CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208712Orig1s000
`
`INTEGRATED REVIEW
`
`
`
`
`
`

`

`NDA 208712
`Vonjo (pacritinib)
`
`Integrated Review
`
`Table 1. Administrative Application Information
`Category
`Application Information
`Application type
`NDA
`Application number(s)
`208712
`Priority or standard
`Priority
`Submit date(s)
`3/30/2021
`Received date(s)
`3/30/2021
`PDUFA goal date
`11/30/2021
`Division/office
`Division of Nonmalignant Hematology (DNH)
`Review completion date
`Click or tap to enter a date.
`Established/proper name
`pacritinib
`(Proposed) proprietary name
`Vonjo
`Pharmacologic class
`Kinase Inhibitor
`Code name
`N/A
`Applicant
`CTI BioPharma Corp
`Dosage form(s)/formulation(s) Capsules
`Dosing regimen
`Oral twice daily (BID)
`Applicant proposed
`Treatment of adult patients with intermediate- or high-risk
`indication(s)/ population(s)
`primary or secondary (post-polycythemia vera or post-essential
`thrombocythemia) myelofibrosis (MF)
`Proposed SNOMED indication Treatment of adult patients with intermediate- or high-risk
`primary or secondary (post-polycythemia vera or post-essential
`thrombocythemia) myelofibrosis (MF)
`Accelerated approval
`200 mg administered orally
`
`
`
`Regulatory action
`Approved dosage (if
`applicable)
`Approved indication(s)/
`population(s) (if applicable)
`
`Approved SNOMED term for
`indication (if applicable)
`
`
`
`
`
`Treatment of adults with intermediate- or high-risk primary or
`secondary (post-polycythemia vera or post-essential
`thrombocythemia) myelofibrosis with thrombocytopenia with a
`baseline platelet count of <50×109/L
`Myelofibrosis
`
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`Reference ID: 4944832
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`(b) (4)
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`NDA 208712
`Vonjo (pacritinib)
`
`Table of Contents
`Table of Tables .................................................................................................................. vi
`Table of Figures ...................................................................................................................x
`Glossary ...............................................................................................................................1
`I. Executive Summary ..........................................................................................................3
`1. Summary of Regulatory Action ...................................................................................3
`2. Benefit-Risk Assessment ..............................................................................................5
`2.1. Benefit-Risk Framework .......................................................................................5
`2.2. Conclusions Regarding Benefit-Risk ....................................................................9
`II. Interdisciplinary Assessment.........................................................................................13
`3. Introduction ................................................................................................................13
`3.1. Review Issue List .................................................................................................15
`3.1.1. Key Review Issues Relevant to Evaluation of Benefit .................................15
`3.1.1.1. Premature Stopping of PERSIST-2 ........................................................15
`3.1.1.2. PERSIST-2 Failed on One Coprimary Efficacy Endpoint .....................15
`3.1.1.3. Pacritinib 400 mg QD Appears Less Effective on SVR than
`Pacritinib 200 mg BID in PERSIST-2 ................................................15
`3.1.1.4. Scientific Basis for Establishing Substantial Evidence of
`Effectiveness .......................................................................................15
`3.1.2. Key Review Issues Relevant to Evaluation of Risk ......................................15
`3.1.2.1. Major Adverse Cardiac Events ...............................................................15
`3.1.2.2. Bleeding ..................................................................................................15
`3.2. Approach to the Review ......................................................................................16
`4. Patient Experience Data .............................................................................................18
`5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology ..................19
`5.1. Nonclinical Assessment of Potential Effectiveness .............................................23
`5.1.1. Primary Pharmacology ..................................................................................23
`5.1.2. Animal Model Data Showing Proof of Concept ...........................................23
`6. Assessment of Effectiveness ......................................................................................25
`6.1. Dose and Dose Responsiveness ...........................................................................25
`6.2. Clinical Trial Intended to Demonstrate Efficacy .................................................27
`6.2.1. Study PERSIST-2 .........................................................................................27
`6.2.2. Results of Analyses, PERSIST-2 ..................................................................36
`6.3. Key Review Issues Relevant to Evaluation of Benefit ........................................52
`6.3.1. Premature Stopping of PERSIST-2 ...............................................................52
`6.3.2. PERSIST-2 Failed on One Coprimary Efficacy Endpoint ............................53
`6.3.3. Pacritinib 400 mg QD Appears Less Effective on SVR Than
`Pacritinib 200 mg BID in PERSIST-2 ......................................................54
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`NDA 208712
`Vonjo (pacritinib)
`6.3.4. Scientific Basis for Establishing Substantial Evidence of
`Effectiveness .............................................................................................55
`7. Risk and Risk Management ........................................................................................56
`7.1. Potential Risks or Safety Concerns Based on Nonclinical Data ..........................56
`7.2. Potential Risks or Safety Concerns Based on Drug Class or Other Drug-
`Specific Factors ..............................................................................................58
`7.3. Potential Safety Concerns Identified Through Postmarket Experience ..............63
`7.4. FDA Approach to the Safety Review ..................................................................63
`7.5. Adequacy of Clinical Safety Database ................................................................64
`7.6. Safety Findings and Concerns Based on Review of Clinical Safety
`Database ..........................................................................................................65
`7.6.1. Safety Findings and Concerns, PERSIST-2 ..................................................65
`7.6.1.1. Overall Treatment-Emergent Adverse Event Summary .........................65
`7.6.1.2. Deaths .....................................................................................................70
`7.6.1.3. Laboratory Findings ...............................................................................71
`7.7. Key Review Issues Relevant to Evaluation of Risk ............................................72
`7.7.1. Major Adverse Cardiac Events .....................................................................72
`7.7.2. Bleeding ........................................................................................................75
`8. Therapeutic Individualization ....................................................................................78
`8.1. Intrinsic Factors ...................................................................................................78
`8.2. Drug Interactions .................................................................................................79
`8.3. Plans for Pediatric Drug Development ................................................................83
`8.4. Pregnancy and Lactation......................................................................................84
`9. Product Quality ..........................................................................................................85
`9.1. Device or Combination Product Considerations .................................................86
`10. Human Subjects Protections/Clinical Site and Other Good Clinical Practice
`Inspections/Financial Disclosure ...........................................................................86
`11. Advisory Committee Summary ................................................................................86
`III. Appendices ...................................................................................................................87
`12. Summary of Regulatory History ..............................................................................87
`13. Pharmacology Toxicology: Additional Information and Assessment .....................88
`13.1. Summary Review of Studies Submitted Under the IND ...................................88
`13.1.1. Pacritinib Pharmacology .............................................................................88
`13.1.1.1. In Vivo and Ex Vivo Pharmacodynamic Activity ................................91
`13.1.1.2. Safety Pharmacology ............................................................................92
`13.1.2. ADME/Pharmacokinetics ...........................................................................93
`13.1.3. Toxicology ................................................................................................101
`13.1.3.1. General Toxicology ............................................................................101
`13.1.3.2. Genotoxicity Studies ..........................................................................110
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`NDA 208712
`Vonjo (pacritinib)
`13.1.3.3. Carcinogenicity Studies ......................................................................112
`13.1.3.4. Reproductive and Developmental Toxicity ........................................114
`13.2. Individual Reviews of Studies Submitted to the NDA ....................................122
`14. Clinical Pharmacology: Additional Information and Assessment .........................122
`14.1. In Vitro Studies ................................................................................................122
`14.2. In Vivo Studies ................................................................................................130
`14.3. Summary of Bioanalytical Method Validation ................................................167
`14.4. Pharmacometrics Review ................................................................................169
`14.4.1. Summary of Findings ................................................................................169
`14.4.2. Population PK Analysis ............................................................................170
`14.4.2.1. Applicant’s Population PK Model Development ...............................172
`14.4.2.2. Reviewer’s Population PK Model Development ...............................178
`14.4.2.3. Impact of Selected Covariates on Pacritinib Exposures .....................185
`14.4.2.4. Comparisons of Pacritinib Exposures Between Different
`Dosage Regimens .............................................................................186
`14.4.3. Population PK-PD Analyses .....................................................................187
`14.4.3.1. Applicant’s Exposure vs. Spleen Volume Analyses ..........................187
`14.4.3.2. Applicant’s Exposure vs. Total Symptom Score Analyses ................192
`14.4.3.3. Applicant’s Exposure vs. Spleen Volume Responder Rate
`Analyses ............................................................................................194
`14.4.3.4. Applicant’s Exposure vs. Safety Analyses .........................................196
`14.4.3.5. Reviewer’s PKPD Model Development .............................................198
`14.4.3.6. Reviewer’s Exposure vs. Safety Modeling ........................................204
`14.4.3.7. Assessment of the Impact of Dose Reduction on Spleen
`Volume Response .............................................................................207
`14.4.3.8. Predicted Probabilities of Death Events at 200 mg BID and
`400 mg QD .......................................................................................210
`15. Trial Design: Additional Information and Assessment ..........................................213
`16. Efficacy: Additional Information and Assessment ................................................214
`17. Clinical Safety: Additional Information and Assessment ......................................214
`18. Mechanism of Action/Drug Resistance: Additional Information and
`Assessment ...........................................................................................................214
`19. Other Drug Development Considerations: Additional Information and
`Assessment ...........................................................................................................214
`20. Data Integrity-Related Consults (Office of Scientific Investigations, Other
`Inspections) ..........................................................................................................214
`21. Labeling Summary of Considerations and Key Additional Information ...............215
`22. Postmarketing Requirements and Commitments ...................................................218
`23. Financial Disclosure ...............................................................................................220
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`NDA 208712
`Vonjo (pacritinib)
`24. References ..............................................................................................................220
`25. Review Team ..........................................................................................................221
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`NDA 208712
`Vonjo (pacritinib)
`
`Table of Tables
`Table 1. Administrative Application Information ............................................................... i
`Table 2. Benefit-Risk Framework........................................................................................5
`Table 3. Benefit-Risk Value Tree ......................................................................................11
`Table 4. Clinical Trial Submitted in Support of Efficacy and/or Safety
`Determinations1 for Pacritinib .....................................................................................17
`Table 5. Patient Experience Data Submitted or Considered ..............................................18
`Table 6. Summary of General Clinical Pharmacology and Pharmacokinetics ..................19
`Table 7. Pharmacokinetic Parameters of Pacritinib From the Population PK Model in
`Patients With Myelofibrosis ........................................................................................20
`Table 8. Pacritinib Effects on Clinically Relevant Endpoints in Animal Models of
`Myeloproliferative Disease ..........................................................................................24
`Table 9. Dosage Modification for Pacritinib-Related Diarrhea .........................................25
`Table 10. Dose Modification for Pacritinib-Related Thrombocytopenia ..........................25
`Table 11. Dose Modification for Hemorrhage ...................................................................25
`Table 12. Patient Disposition in PERSIST-2 (ITT Efficacy Population) ..........................37
`Table 13. Patient Disposition in PERSIST-2 Patients With Baseline Platelet Counts
`Less Than 50×109/L (ITT Efficacy Population) ..........................................................37
`Table 14. Summary of Demographic Characteristics in PERSIST-2 (ITT Efficacy
`Population) ...................................................................................................................38
`Table 15. Demographic Characteristics of PERSIST-2 Patients With Baseline Platelet
`Counts Less Than 50×109/L (ITT Efficacy Population) ..............................................39
`Table 16. Proportion of Subjects Achieving a ≥35% Spleen Volume Reduction From
`Baseline to Week 24, ITT Efficacy Population ...........................................................41
`Table 17. Proportion of Subjects Achieving a ≥35% Spleen Volume Reduction From
`Baseline to Week 24, All Randomized Patients ..........................................................42
`Table 18. Proportion of Patients With ≥35% Reduction in Spleen Volume From
`Baseline to Week 24—PERSIST-2 (ITT Efficacy Population and Patients With
`Platelet Counts Less Than 50×109/L) ..........................................................................42
`Table 19. Proportion of Patients With at Least 50% Reduction in Original Total
`Symptom Score (Including Tiredness) in PERSIST-2 (ITT Efficacy Population
`and Patients With Platelet Counts Less Than 50×109/L) .............................................44
`Table 20. Proportion of Patients With at Least 50% Reduction in Original Total
`Symptom Score (Including Tiredness) in PERSIST-2 (ITT All Randomized
`Patients)........................................................................................................................45
`Table 21. Proportion of Patients With at Least 50% Reduction in the Modified Total
`Symptom Score (Excluding Tiredness) at Week 24 in PERSIST-2 (ITT Efficacy
`Population and Patients With Platelet Counts Less Than 50×109/L) ..........................45
`Table 22. Proportion of Patients With at Least 50% Reduction in the Modified Total
`Symptom Score (Excluding Tiredness) at Week 24 in PERSIST-2 (ITT All
`Randomized Population) ..............................................................................................46
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`NDA 208712
`Vonjo (pacritinib)
`Table 23. Proportion of Patients With ≥35% Reduction in SPV, With at Least 50%
`Reduction in the Total and Modified Symptom Score at Week 24 in PERSIST-2
`(ITT Efficacy Population and Patients With Platelet Counts Greater Than
`50×109/L) .....................................................................................................................46
`Table 24. Proportion of Patients With at Least 35% Reduction in Spleen Volume
`From Baseline to Week 24 by Sex in PERSIST-2 Efficacy Results Secondary
`Endpoint (ITT Population and Patients With Platelet Counts Less Than 50×109/L) ..47
`Table 25. Proportion of Patients With at Least 50% Reduction in the Modified TSS
`(Excluding Tiredness) From Baseline to Week 24 by Sex in PERSIST-2 (ITT
`Population and Patients With Platelet Counts Less Than 50×109/L) ..........................47
`Table 26. Proportion of Patients With at Least 35% Reduction in Spleen Volume
`From Baseline to Week 24 by Age in PERSIST-2 (ITT Population and Patients
`With Platelet Counts Less Than 50×109/L) .................................................................48
`Table 27. Exposure Margins (Chronic Toxicology Studies, Pivotal) ................................57
`Table 28. Duration of Treatment, Safety Population, PERSIST-2 ....................................64
`Table 29. Treatment-Emergent Adverse Events, PERSIST-2 ...........................................65
`Table 30. AEs Occurring in ≥10% of Patients Receiving Pacritinib 200 mg BID or
`BAT, PERSIST-2 .........................................................................................................66
`Table 31. SAEs Occurring in ≥3% Patients Receiving Pacritinib 200 mg BID or BAT,
`PERSIST-2 ...................................................................................................................67
`Table 32. Proportion of Patients With Fatal AEs, PERSIST-2..........................................68
`Table 33. Adverse Events Leading to Permanent Discontinuation of Study Drug in
`≥2% of Patients ............................................................................................................69
`Table 34. Adverse Events Leading to Interruption of Study Drug in ≥2% of Patients .....69
`Table 35. Adverse Events Leading to Study Drug Dose Reduction in ≥2% of Patients ...70
`Table 36. Proportion of Patients Who Died on Study or Within 30 Days of Last Dose
`of Study Treatment, PERSIST-2 and PERSIST-1 .......................................................71
`Table 37. Visit Distribution of ITT Efficacy Population ...................................................73
`Table 38. Proportion of Patients With Bleeding Events (Baseline Platelet Count
`<50×109/L) ...................................................................................................................77
`Table 39. Point Estimators (LS-Means) and Two-Sided 90% CIs for PK Parameters
`of Pacritinib in Plasma After a Single Oral Dose of 400 mg .......................................79
`Table 40. Comparison of the Predicted and Observed Pacritinib PK Data, Trial
`SB1518-2007-001§ .......................................................................................................82
`Table 41. Nonclinical Data Supporting Labeling on Pregnancy and Lactation ................84
`Table 42. Reproductive Toxicity Exposure Margins/Dose Multiples ...............................85
`Table 43. Pacritinib (Parent Molecule) In Vitro Kinase Inhibition Profile .......................89
`Table 44. Pacritinib (M1 Metabolite) In Vitro Kinase Inhibition Profile ..........................90
`Table 45. Pacritinib (M2 Metabolite) In Vitro Kinase Inhibition Profile ..........................90
`Table 46. Pacritinib In Vitro Inhibitory Activity in Tumor Cell Lines .............................91
`Table 47. Safety Pharmacology Studies ............................................................................93
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`NDA 208712
`Vonjo (pacritinib)
`Table 48. Mean Tissue/Plasma PK Parameters of SB1518 After Oral Dosing in
`BALB/c Mice ...............................................................................................................94
`Table 49. Toxicokinetic Data From Repeat-Dose Toxicology Studies .............................99
`Table 50. TK Parameters in BALB/C Mice .......................................................................99
`Table 51. TK Parameters in Beagle Dog ...........................................................................99
`Table 52. CD-1 Mouse EFD TK Parameters; GD 6 of 15 ...............................................100
`Table 53. New Zealand White Rabbit EFD TK Parameters; GD 7 of 20 ........................100
`Table 54. Study Information, Study RPT233 ..................................................................102
`Table 55. Observations and Results, Study RPT233 .......................................................102
`Table 56. Study Information, Study RPT241 ..................................................................104
`Table 57. Observations and Results, Study RPT241 .......................................................105
`Table 58. Genetic Toxicology..........................................................................................111
`Table 59. Study Information, Study RPT8000745 ..........................................................112
`Table 60. Study Information, Study 001178-T ................................................................113
`Table 61. Methods of Oral Fertility Study in Male BALB/c Mice. Study RPT322 ........114
`Table 62. Observations and Results, Study RPT322 .......................................................115
`Table 63. Methods of Oral Fertility and Early Embryonic Development to
`Implantation Study in CD-1 Mice, Study RPT112504 ..............................................116
`Table 64. Observations and Results, Study RPT112504 .................................................116
`Table 65. Methods of Oral Embryo-Fetal Developmental Toxicity Study in CD-1
`Mice, Study RPT 112506 ...........................................................................................117
`Table 66. Observations and Results, Study RPT 112506 ................................................117
`Table 67. Methods of Oral Embryo-Fetal Developmental Toxicity Study in New
`Zealand White Rabbits, Study RPT112503 ...............................................................118
`Table 68. Observations and Results, Study RPT112503 .................................................119
`Table 69. Methods of Oral Pre- and Postnatal Developmental Toxicity Study in CD-1
`Mice, Study RPT112507 ............................................................................................120
`Table 70. Observations and Results, Study RPT112507 .................................................120
`Table 71. Test Article and CYP Enzyme Assays Conducted in Study RPT200 .............125
`Table 72. Test Article and CYP Enzyme Assays Conducted in Study RPT200 .............125
`Table 73. Test Article and CYP Enzyme Assays in Study RPT211 ................................128
`Table 74. Test Article and Transporter Assays Conducted in Study RPT200.................130
`Table 75. Statistical Analysis of Relative Bioavailability Data: Effect of Formulation
`on the Pharmacokinetics of Pacritinib .......................................................................132
`Table 76. Pharmacodynamic Parameters of pSTAT3 Following Single-Dose
`Administration of Pacritinib (400 mg Pacritinib Oral Capsule and 80 mg
`Pacritinib Oral Solution) ............................................................................................134
`Table 77. Pacritinib and Metabolite Concentrations From Radio-Quantitation of
`Individual Plasma Samples Using an HPLC Method ................................................136
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`NDA 208712
`Vonjo (pacritinib)
`Table 78. Percentage of Dose for Pacritinib and Metabolites in Six Human Urine
`Samples ......................................................................................................................137
`Table 79. Percentage of Dose for Pacritinib and Metabolites in Six Human Fecal
`Samples ......................................................................................................................138
`Table 80. Summary of SB1518 Pharmacokinetic Parameters (Pharmacokinetic
`Analysis Population) ..................................................................................................143
`Table 81. Summary of the Fit of the Power Model to Cmax and AUC0-inf Versus Dose ..143
`Table 82. Day 1 Pharmacokinetics: Phase 1 (All Enrolled Population) ..........................145
`Table 83. Day 15 Pharmacokinetics: Phase 1 (All Enrolled Population) ........................146
`Table 84. Summary of Pharmacokinetic Parameters: Day 1 (All Enrolled Population) .148
`Table 85. Summary of Pharmacokinetic Parameters: Day 15 (All Enrolled
`Population) .................................................................................................................149
`Table 86. Summary of Pacritinib Pharmacokinetics Parameters .....................................152
`Table 87. Summary of Inferential Statistical Analysis for Pacritinib Main PK
`Parameters ..................................................................................................................152
`Table 88. Summary of Pacritinib Pharmacokinetic Parameters ......................................155
`Table 89. Summary of Inferential Statistical Analysis for Pacritinib Main PK
`Parameters ..................................................................................................................156
`Table 90. Summary of the Pharmacokinetic Parameters of Pacritinib Following
`Administration of Pacritinib Alone and Coadministration With Clarithromycin ......159
`Table 91. Statistical Analysis of Pharmacokinetic Data: Effect of Clarithromycin on
`the Pharmacokinetics of Pacritinib ............................................................................159
`Table 92. Summary of the Pharmacokinetic Parameters of Pacritinib Following
`Administration of Pacritinib Alone and Coadministration With Rifampin ...............163
`Table 93. Statistical Analysis of Pharmacokinetic Data: Effect of Rifampin on the
`Pharmacokinetics of Pacritinib ..................................................................................163
`Table 94. Schematic of the Crossover Design Study .......................................................164
`Table 95. Summary of the Pharmacokinetic Parameters of Pacritinib Following
`Administration of FMI (Test) Formulation and P3CT (Reference) Formulation ......165
`Table 96. Statistical Analysis of Bioequivalence Data: Effect of Formulation on the
`Pharmacokinetics of Pacritinib ..................................................................................167
`Table 97. Summary Review of Bioanalytical Methods Measuring Pacritinib Acid and
`Its Metabolite M1 in Human Urine ............................................................................167
`Table 98. Summary Review of Bioanalytical Methods Measuring Pacritinib Acid and
`Its Metabolite M1 in Human Plasma .........................................................................168
`Table 99. Reviewer’s Specific Comments on the Population PK Model ........................171
`Table 100. Summary of Clinical Studies Used in the Population Pharmacokinetic
`Analysis......................................................................................................................172
`Table 101. Summary of Baseline Demographic and Laboratory Characteristics ............173
`Table 102. Parameter Estimates and OFV of the Applicant’s Base Model .....................174
`Table 103. Covariates Tested in the Population Pharmacokinetic Analysis ...................175
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`NDA 208712
`Vonjo (pacritinib)
`Table 104. Parameter Estimates and OFV of the Applicant’s Final Model ....................176
`Table 105. Parameter Estimates and OFV of the Reviewer’s Alternative Final Model ..181
`Table 106. Summary Statistics of Model Estimated Individual PK Parameters for All
`Subjects in the Phase 2 and Phase 3 Studies Stratified by Dosing Regimen .............184
`Table 107. Descriptive Statistics of Average Concentrations Among Subjects With
`No Dose Change or Dose Interruption Until Week 22 of Treatment ........................187
`Table 108. Descriptive Statistics of Maximum Concentrations Among Subjects With
`No Dose Change or Dose Interruption Until Week 22 of Treatment ........................187
`Table 109. Summary of Baseline Demographic and Laboratory Characteristics of the
`Patients With Myelofibrosis Included in the PKPD Analyses...................................188
`Table 110. Parameter Estimates of the Applicant’s Final Spleen Volume PKPD
`Model .........................................................................................................................190
`Table 111. Parameter Estimates of the Applicant’s Final TSS PKPD Model .................193
`Table 112. Parameter Estimates of the Reviewer's Final SPV PKPD Model ..................201
`Table 113. Descriptive Statistics of Cmax (µg/mL) and AUC0-24 (hr×µg/mL) Among
`Subjects With PK and Adverse Events Data in Studies PAC203, PERSIST-1 and
`PERSIST-2 .................................................................................................................211
`Table 114. Proportions of Deaths in Pacritinib Dosage Groups After 6 Months of
`Treatment ...................................................................................................................211
`Table 115. Parameter Estimates of Logistic Regression Model of AUC0-24 Versus
`Death ..........................................................................................................................211
`Table 116. Parameter Estimates of Logistic Regression Model for Cmax(µg/mL)
`Versus Death