxicology............................................................................154
`
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`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`21.4
`21.5
`
`OCP Appendices (Technical documents supporting OCP recommendations)..........154
`Additional Clinical Outcome Assessment Analyses ..................................................154
`
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`Reference ID: 4297867
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`

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`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`List of Tables
`
`Table 1: Biodistribution of carrier-added and no-carrier-added 131-I MIBG in tissues from
`xenograft implanted nude mice as a percentage of the injected dose per gram of tissue ..........36
`Table 2: Increased Activity in 131I-MIBG Treated Mice Implanted with Pheochromocytoma .....41
`Table 3: Males-Percent Changes from Control in Cardiac Parameters (MIBG only) ....................43
`Table 4: IC50 s for inhibitions of MIBG uptake by SK-N-SH cells of selected adrenergic ligands...43
`Table 5: Summary of Blood PK Parameters for 131I-MIBG in 11 Patients .....................................58
`Table 6: Summary of Urinary Excretion Data of Radioactivity in 11 Patients...............................59
`Table 7: Metabolic Profiling in Urine (% Injected Dose)...............................................................59
`Table 8: Reduction in Use of Antihypertensive Medication Following 131I-MIBG – All treated 68
`evaluable PPGL Patients ...............................................................................................................61
`Table 9: Reduction in Use of Antihypertensive Medication Following 131I-MIBG by Number of
`Therapeutic Doses Administered .................................................................................................61
`Table 10: Duration of clinical Benefit in patients who Achieved the Primary Endpoint...............62
`Table 11: Incidence of TEAEs occurring in ≥10% of 74 evaluable patients...................................62
`Table 12: The Point Estimates and the 90% CIs of of ΔQTcF Corresponding to the Largest Upper
`Bounds for All-Treated 131I-MIBG Group (FDA Analysis for Study MIP-IB12B) .............................63
`Table 13: Comparison of Mean Radiation Absorbed Dose Estimates for Patients with Normal
`Renal Function and Patients with Mild-to-Moderate Renal Impairment.....................................64
`Table 14: Patients with Reduced Therapeutic Dose Based on Critical Organ Exposure Estimates
`from Study MIP-IB12B (Reviewer’s Table)....................................................................................64
`Table 15: Projected Maximum Therapeutic Dose in Individual Patients from Study MIP-IB11
`(mCi)* ...........................................................................................................................................66
`Table 16: Radiographic Response by RECIST in Patients Receiving One 131I-MIBG Therapeutic
`Dose in Studies MIP-IB12 AND MIP-IB12B ...................................................................................66
`Table 17: Summary of Inhibition of CYP-Enzyme Activities by MIBG in Pooled Human Hepatic
`Microsomes ..................................................................................................................................67
`Table 18: Effect of MIBG on CYP Enzyme Activities in Human Hepatocytes ................................68
`Table 19: Apparent Permeability and Efflux Ratios from Caco-2 Cells .........................................69
`Table 20: Clinical Studies Included in NDA 209607 ......................................................................71
`Table 21: Patient Disposition, Study MIP-IB12B...........................................................................82
`Table 22: Major Protocol Deviations During Study MIP-IB12B.....................................................84
`Table 23: Demographic Characteristics of all Enrolled Patients, Study MIP-IB12B ......................85
`Table 24: Baseline Characteristics, Study MIP-IB12B ...................................................................87
`Table 25: Results of the Primary Endpoint (FAS)..........................................................................89
`Table 26: Results of Sensitivity Analyses ......................................................................................90
`Table 27: Duration of Response for Patients Who Attained at Least 50% Reduction in
`Antihypertensive Medications......................................................................................................90
`Table 28: Patients with a Decrease in Systolic Blood Pressure > 20 mm Hg, Study MIP-IB12B ...92
`Table 29: Changes in Systolic Blood Pressure During Study MIP-IB12B .......................................92
`Table 30: Best Confirmed Overall Tumor Response and Duration of Response ..........................93
`Table 31: Best Confirmed Overall Tumor Response and Duration of Benefit ..............................94
`
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`Reference ID: 4297867
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`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`Table 32: Best Confirmed Overall Tumor Response and Duration of Benefit ..............................95
`Table 33: Primary Endpoint in Subgroups ....................................................................................96
`Table 34: Distribution of 131I-MIBG Administrations in the MIP-IB12/MIP-IB12B Safety
`Population (N=88) ......................................................................................................................103
`Table 35: Serious Adverse Events, Study MIP-IB12/MIP-IB12B Safety Population, Primary
`Analysis.......................................................................................................................................110
`Table 36: Adverse Events of Special Interest, Studies MIP-IB12/MIP-IB12B, Primary Analysis..114
`Table 37: Cases of Renal Failure in the MIP-IB12/MIP-IB12B Safety Population .......................116
`Table 38: Treatment Emergent Adverse Events in at Least 5% of Patients, Studies MIP-
`IB12/MIP-IB12B Safety Population, Primary Analysis ................................................................117
`Table 39: Laboratory Abnormalities, Studies MIP-IB12B & MIP-IB12 ........................................121
`Table 40: International Normalized Ratio Abnormalities, Study MIP-IB2B ................................122
`Table 41: Activated Partial Thromboplastin Time Abnormalities, Study MIP-IB2 ......................122
`Table 42: The Point Estimates and the 90% CIs of ΔQTcF Corresponding to the Largest Upper
`Bounds for All-Treated 131I-MIBG Group (FDA Analyses for Study IB12B)..................................126
`Table 43: Completion Rates by Visit ...........................................................................................155
`
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4297867
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`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`List of Figures
`
`Figure 1: Selective Uptake of MIBG in Cells Expressing Noradrenaline Transporter....................36
`Figure 2: Radioactive vs. MIBG Exposure in High vs Low Specificity Activity Radiolabeled MIBG
`Products........................................................................................................................................37
`Figure 3: The Effect of Reserpine on the Retention of I125 MIBG by SK-N-SH (top) and PC-12
`(bottom) Cells...............................................................................................................................38
`Figure 4: Cytotoxic Effects of 100 mCi of I-125 MIBG and I-131 MIBG with Equivalent Specific
`Activity on SK-N-LO and SK-N-SH Cells .........................................................................................38
`Figure 5: Calculated Values of Absorbed Radiation Dose per Unit of Injected Radioactivity
`(Gy/MBq) to Tumor and Normal Organs for Non-Carrier-Added (White Bars) and Exchange
`Preparation (Black Bars) of 131I MIBG ...........................................................................................39
`Figure 6: Specific Uptake by SK-N-BE(2c) Neuroblastoma Cells of No Carrier-Added 131I-MIBG
`(closed circles) and a Commercial Carrier-Added Preparation (open circles) ..............................40
`Figure 7: Increased Exposure in Pheochromocytoma versus Neuroblastoma Implants ..............40
`Figure 8: Dose Dependent Increase in 131I-MIBG-Mediated Anti-Tumor Activity in PC-12
`Implanted Animals........................................................................................................................41
`Figure 9: Change In Tumor Volume and Days of Tumor Doubling Time after Administration of
`131I Ultratace and 131I Comparison product ..................................................................................42
`Figure 10: Tumor Doubling Times After 131I-MIBG Administration ..............................................42
`Figure 11: Distribution of Total Injected Dose and Occurrence of DLTs Across Sequential Dose
`Cohorts .........................................................................................................................................60
`Figure 12: Swimmer Plot for the Patients Who had Reduction in Antihypertensive Medications
`by at Least 50% for at Least 6 Months .........................................................................................91
`Figure 13: Mean Score of PF by Visit ..........................................................................................156
`Figure 14: Mean Percentage* Change in PF Score from Baseline over Visit ..............................157
`
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4297867
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`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`Reviewers of Multi-Disciplinary Review and Evaluation
`
`Regulatory Project Manager
`Nonclinical Reviewer
`Nonclinical Team Leader
`Office of Clinical Pharmacology Reviewer(s)
`Office of Clinical Pharmacology Team Leader(s)
`Clinical Reviewer
`Clinical Team Leader
`Statistical Reviewer
`Statistical Team Leader
`Cross-Disciplinary Team Leader
`Division Director (DHOT)
`Division Director (OCP)
`Division Director (OB)
`Associate Division Director (OHOP)
`
`Sharon Sickafuse
`Dubravka Kufrin
`Whitney Helms
`Safaa Burns
`Jeanne Fourie Zirkelbach
`Diana Bradford
`Suzanne Demko
`Xiaoping (Janet) Jiang
`Lisa Rodriguez
`Suzanne Demko
`John Leighton
`Nam Atiqur Rahman
`Rajeshwari Sridhara
`Steven Lemery
`
`Additional Reviewers of Application
`
`OPQ
`Microbiology
`Facilities
`OPDP
`OSI
`OSE/DEPI
`OSE/DMEPA
`OSE/DRISK
`DMIP
`
`Sithamalli Chandramouli and Dhanalakshmi Kasi
`Julie Nemecek
`Rebecca Dombrowski
`Carole Broadnax
`David Menschik
`Carolyn McCloskey
`Janine Stewart
`Till Olickal
`Stanley Stern
`
`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
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
`DMIP=Division of Medical Imaging Products
`
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`Reference ID: 4297867
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`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`Glossary
`
`AC
`ADME
`AE
`BLA
`BPCA
`BRF
`CBER
`CDER
`CDRH
`CDTL
`CFR
`CMC
`COSTART
`CRF
`CRO
`CRT
`CSR
`CSS
`DDI
`DHOT
`DMC
`ECG
`eCTD
`ETASU
`FDA
`FDAAA
`FDASIA
`GCP
`GRMP
`ICH
`IND
`ISE
`ISS
`ITT
`IV
`MedDRA
`MIBG
`mITT
`NCI-CTCAE
`
`advisory committee
`absorption, distribution, metabolism, excretion
`adverse event
`biologics license application
`Best Pharmaceuticals for Children Act
`Benefit Risk Framework
`Center for Biologics Evaluation and Research
`Center for Drug Evaluation and Research
`Center for Devices and Radiological Health
`Cross-Discipline Team Leader
`Code of Federal Regulations
`chemistry, manufacturing, and controls
`Coding Symbols for Thesaurus of Adverse Reaction Terms
`case report form
`contract research organization
`clinical review template
`clinical study report
`Controlled Substance Staff
`Drug-Drug Interactions
`Division of Hematology Oncology Toxicology
`data monitoring committee
`electrocardiogram
`electronic common technical document
`elements to assure safe use
`Food and Drug Administration
`Food and Drug Administration Amendments Act of 2007
`Food and Drug Administration Safety and Innovation Act
`good clinical practice
`good review management practice
`International Conference on Harmonization
`Investigational New Drug
`integrated summary of effectiveness
`integrated summary of safety
`intent to treat
`intravenous
`Medical Dictionary for Regulatory Activities
`metaiodobenzylguanidine
`modified intent to treat
`National Cancer Institute-Common Terminology Criteria for Adverse Event
`
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`Reference ID: 4297867
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`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`NDA
`NME
`OCS
`OPQ
`OSE
`OSI
`PBRER
`PD
`PI
`PK
`PMC
`PMR
`PP
`PPGL
`PPI
`PREA
`PRO
`PSUR
`REMS
`SAE
`SAP
`SGE
`SOC
`TEAE
`
`New Drug Application
`New Molecular Entity
`Office of Computational Science
`Office of Pharmaceutical Quality
`Office of Surveillance and Epidemiology
`Office of Scientific Investigation
`Periodic Benefit-Risk Evaluation Report
`Pharmacodynamics
`prescribing information
`Pharmacokinetics
`Postmarketing Commitment
`Postmarketing Requirement
`per protocol
`pheochromocytoma and paraganglioma
`patient package insert
`Pediatric Research Equity Act
`patient reported outcome
`Periodic Safety Update report
`risk evaluation and mitigation strategy
`serious adverse event
`statistical analysis plan
`special government employee
`standard of care
`treatment emergent adverse event
`
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4297867
`
`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`1 Executive Summary
`
`1.1 Product Introduction
`
`On October 31, 2017, Progenics Pharmaceuticals, Inc. (Progenics) submitted a New Drug
`Application (NDA) under 505(b)(1) of the Federal Food, Drug, and Cosmetic Act for
`131I-iobenguane (metaiodobenzylguanidine, 131I-iobenguane, iobenguane I-131, 131I-MIBG,
`Azedra), a radiopharmaceutical.
`Iobenguane is a guanethidine derivative that resembles norepinephrine in structure; it acts as a
`substrate for the norepinephrine transporter (NT) expressed on neuroendocrine cell surfaces. It
`can be labeled with radioactive isotopes of iodine for diagnostic or therapeutic applications.
`Conventional formulations of MIBG are known as the “carrier-added” or “carrier-containing”
`forms of MIBG, because a significant quantity of non-radioactive (or “cold”) carrier MIBG is
`present in the iobenguane I-131 dose administered to patients. In therapeutic administrations
`of carrier-added iobenguane I-131, the molar ratio of nonradioactive to radioactive MIBG
`molecules approaches
`. This imbalance of “cold” to radioactive MIBG can lead to pressor
`effects and reduction in efficacy in patients.
`
`The carrier molecule iobenguane is a biogenic amine that interferes with the reuptake of
`norepinephrine, resulting in increased noradrenergic activity. When administered at high-mass
`doses, carrier-added MIBG can cause hypertension and other cardiovascular toxicity. The
`selective active uptake by the NT expressed on neuroendocrine cell surfaces is a competitive
`process; therefore, the presence of cold iobenguane molecules in the infusion solution can
`decrease the uptake in target neuroendocrine tumor cells.
`
`FDA has approved carrier-added iobenguane as a diagnostic agent for use in localization of
`pheochromocytoma and neuroblastoma, and it has been studied as treatment for patients with
`advanced pheochromocytoma and paraganglioma (PPGL) and other neuroendocrine
`malignancies.
`
`Progenics has developed a no-carrier-added version of iobenguane I-131 and the final product
`formulation
`. The final formulation is an injection containing 555
`MBq/mL (15 mCi/ml) at TOC as a clear solution in a single-dose vial. The intended dosimetric
`dose is 5 – 6 mCi for patients weighing 50.0 kg or more, and 0.1 mCi/kg for those weighing less
`than 50.0 kg. The intended therapeutic dose is 500 mCi (or 8 mCi/kg for patients weighing 62.5
`kg or less, and an iobenguane chemical mass of
`).
`
`The current application proposes an indication for 131I-iobenguane for the treatment of patients
`with iobenguane-avid metastatic or recurrent pheochromocytoma and paraganglioma (PPGL).
`The indication to be granted is “…for the treatment of adult and pediatric patients 12 years and
`older with iobenguane scan positive, unresectable, locally advanced or metastatic
`pheochromocytoma or paraganglioma who require systemic anticancer therapy.”
`
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`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
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`Reference ID: 4297867
`
`APPEARS THIS WAY ON ORIGINAL
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`13
`Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)
`
`Reference ID: 4297867
`
`APPEARS THIS WAY ON ORIGINAL
`
`

`

`NDA/BLA Multi-Disciplinary Review and Evaluation {NDA 209607}
`{AZEDRA, 131I-MIBG}
`
`1.2 Conclusions on the Substantial Evidence of Effectiveness
`
`The recommendations for approval of Azedra are supported primarily by one single-arm, multicenter trial entitled, “A Phase II Study
`Evaluating the Efficacy and Safety of 131I-MIBG in Patients with Malignant Relapsed/Refractory Pheochromocytoma/Paraganglioma,”
`Study MIP-IB12B. The trial was conducted in patients greater than 12 years of age who were diagnosed with pheochromocytoma or
`paraganglioma (PPGL) and who were ineligible for curative therapy. Patients had also progressed on prior therapy or were not
`candidates for chemotherapy. Other eligibility criteria required tumors to have definitive iobenguane avidity, at least one tumor site
`identified by computed tomography (CT), magnetic resonance imaging (MRI), or iobenguane I 131 scan, Karnofsky performance
`status greater than 60, no active central nervous system lesions, and no changes to their antihypertensive regimen in the 30 days
`prior to the first therapeutic dose.
`Iobenguane I 131 was administered in two therapeutic doses at 500 mCi each (8 mCi/kg, for patients weighing 62.5 kg or less)
`approximately three months apart. The doses were administered after an imaging dose and dosimetry. A total of 74 patients
`received the dosimetric dose. Following dosimetry, 68 patients received at least one therapeutic dose, and 50 patients received two
`therapeutic doses, administered at least 90 days apart. Among the 68 patients who received at least one dose, the median age was
`55 years (16 to 72 years), 57% were male, 75% were White, 21% were Black, 4% were Asian and the remainder had no race or
`ethnicity reported. For the primary tumor diagnosis, 78% had pheochromocytoma, 21% had paraganglioma, and 1% had both. Fifty
`percent (50%) of patients with evaluable imaging studies had lung or liver metastases and 61% had bone metastases at baseline.
`Eighty-eight percent (88%) underwent prior surgery, 50% received prior external beam radiation.
`
`The primary endpoint of the trial was the proportion of patients with a reduction by at least 50%, or discontinuation, of all
`antihypertensive medications for at least six months. The secondary objectives of the trial included assessment by RECIST for overall
`tumor response (ORR) to include complete response (CR) and partial