CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

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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 BLA 761104, Lumoxiti, Moxetumomab pasudotox

NDA/BLA Multi-disciplinary Review and Evaluation

Application Type BLA Application Number(s) 761104 Priority or Standard Priority Submit Date(s) November 30, 2017 and January 29, 2018 Received Date(s) November 30, 2017 and January 29, 2018 PDUFA Goal Date September 29, 2018 Division/Office Division of Hematology Products/Office of Hematology and Oncology Products Review Completion Date September 12, 2018 Established Name Moxetumomab pasudotox (Proposed) Trade Name Lumoxiti Pharmacologic Class CD22-directed cytotoxin Code name CAT-8015 Applicant AstraZeneca AB Formulation(s) Lyophilized powder Dosing Regimen 0.04 mg/kg administered as a 30-minute intravenous infusion on Days 1, 3, and 5 of each 28-day cycle Applicant Proposed Treatment of adult patients with relapsed or refractory hairy cell Indication(s)/Population(s) leukemia who received at least two prior systemic therapies, including with a purine nucleoside analog Recommendation on Approval Regulatory Action Recommended Treatment of patients with relapsed or refractory hairy cell Indication(s)/Population(s) leukemia who received at least two prior systemic therapies, (if applicable) including a purine nucleoside analog

1 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ...... 9 Additional Reviewers of Application ...... 9 Glossary ...... 11 1 Executive Summary ...... 13 Product Introduction ...... 13 Conclusions on the Substantial Evidence of Effectiveness ...... 13 Benefit-Risk Assessment ...... 15 Patient Experience Data ...... 18 2 Therapeutic Context ...... 20 Analysis of Condition ...... 20 Analysis of Current Treatment Options ...... 20 3 Regulatory Background ...... 24 U.S. Regulatory Actions and Marketing History ...... 24 Summary of Presubmission/Submission Regulatory Activity ...... 24 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ...... 25 Office of Scientific Investigations (OSI) ...... 25 Product Quality ...... 25 Clinical Microbiology ...... 26 Devices and Companion Diagnostic Issues ...... 26 5 Nonclinical Pharmacology/Toxicology...... 27 Executive Summary ...... 27 Referenced NDAs, BLAs, DMFs ...... 29 Pharmacology ...... 29 ADME/PK ...... 32 Toxicology ...... 32 General Toxicology ...... 32 Genetic Toxicology ...... 41 Carcinogenicity ...... 41 Reproductive and Developmental Toxicology ...... 41 Other Toxicology Studies ...... 42 6 Clinical Pharmacology ...... 43

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Executive Summary ...... 43 Summary of Clinical Pharmacology Assessment ...... 44 Pharmacology and Clinical Pharmacokinetics ...... 44 General Dosing and Therapeutic Individualization ...... 45 Comprehensive Clinical Pharmacology Review ...... 46 General Pharmacology and Pharmacokinetic Characteristics ...... 46 Clinical Pharmacology Questions ...... 47 7 Sources of Clinical Data and Review Strategy ...... 53 Table of Clinical Studies ...... 53 Review Strategy ...... 55 8 Statistical and Clinical and Evaluation ...... 57 Review of Relevant Individual Trials Used to Support Efficacy ...... 57 Study CD-ON-CAT-8015-1053 ...... 57 Study Results ...... 63 Assessment of Efficacy Across Trials ...... 78 Study CAT-8015-1053 is the only trial supporting the efficacy of moxetumomab pasudotox in patients with R/R HCL...... 78 Integrated Assessment of Effectiveness ...... 78 Safety Review Approach ...... 80 Review of the Safety Database ...... 81 Adequacy of Applicant’s Clinical Safety Assessments ...... 84 Safety Results ...... 85 Analysis of Submission-Specific Safety Issues ...... 94 Capillary Leak Syndrome ...... 94 Hemolytic Uremic Syndrome (HUS) ...... 97 Infusion-related reactions ...... 100 Hepatic function abnormality ...... 102 Nephrotoxicity ...... 105 Electrolyte abnormalities ...... 107 Ocular Toxicity ...... 109 Fluid Retention ...... 110 Severe Infections (Including Opportunistic Infections) ...... 111

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability 112 Safety Analyses by Demographic Subgroups ...... 112 Specific Safety Studies/Clinical Trials ...... 116 Additional Safety Explorations ...... 116 Safety in the Postmarket Setting ...... 117 Integrated Assessment of Safety ...... 117 Statistical Issues ...... 118 Conclusions and Recommendations ...... 119 9 Advisory Committee Meeting and Other External Consultations ...... 121 10 Pediatrics ...... 122 11 Labeling Recommendations ...... 123 Prescription Drug Labeling ...... 123 12 Risk Evaluation and Mitigation Strategies (REMS) ...... 124 13 Postmarketing Requirements and Commitment ...... 125 14 Division Director (DHOT) ...... 126 15 Division Director (OCP) ...... 127 16 Division Director (OB) ...... 128 17 Division Director (Clinical) ...... 129 18 Office Director (or designated signatory authority) ...... 131 19 Appendices ...... 132 References ...... 132 Financial Disclosure ...... 133 OCP Appendices (Technical documents supporting OCP recommendations) ...... 134 Bioanalytical Method Validation and Performance ...... 134 Clinical Pharmacokinetics and Pharmacodynamics ...... 139 Immunogenicity ...... 145 Pharmacometrics ...... 147 Additional Clinical Outcome Assessment Analyses ...... 154

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Table of Tables

Table 1 Treatment Options for Patients with Relapsed HCL ...... 21 Table 2 Key Regulatory Interactions related to BLA 761104 ...... 24 Table 3 OSI Inspection Sites ...... 25 Table 4 Non-reproductive Microscopic Findings in the Monkey at the End of Dosing (Study Report 20009858) ...... 36 Table 5 Non-reproductive Microscopic Findings in the Monkey at the End of Recovery (Study Report 20009858) ...... 39 Table 6 Reproductive Microscopic Findings in the Monkey (Study Report 20009858) ...... 40 Table 7. Subgroup Analysis of Safety Parameters–Immunogenicity (Study 1053) ...... 50 Table 8 Clinical Trials Relevant to this BLA ...... 53 Table 9 Study Calendar for Cycle 1 and Subsequent Cycles ...... 59 Table 10 Study Calendar for End of Treatment and Follow -up ...... 60 Table 11 Study 1053-Patient Disposition ...... 64 Table 12 Important Protocol Violations/Deviations ...... 65 Table 13 Demographic Characteristics- ITT Population ...... 66 Table 14 Baseline Disease Characteristics-ITT Population ...... 67 Table 15 Study 1053-Prior HCL Therapy ...... 67 Table 16 Concordance of Durable CR between BICR and investigator’s assessment ...... 69 Table 17 Complete Response, Time to Complete Response and Duration of Complete Response by BICR and Investigator’s Assessment – ITT Population ...... 72 Table 18 Objective Response per BICR and Investigator Assessment – ITT population ...... 72 Table 19 Disease Response Assessed by BICR and investigator assessment – ITT Population .... 73 Table 20 Best Overall Response Comparison – Investigator’s Assessment vs BICR – ITT Population ...... 73 Table 21 Hematologic Remission from Onset of Hematologic Remission – ITT Population ...... 74 Table 22 Hematologic Remission for Subjects with Complete Response per BICR and Investigator’s Assessment – ITT Population ...... 74 Table 23 Safety Population ...... 81 Table 24 Overall Exposure-Safety Population ...... 81 Table 25 Demographics-Safety Population...... 82 Table 26 Deaths- HCL Population ...... 85 Table 28 Summary of TEAEs Leading to Discontinuations and Treatment Modifications ...... 88 Table 29 TEAEs Leading to Treatment Discontinuation ...... 88 Table 30 Safety Analysis-Common TEAEs (>10% in the Pivotal HCL Population) ...... 89 Table 31 FDA criteria for Identifying Cases of Possible CLS ...... 96 Table 32 HUS or HUS- like AEs-HCL population ...... 98 Table 33 IRR related TEAEs -HCL Population ...... 100 Table 34 AESI of Hepatic Function Abnormality-HCL Population ...... 102 Table 35 TEAEs of AST/ALT Elevations-HCL population ...... 103 Table 36 Adverse Events Related to Renal Toxicity-Safety Population ...... 106 Table 37 TEAEs of Electrolyte abnormalities-HCL population ...... 108

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Table 38 Changes in Electrolyte laboratory values ...... 108 Table 39 TEAEs of Fluid Retention -HCL Population ...... 111 Table 40 Overall Safety by Age- Primary HCL population ...... 112 Table 41 TEAEs by Age Subgroups -Primary HCL Population ...... 113 Table 42 Outcomes-Moderate Renal Impairment ...... 115 Table 43. Bioanalytical Methods for Moxetumomab Pasudotox Concentration Determinations in Plasma ...... 135 Table 44. Summary of Validation ADA Assay Parameters ...... 136 Table 45. Summary of Validation nAb Assay Parameters...... 137 Table 46. PK Parameters Following Multiple IV Administration of 40 µg/kg Moxetumomab Pasudotox in Patients with HCL (Study 1053)...... 141 Table 47. Summary of Cycle 1 PK Parameters of Moxetumomab Pasudotox in Patients with HCL (Trial 1001) ...... 144 Table 48. Summary of studies included in the analysis ...... 148

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Table of Figures

Figure 1 The Internalization of Moxetumomab Pasudotox on CD22-expressing Cells ...... 29 Figure 2 ADP-ribosylation of Eukaryotic Elongation Factor 2 by Moxetumomab Pasudotox ...... 30 Figure 3 Dose-response Curve of the Apoptosis Bioassay for Moxetumomab Pasudotox ...... 30 Figure 4 Moxetumomab Pasudotox Inhibits Growth of JD38 Tumors in a Xenograft Model ...... 31 Figure 5. Median Baseline Normalized CD19+ B Cell Counts Over Time (Study 1053) ...... 47 Figure 6. Relationships between PK exposure (AUC on Day 1 Cycle 2) and durable CR, CR or ORR (Study 1053) ...... 48 Figure 7. Correlation between PK exposure (AUC on Day 1 Cycle 1) and adverse events (Study 1053 and 1001) ...... 49 Figure 8. Relationship between ADA Titer and Efficacy Endpoints in Study 1053 ...... 50 Figure 9. Comparison of AUC by Renal Function (Study 1053, population PK analysis) ...... 51 Figure 10 Study 1053 Flow Diagram ...... 57 Figure 11 Forest Plot of Durable CR Assessed by BICR – ITT population ...... 76 Figure 12 Forest Plot of Durable CR Assessed by BICR, prior cancer therapy – ITT population... 77 Figure 13 Mean Change and Standard Deviation from Baseline in Hemoglobin ...... 91 Figure 14 Mean Change and Standard Deviation from Baseline in Absolute Neutrophil Count . 91 Figure 15 Mean Change and Standard Deviation from Baseline in Platelets ...... 92 Figure 16 Serum AST levels -Pivotal HCL population ...... 104 Figure 17 Serum ALT Levels (U/L) -Pivotal HCL Population ...... 105 Figure 18 Creatinine values (mg/dL), Pivotal HCL population ...... 107 Figure 19. Mean Concentration-time Profiles of Moxetumomab Pasudotox Following IV Administration in the First Two Cycles of Treatment – PK Population ...... 140 Figure 20. Mean Peak Concentration Levels of Moxetumomab Pasudotox in HCL Subjects after Each Cycle ...... 141 Figure 21. Relationship Between PK and Baseline CD19+ B cells in Subjects after First (Left) and Third Dose (Right) of Cycle 1 (Trial 1053) ...... 142 Figure 22. Moxetumomab Pasudotox Exposure Comparison between CD19 Low and CD19 High Group at Baseline ...... 143 Figure 23. Mean Concentration-time Profiles of Moxetumomab Pasudotox in Patients with HCL Following the First and Third Dose of Cycle 1 (Study 1001) ...... 144 Figure 24. Median Baseline Normalized CD19+ B Cell Counts Over Time Stratified by Clinical Response Category (Trial 1053) ...... 145 Figure 25. ADA Titers in HCL Subjects with Positive Neutralizing ADA Results (Trial 1053)...... 146 Figure 26. Effect of Post-Baseline ADA Status by Cycle on PK Exposure in Subjects with HCL (Trial 1053) ...... 147 Figure 27. Pharmacokinetics Model ...... 149 Figure 24. Exposure-Response Relationships Between Cmax or AUC and ORR (Trial 1053) ..... 150 Figure 25. Exposure-Response Relationships Between AUC in Cycle 2 and Durable CR, CR, and ORR (Trial 1053) ...... 151 Figure 26. Distribution of AUC in Cycle 1, 2, and 5 Among Subjects with Various Responses (Trial 1053) ...... 151

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Figure 27. Exposure-Response Relationships by ADA Titer (Trial 1053) ...... 152 Figure 28. Exposure-Response Relationships for Safety Endpoints (Trial 1053 and Trial 1001) 154

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Reviewers of Multi-Disciplinary Review and Evaluation

Nonclinical Reviewer Matthew Thompson, PhD Nonclinical Team Leader Christopher Sheth, PhD Clinical Pharmacology Reviewer Guoxiang Shen, PhD Pharmacometrics Reviewer Jee Eun Lee, PhD Pharmacometrics Team Leader Lian Ma, PhD Clinical Pharmacology Team Leader Olanrewaju Okusanya, PharmD, MS, Clinical Reviewer Bindu Kanapuru, MD Clinical Team Leader Nicole Gormley, MD Statistical Reviewer Jiaxi Zhou, MS Statistical Team Leader Yuan Li Shen, DrPH Cross-Disciplinary Team Leader Nicole Gormley, MD Division Director (DHOT) John Leighton, PhD Deputy Division Director (OCP) Brian Booth, PhD Deputy Division Director (OB) Thomas Gwise, PhD Acting Deputy Division Director (DHP) Nicole Gormley, MD Office Director (or designated signatory authority) Richard Pazdur, MD

Additional Reviewers of Application

RPM Wanda Nguyen, PharmD Associate Director of Labeling Virginia Kwitkowski, MS, RN, ACNP-BC DHP DDS Barry Miller, MS, CRNP OPQ Chana Fuchs, PhD/Sang Bong Lee PhD Microbiology Maria Jose Lopez-Barragan, PhD/ Virginia Carroll, PhD OPDP Nisha Patel, PharmD PLT Morgan Walker, PharmD, MBA, CPH OSI Anthony Orencia, MD, FACP OSE/DEPI Peter Waldron, MD/Afrouz Nayernama, PharmD OSE/DMEPA Casmir Ogbonna, PharmD, MBA, BCPS, BCGP/Hina Mehta, PharmD OSE/DRISK Ingrid Chapman, PharmD, BCPS/Elizabeth Everhart, MSN, RN, ACNP QT Lars Johannesen, PhD/Christine E. Garnett, PharmD CDRH Janaki Veeraraghavan, PhD DTOP Wiley Chambers, MD OPQ=Office of Pharmaceutical Quality OPDP=Office of Prescription Drug Promotion OSI=Office of Scientific Investigations

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

OSE= Office of Surveillance and Epidemiology DEPI= Division of Epidemiology DMEPA=Division of Medication Error Prevention and Analysis DRISK=Division of Risk Management

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Glossary

ADA anti-drug antibodies ADME absorption, distribution, metabolism, excretion AE adverse event AESI adverse event of special interest ALT alanine aminotransferase AST aspartate aminotransferase BICR blinded independent central review BLA biologics license application CDRH Center for Devices and Radiological Health CFR Code of Federal Regulations CI confidence interval CLS capillary leak syndrome CMC chemistry, manufacturing, and controls CR complete response CSR clinical study report DHOT Division of Hematology Oncology Toxicology ECG electrocardiogram ECL electrochemiluminescent (assay) EOT end of treatment FDA Food and Drug Administration GCP good clinical practice HCL hairy cell leukemia HUS Hemolytic uremic syndrome ICH International Conference on Harmonization IND Investigational New Drug IRR infusion-related reactions ITT intent to treat IV intravenous LDH Lactate dehydrogenase MAED MedDRA Adverse Events Diagnostic MedDRA Medical Dictionary for Regulatory Activities MRD minimal residual disease NCI CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Event NDA new drug application NHL non-Hodgkin lymphoma NME new molecular entity OPQ Office of Pharmaceutical Quality OR objective response ORR objective response rate OSE Office of Surveillance and Epidemiology

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

OSI Office of Scientific Investigation PD progressive disease PK pharmacokinetics PNA purine nucleoside analogue PR partial response PT preferred term REMS risk evaluation and mitigation strategy SAE serious adverse event SOC system organ class TEAE treatment emergent adverse event

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

1 Executive Summary

Product Introduction

Established Names: Moxetumomab pasudotox, CAT-8015 Trade Name: Lumoxiti Applicant: AstraZeneca Drug Class: Recombinant cytotoxin targeting CD22 Applicant’s Proposed For the treatment of adult patients with relapsed or refractory Indication: hairy cell leukemia (HCL) who received at least two prior systemic therapies, including treatment with a purine nucleoside analog (PNA). Applicant’s Proposed 40 μg/kg administered intravenously over 30 minutes on Days 1, 3, and Dosage: 5 of a 28-day cycle for a maximum of 6 cycles.

Conclusions on the Substantial Evidence of Effectiveness

The review team recommends regular approval of moxetumomab pasudotox for the following indication: “treatment of patients with relapsed or refractory hairy cell leukemia (HCL) who have received two prior therapies including (b) (4) treatment with a purine nucleoside analog”. This recommendation is based on the finding of high rates of durable complete response (CR) in the pivotal Phase 3 study CD-ON-CAT-8015-1053 (Study 1053). The recommended dose is 0.04 mg/kg administered as a 30-minute intravenous (IV) infusion on Days 1, 3, and 5 of each 28-day cycle.

Study 1053 was an open-label single-arm multicenter clinical trial of moxetumomab pasudotox which enrolled adults with relapsed or refractory HCL. The median age was 60 years (range: 34- 84) and the median number of prior therapies was 3 (range: 2-11). The primary endpoint was rate of durable CR based on CR as determined by blinded independent central review (BICR). Durable CR was defined as the overall response that meets blood, bone marrow, and imaging criteria for CR per BICR, followed by hematologic remission with duration of > 180 days, with hematologic remission defined as the blood counts needed for CR. No statistical hypothesis tests were performed but the 95% confidence interval (CI) for the durable CR rate was constructed using the Clopper-Pearson exact method. The protocol indicated that a lower bound of the 95% CI above 13% was considered clinically meaningful (the estimated durable CR rate to best alternative therapy rituximab). FDA’s analysis of the primary endpoint includes 80 subjects with relapsed HCL; the durable CR rate for Study 1053 was 30.3% (95% CI: 20.3%, 41.3%)

The Agency has previously granted regular approval of new therapies for treatment of patients with HCL based on single arm trials. For example, the initial regular approval of cladribine for

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treatment of patients with HCL was based on CR supported by duration of response. Durable CR as defined in the pivotal Study 1053 has not been used to support previous regulatory approvals in patients with HCL. The durable CR rate can be considered a more stringent definition of CR as it requires patients in CR to maintain hematological counts required for CR for >180 days. Additionally, as presence of cytopenia (as defined in Study 1053 is an indication for treatment (to prevent associated complications); durable CR rate may be considered as an endpoint that predicts meaningful clinical benefit in this patient population.

Study 1053 enrolled a heavily pretreated population with 75% receiving 3 or more prior therapies and all patients having received at least one prior therapy with PNA. Seventy-five percent of the patients had received rituximab either as single agent or in combination with a purine analog. In these patients with limited treatment options, the CR rate assessed by the BICR was 41.3% (95% CI: 30.4%, 52.8%) and the median duration of CR was not reached. It is concluded that the results of Study 1053 constitute substantial evidence of effectiveness in this patient population.

Study 1053 enrolled only 3 patients with HCL variant (HCL-V) and none of these patients achieved a durable CR. The small number of patients enrolled in this trial precludes any definitive conclusions for efficacy in the HCL-V population. Like patients with classic HCL, those with HCL-V express CD22, the target for moxetumomab pasudotox action. (b) (4)

An enhanced pharmacovigilance program to minimize the risk of adverse events related to capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS) in patients with HCL is planned. As this condition is a potentially severe one with limited treatment options, the reviewer recommends Regular approval for moxetumomab pasudotox for treatment of patients with relapsed or refractory hairy cell leukemia (HCL) who have received two prior therapies including (b) (4) treatment with a purine nucleoside analog.

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Benefit-Risk Assessment

Benefit-Risk Summary and Assessment

The benefit risk assessment supports regular approval of moxetumomab pasudotox for treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies, including treatment with a purine nucleoside analog (PNA).

Relapsed HCL is a rare and incurable malignancy. Current therapeutic options for patients with relapsed HCL include retreatment with PNA analogues approved for HCL. Re-treatment with PNA is associated with shorter duration of remission with each successive treatment. Patients refractory to PNA or relapsed after two or more lines of previous systemic therapy have limited treatment options. Rituximab, vemurafenib and ibrutinib are not approved for this indication but are recommended by consensus guidelines based on response rates in small non-randomized trials but confirmatory data on long-term efficacy is lacking. Effective agents are still needed for the treatment of relapsed or refractory HCL.

The efficacy of moxetumomab pasudotox is primarily based on the results of a single-arm, open-label study evaluating moxetumomab pasudotox monotherapy in patients with relapsed or refractory HCL. This study enrolled a heavily pretreated population. All subjects received prior treatment with PNA. Several patients had received rituximab (75%), either as a monotherapy or in combination with a PNA, and a v-Raf murine sarcoma viral oncogene homolog B (BRAF) inhibitor (17.5%). Both of these therapies are off-label HCL treatments. The study used a primary endpoint of durable CR rate defined as the overall response that meets blood, bone marrow, and imaging criteria for CR per BICR, followed by hematologic remission with duration of > 180 days, with hematologic remission defined as the blood counts needed for CR determined by BICR. The efficacy of moxetumomab pasudotox was established in 80 patients with relapsed or refractory HCL based on a durable CR rate of 30.3% (95% CI: 20.3%, 41.3%) per BICR. In this heavily pretreated population, CR rate assessed by the BICR was 41.3% (95% CI: 30.4%, 52.8%) and the median duration of CR was not reached.

The major safety issue identified with moxetumomab pasudotox is CLS and HUS. The overall incidence of CLS may be as high as 40% based on an algorithmic approach. Serious and life-threatening cases of CLS and HUS have occurred in patients receiving moxetumomab pasudotox. The seriousness of these risks warrants a boxed warning and instructions to patients regarding the risks and need for early intervention. Other primary safety issues identified with moxetumomab pasudotox including renal toxicity and electrolyte abnormalities can be mitigated with appropriate labeling.

In summary, the evidence of effectiveness with the rate of durable CR and CR rates with a median duration of response that has not been

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Reference ID: 4319411

NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

2 Therapeutic Context

Analysis of Condition

Hairy cell leukemia (HCL) is an uncommon chronic B-cell leukemia comprising 2% of all leukemias and accounting for an estimated 1,100 new cases per year in the US (1). HCL affects middle‐aged men more commonly than women; the male: female ratio is 4·5:1 and the median age at onset is 50 years (2). Patients may present with symptoms of fatigue and opportunistic infections. More commonly, patients present because of incidental findings of pancytopenia (3). Splenomegaly is a less common presentation due to earlier diagnosis of the disease. The characteristic immunophenotype of CD19+, CD20+, CD11c+, CD25+, CD103+, CD123+ co- expressing cells confirms the diagnostic features of classic HCL. In contrast, leukemic cells in patients with HCL-V are most often negative for CD25 and CD123. The BRAF v600E mutation is present in most patients with classic HCL but is absent in HCL-V. The classic form of hairy cell leukemia is recognized as separate from HCL-V.

Although most patients with HCL require treatment, a small number (about 10%) may not require immediate therapy and may be closely observed until therapy is needed. Treatment is recommended if patients have symptoms from the disease or if their hematologic parameters are declining. In general, hematologic parameters indicating a need for treatment include at least one of the following: hemoglobin <11 g/dL, platelet count <100 000/µL, or absolute neutrophil count <1000/µL. However, some patients with moderate asymptomatic pancytopenia may remain progression-free for many years without therapy. Others present with profound pancytopenia which may be accompanied by massive splenomegaly. Despite the high percentage of durable complete remissions with modern therapy, the disease is still incurable(4).

Analysis of Current Treatment Options

While HCL is not curable, it is responsive to available therapies and the goal is to achieve complete remission. Purine analogues cladribine and pentostatin are approved for patients with HCL and induce durable complete remissions. Retreatment with a PNA may yield a reasonable duration of disease control after an initial durable remission to PNA therapy. However, retreatment can be associated with shorter duration of remission with each successive treatment(5).

The National Comprehensive Cancer Network guidelines (6) for the treatment of HCL recommend that initial first-line treatment consist of PNA (cladribine or pentostatin) in patients presenting with systemic symptoms, splenic discomfort, recurrent infection, or cytopenia. In patients who achieve CR but who relapse at ≥ 1 year, second-line treatment consists of retreatment with the initial or alternative PNA with or without rituximab. In patients who do

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

not achieve CR, or who achieve CR but relapse at < 1 year, recommended second-line treatment options are participation in clinical trials or retreatment with an alternate PNA with or without rituximab, IFN-α, or rituximab alone.

There is no standard approach to management of patients who have relapsed after two prior therapies. National Comprehensive Cancer Network guidelines recommend clinical trial, ibrutinib, or vemurafenib with or without rituximab are appropriate options for progressive disease after second-line therapy. The evidence for efficacy for these unapproved therapies comes from small single-arm studies. In real-world settings, cladribine was the most common first-line therapy and rituximab was the most common second-line therapy among patients who received second-line treatment(7).

In comparison to classic HCL, HCL-V tends to be associated with a more aggressive disease course and may not respond to standard HCL therapies.

Approved therapies for patients with HCL are summarized in Table 1.

Table 1 Treatment Options for Patients with Relapsed HCL Product (s) Relevant Year of Dosing/ Efficacy Data Safety and Comments Name Indication Approval Administ Tolerability -ration Issues FDA Approved Treatments Cladribine Treatment 1993 Single In single-arm Myelosup (Leustatin) of active course studies, complete pression, HCL infusion response rates for infections with clinically for 7 Study A and Study including significant consecutiv B were fatal anemia, e days at a 54% and 53%, infections neutropenia, dose of respectively thrombocyto 0.09 (combined CR penia or mg/kg/day rate=54%) disease- related symptoms. Pentostatin Untreated 2nd line: 4 mg/m2 SWOG 8691 Myelosup Withhold in (Nipent) and alpha- 1991; every randomized study; pression, patients with interferon- untreated other Frontline therapy infections severe rash, refractory and alpha week. pentostatin (ITT, in some and withheld patients with interferon n=170) CR 68% PR cases or active refractor 5%, median DOR leading to discontinued disease as HCL: 1992 =NR; IFN (ITT, death, in patients defined by n=170) CR 14%, PR reversible showing

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Product (s) Relevant Year of Dosing/ Efficacy Data Safety and Comments Name Indication Approval Administ Tolerability -ration Issues clinically 18%, median DOR elevations evidence of significant =8.3. in liver nervous anemia, IFN refractory in function system neutropenia, evaluable patients tests, toxicity thrombocyto SWOG 8691 renal penia, or Crossover (n=79) toxicity, disease- CR 85% PR 4%; NCI and related Phase 2 studies rashes symptoms (n=44) CR 58%, PR 28% Interferon Treatment 2 million Sustained Warnings: Contraindica alpha -2b of patients IU/m2 improvements in Cardiovas tion: (Intron A 18 years or intramus granulocytes, cular hypersensitiv and Roferon older with cularly or platelets, and disorders, ity to -A) HCL subcutan hemoglobin cerebrova interferon eously 3 levels in 75% of scular alpha or any times a treated patients disorders, component week for neuropsyc of the up to 6 hiatric product, months disorders, autoimmune bone hepatitis and marrow decompensa toxicity ted liver and flu- disease like symptoms CR = complete response; DOR = duration of response; HCL = =hairy cell leukemia; NCI = =National Cancer Institute; PR = partial response;

As mentioned earlier, although not an approved agent for the treatment of HCL, rituximab is frequently administered off-label to relapsed or refractory patients either as a single agent or in combination with a PNA as per NCCN guidelines(6) and based on real-world evidence(7). The largest prospective trial of rituximab monotherapy for HCL included patients who had received a median of 2 prior treatment regimens with only 1 prior treatment with PNA. This trial showed an investigator-reported CR rate of 13% (95% CI: 2.7-32.4) among 24 patients, with median duration of response lasting 23 months (8).

Vemurafenib, a BRAF inhibitor is also used off-label for patients with relapsed or refractory HCL. Results of Two Phase 2, single-group, multicenter studies one in Italy and one in the United States evaluating vemurafenib in patients with relapsed or refractory HCL following a median of 22 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

3 prior lines of therapy was reported vemurafenib was administered for 16 weeks in the Italian study and 18 weeks in the U.S study (9).The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) respectively. In the Italian trial, the median relapse free survival was 9 months. Patients who had a complete response had a longer relapse free survival compared to patients with partial response (19 months vs. 6 months; hazard ratio for relapse, 0.26; 95% CI, 0.10 to 0.68).

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

3 Regulatory Background

U.S. Regulatory Actions and Marketing History

Moxetumomab pasudotox is not currently marketed in the US.

Summary of Presubmission/Submission Regulatory Activity

The key U.S. pre-submission regulatory activities are outlined in Table 2. On January 26, 2018, moxetumomab pasudotox was granted Fast Track designation and permission to proceed with rolling submission. The sponsor submitted an initial component of the rolling review marketing application for moxetumomab pasudotox under BLA 761104 supporting document 1 letter dated November 29, 2017. The final document of the rolling review was submitted on January 29, 2018. The sponsor requested priority review which was granted by the agency. The application was filed on March 30, 2018. Table 2 Key Regulatory Interactions related to BLA 761104 IND 100372 for hematologic malignancies 16Oct2006 Original IND 100372 submitted to support initiation of a Phase 1 study (CAT- 8015-1001) with HCL. 15 Nov 2007 Orphan drug designation granted for the treatment of CD22-positive HCL. 20 Feb 2009 Approved change of the orphan drug designation indication to “treatment of HCL.” 14Nov2012 Type C meeting to discuss the Phase 3 dose adjustment due to change in manufacturing process. IND 115709 for HCL 01Aug2012 Type B Pre-IND/Pre-Phase 3 meeting between FDA, NCI, and MedImmune to discuss design of proposed pivotal Phase 3 HCL study. 08Mar2013 Original IND 115709 submitted to support initiation of Phase 3 study (CD-ON- CAT-8015-1053) with HCL 08Sep2016 Teleconference to discuss the preliminary request for Breakthrough Therapy designation based on interim Phase 3 HCL data. 14Dec2016 Type C meeting to discuss potential for early registration of moxetumomab pasudotox based on interim Phase 3 HCL data. Agreement on waiver of embryofetal development toxicity study. Jul 2017 Receipt of Type C Written Request Only feedback regarding Sponsor’s proposals for clinical analyses for the BLA 23 Oct 2017 Receipt of Type B Pre-BLA preliminary meeting comments regarding the acceptability of the HCL study to support a BLA filing Source: Adapted from Table 2.5.1.6.1-1 Clinical overview

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety

Office of Scientific Investigations (OSI)

One clinical site (Dr. Wyndham Wilson) was selected by the Division of Hematology Products for inspection of study conduct for Study CD-ON-CAT-8015-1053, submitted in support of BLA 761104. This site enrolled the highest percentage of patients in Study 1053. The sponsor was also inspected for this application.

Table 3 OSI Inspection Sites Name of Clinical Protocol # 761104/ Inspection Dates Classification Investigator/Sponsor Address Site #/# Subjects Wyndham Wilson, M.D., 9000 Site # 1010 January 23 to 25, VAI Rockville Pike, Building 37, 26 total 2018 Room 5124 Bethesda, MD 20892 AstraZeneca AB (subsidiary, Sponsor for Study January 31 to NAI MedImmune) Protocol 761104 February 5, 2018 1 MedImmune Way Gaithersburg, MD 20878 Source: FDA reviewer

The regulatory classification for Dr. Wyndham was Voluntary Action Indicated (VAI). In general, this clinical site appeared to be compliant with Good Clinical Practice. A Form FDA 483 (Inspectional Observations) was issued. Specifically, a severe adverse event (SAE) (Grade 3 pneumonia with prolongation of hospitalization) that required expedited reporting was reported three days late to the sponsor. This isolated finding was eventually reported to the sponsor and included in the study report. OSI concluded that Dr. Kreitman’s written response dated February 1, 2018, appeared adequate.

OSI reported that oversight by the sponsor appeared to be adequate in general. A Form FDA 483 was not issued to the sponsor at the end of the inspection.

Reviewer comment: The reviewer concurs with the OSI assessment. No further action is indicated.

Product Quality

The commercial Drug Product is a sterile lyophilized dosage form presented in 3-cc vials. After reconstitution, each vial contains a target of 1 mg of drug in 1 mL volume. A comparability analyses demonstrated that the commercial moxetumomab pasudotox Drug Product is 25 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

comparable to the clinical Drug Product used in the Phase 3 HCL study. An Intravenous (IV) Solution Stabilizer will also be supplied in the commercial setting (b) (4) .

Three manufacturing processes have been used during the development of moxetumomab pasudotox. Process 1 (b) (4) and Process 2 (lyophilized) were used for nonclinical and clinical manufacturing, and both materials were administered in the Phase 1 HCL study (CAT-8015- 1001). Process 3 (lyophilized) was used for clinical and commercial manufacturing. Process 3 material was used in Study 1053. To account for the difference in bioactivity between Process 2 and Process 3 Drug Substance (b) (4) a dose adjustment was performed to ensure that patients treated with Process 3 received a similar amount of biologically equipotent active product as patients treated with prior process materials. The data and rationale to support the proposal for a dose adjustment was discussed with the FDA during a 14Nov2012 Type C meeting. The Agency found acceptable the rationale to use a dose of 40 μg/kg Process 3 material (corresponding to 50 μg/kg of previously manufactured material) in Study 1053.

The product quality reviewer has recommended approval of moxetumomab pasudotox.

Clinical Microbiology

The Drug Product is a sterile lyophilized dosage form manufactured by a (b) (4) process. The Drug Product is intended for single-dose only and does not contain a preservative. The microbiological quality and sterility are controlled and assessed by various measures outlined by the Applicant.

The microbiology reviewer has recommended approval of moxetumomam pasudotox.

Devices and Companion Diagnostic Issues

A device or companion diagnostic is not required to select patients for therapy with moxetumomab pasudotox and is not required to ensure safe use of moxetumomab when marketed.

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5 Nonclinical Pharmacology/Toxicology

Executive Summary

Moxetumomab pasudotox (Lumoxiti, CAT-8015, GCR-8015) is a CD22-directed cytotoxin. Moxetumomab pasudotox (approximately 63 kDa) is composed of an immunoglobulin light chain variable domain (VL) and a heavy chain variable domain (VH) genetically fused to a truncated form of Pseudomonas exotoxin, PE38. The VL and VH domains of moxetumomab pasudotox are derived from the murine anti-CD22 monoclonal antibody(b) (4) .

Moxetumomab pasudotox binds CD22 on the cell surface of B cells and is internalized. Moxetumomab pasudotox internalization results in ADP-ribosylation of eukaryotic elongation factor 2, inhibition of protein synthesis, and apoptotic cell death. Based on the mechanism of action, the established pharmacologic class of CD22-directed cytotoxin will be used in labeling.

In single-dose pharmacokinetic studies in rodents and cynomolgus monkeys, moxetumomab pasudotox had a short half-life of less than 2 hours. In the single-dose pharmacokinetic study in monkeys, AUC and Cmax were generally dose proportional. Volume of distribution at steady state (Vss) suggested restricted tissue distribution of moxetumomab pasudotox. In the 13-week repeat-dose toxicology study, moxetumomab pasudotox accumulation was apparent at the high dose. Cmax was dose proportional on Day 1. Half-life was more variable in the 13-week study, ranging from 1 to 9 hours in the monkey after repeat dosing. Anti-drug antibodies may have impacted systemic exposure.

Cynomolgus monkeys (5/sex/group) were intravenously administered vehicle, 0.135, 0.405, or 1.35 mg/kg (human equivalent doses of 0.044, 0.131, and 0.435 mg/kg, respectively) of moxetumomab pasudotox 3 times per week for 13 weeks. The human equivalent dose is based on mg/kg, as data on volume of distribution at steady state indicate moxetumomab pasudotox is not widely distributed outside the vasculature. Mortality was observed with one female euthanized at the mid dose and three females and one male at the high dose. Main target organs of toxicity in the study were the heart, nervous system, liver, skin, and kidney. Clinical observations included decreased activity, low food consumption, favoring legs, tremors in the feet and/or legs, toes in flexion, poor coordination, general body tremors, weight loss, sloughing of the skin on digits of the hands and/or feet, atrophied legs, and enlarged axillary lymph nodes. Clinical chemistry findings included increased AST, ALT, ALP, LDH, and decreased albumin. Glucose in the urine was noted. Hematology findings included decreased platelets and red cell mass, and the coagulation parameters prothrombin time and activated partial thromboplastin time were prolonged. Microscopic findings included myocardial degeneration, necrosis and/or hemorrhage in the heart, increased injection site inflammation and/or hemorrhage, decreased size of lymphoid follicles within the spleen, mesenteric and mandibular lymph nodes, and Peyer’s patches, degeneration/regeneration, diffuse rarefaction, or necrosis 27 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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of hepatocytes, Kupffer cell hypertrophy, renal tubular epithelium degeneration/regeneration, hypercellular gray matter in the brain characterized by gliosis, axonal degeneration in the lumbar spinal cord, epithelial cell apoptosis and/or necrosis, epidermal and mucosal ulcers and erosions of the oral cavity and skin of the arm, thorax, and dorsum. At a human equivalent dose >3 times the recommended dose, degeneration of heart tissue was observed in cynomolgus monkeys. At a human equivalent dose >10 times the recommended dose, gliosis in the brain, axonal degeneration in the spinal cord, and body tremors were observed in cynomolgus monkeys.

A tissue cross reactivity study found moxetumomab pasudotox had specific positive staining of B cells in tissues. Brain (cortex and cerebellum) and spinal cord tissue samples had diffuse non- granular staining present within the white matter, but reproductive organs were not cross reactive with moxetumomab pasudotox.

The Applicant did not conduct genotoxicity studies per ICH S6. No carcinogenicity studies were conducted or required to support a marketing application for the current indication per ICH S6, ICH S1, and ICH S9.

Reproductive and developmental toxicity studies were not conducted with moxetumomab pasudotox per ICH S5(R3) and ICH S9. Studies of fertility and early embryonic development and pre- and postnatal toxicology were not conducted or determined to be necessary to support a marketing application for the current indication per ICH S9. Regarding embryo-fetal development studies, hairy cell leukemia incidence rates are ~4-fold greater among men than women and the median age of diagnosis in women occurs post-menopause. The draft ICH harmonized guideline S5(R3) Detection of Toxicity to Reproduction for Human Pharmaceuticals indicates that if the female patient population is post-menopausal, there is no utility in evaluating any of the reproduction stages. Therefore, embryo-fetal development studies were not conducted; instead, the Applicant provided a scientific assessment of the reproductive toxicity potential of moxetumomab pasudotox. Notable considerations in the assessment included the age and sex characteristics of the patient population, the half-life (1 to 2 hours), biophysical properties, mechanism of action, and cytotoxic nature of moxetumomab pasudotox, human CD22 expression during development, and the phenotype of CD22 deficient mice.

Section 8 of the full prescribing information includes a statement in subsection 8.1 on the potential risk for embryo-fetal toxicity, (b) (4) when administered to a pregnant woman. This statement is based on the mechanism of action of moxetumomab pasudotox. Subsection 8.3 of the label recommends the use of contraception after cessation of therapy for females based on the mechanism of action of moxetumomab pasudotox. Given the shorter half-life of moxetumomab pasudotox and that it is a biologic, contraception in females is recommended to be one menstrual cycle (30 days). Male contraception is not recommended. Based on the cytotoxic nature of moxetumomab pasudotox, potential adverse effects on the breast-fed child should be taken into consideration. 28 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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The nonclinical pharmacology and toxicology data submitted to this BLA are adequate to support the approval of moxetumomab pasudotox for the proposed indication.

Referenced NDAs, BLAs, DMFs

None

Pharmacology

Primary Pharmacology

A. In vitro studies Moxetumomab pasudotox is derived from the anti-CD22 monoclonal antibody (b) (4) . (b) (4) was observed to cross-react with rhesus, cynomolgus, and human CD22. (b) (4) stained cynomolgus monkey tissue and flow cytometry analysis showed (b) (4) stained peripheral blood lymphocytes from cynomolgus monkeys. The Applicant used a flow cytometry assay with (b) (4) to determine CD22 expression on human peripheral blood B cells and cells line (e.g., Daudi cells - Burkitt's lymphoma; HC-1 cells).

The Applicant measured the target binding of moxetumomab pasudotox to CD22 using a SPR- based assay. The equilibrium dissociation constant (Kd) of moxetumomab pasudotox to CD22 was 1.26 nM. The Applicant assessed the internalization of moxetumomab pasudotox in vitro using quantitative fluorescent imaging. AlexaFluor647-tagged moxetumomab pasudotox was incubated with CD22-expressing Daudi cells and the surface-to-cytoplasm translocation of moxetumomab pasudotox was monitored over time using a confocal fluorescent microscope.

Figure 1 The Internalization of Moxetumomab Pasudotox on CD22-expressing Cells Figure Excerpted from Applicants Submission

Blue line - membrane; red line – cytoplasm

The Applicant determined moxetumomab pasudotox-induced ADP-ribosylation of eukaryotic elongation factor 2 using an in vitro luciferase translation assay. Moxetumomab pasudotox was serially diluted and incubated for 2 hours at ambient temperature with an ADP-ribosylation assay containing purified eukaryotic elongation factor 2 protein, NAD+, luciferase mRNA, a complete amino acid mixture, RNase inhibitor, and wheat germ extract. After incubation, luciferase substrate was added and the luminescence was measured on a plate reader after a 30-minute incubation. The results were graphed as relative light units versus protein 29 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

concentration. The amount of luminescence detected is directly proportional to the amount of translated luciferase protein. Figure 2 shows relative light units decrease as moxetumomab pasudotox concentration increases in the assay system.

Figure 2 ADP-ribosylation of Eukaryotic Elongation Factor 2 by Moxetumomab Pasudotox Figure Excerpted from Applicants Submission

Relative light units

The Applicant showed deamidation of an asparagine residue in PE38 prevented ADP ribosylation of elongation factor 2 in the luciferase translation assay.

The Applicant investigated the ability of moxetumomab pasudotox to induce apoptotic cell death. Moxetumomab pasudotox was added to CD22-expressing Daudi cell suspensions and apoptosis was measured via caspase 3/7 activation. Assay luminescence is proportional to the amount of apoptosis as quantified in a luminometer after reaction with a Caspase 3/7 luciferase substrate. Moxetumomab pasudotox treatment resulted in a dose-dependent induction of apoptosis in Daudi cells.

Figure 3 Dose-response Curve of the Apoptosis Bioassay for Moxetumomab Pasudotox Figure Excerpted from Applicants Submission

Relative light units

A flow cytometric assay was used to measure B cell cytotoxicity in normal human peripheral blood B cells, normal human bone marrow, and cynomolgus monkey PBMCs. Cytotoxicity was measured as the frequency of apoptotic B cells (CD19-postive) normalized to untreated cells, with apoptosis measured by light scatter characteristics correlated with annexin V staining.

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Moxetumomab pasudotox resulted in a dose-dependent cytotoxic response in B cells from peripheral blood and bone marrow (IC50 of 7 pM) but not T cells from peripheral blood.

B. In vivo studies The Applicant investigated the effects of moxetumomab pasudotox on the in vivo growth of subcutaneous JD38 tumors in NCr athymic nude mice. Mice (8-10 females/group) were subcutaneously injected in the flank with 5 x 106 JD38 cells (a CD22-expressing Burkitt's lymphoma-derived cell line) and tumors were allowed to grow until ~150 mm3. Mice were treated on Days 0, 2, and 4 with doses of 0, 6.25, 12.5, 25, 50, 75, 100, 125 or 150 μg/kg moxetumomab pasudotox administered intravenously.

Figure 4 Moxetumomab Pasudotox Inhibits Growth of JD38 Tumors in a Xenograft Model Figure Excerpted from Applicants Submission

Moxetumomab pasudotox exhibited dose-dependent inhibition of tumor growth in the JD38 xenograft model at doses > 6.25 μg/kg.

Secondary Pharmacology

No formal studies were conducted.

Safety Pharmacology

No standalone safety pharmacology studies were conducted. Safety pharmacology endpoints were evaluated in the GLP 13-week repeat-dose toxicology study [A 13-Week Repeat-Dose (3X weekly) Intravenous Bolus Toxicity, Toxicokinetics, and Pharmacodynamics Study with CAT- 8015 in Cynomolgus Monkeys with a 6-Week Recovery Period / Study Report 20009858]. The results were as follows, where the mid dose (MD) = 0.405 mg/kg and the high dose (HD) = 1.35 mg/kg. A. CNS Neurological examinations were conducted on Day 14 of the 13-week repeat-dose study. - One HD female had generalized tremors - One HD female had decreased visual placing reactions in both legs. B. Respiratory 31 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Unremarkable C. CV Systolic blood pressure (male): MD ↓21%; HD ↓17% Diastolic blood pressure (male): HD ↓18% Systolic blood pressure (female): HD ↑32% Diastolic blood pressure (female): HD ↑25%

ADME/PK

Type of Study Major Findings PK data from general Cynomolgus monkey (F, n=5; M, n=5; IV 3 times per week for 13 weeks) t1/2: 1 to 9 hours toxicology studies Anti-drug antibodies may impact pharmacokinetics and systemic exposure; A 13-Week Repeat-Dose (3X accumulation was noted at the high dose level; Cmax was dose proportional on Day 1 Dose (mg/kg) 0.135 0.405 1.35 weekly) Intravenous Bolus Day 1 85 1 85 1 85 Toxicity, Toxicokinetics, and AUC0-last 3.48 0.0116 12.3 13.3 25.3 67.1 Pharmacodynamics Study (mg•h/mL) AUC0-inf 3.19 NR 13.2 49.7 23.5 234 with CAT-8015 in (mg•h/mL) Cmax 3.31 0.0267 10.5 2.55 34.0 10.2 Cynomolgus Monkeys with a (mg/mL) 6-Week Recovery t1/2 (h) 1.02 NR 2.77 6.36 1.43 8.57 Period/Study Report CL (mL/h/kg) 46.9 NR 40.0 38.7 59.6 5.78 F = female, M = male, AUC0-inf = area under concentration-time curve from time zero 20009858 to infinity; AUC0-last = area under concentration-time curve from time zero to last observation; Cmax = maximum observed concentration; CL = clearance; IV = intravenous; NR = no reportable result; t1/2 = half-life. Miscellaneous PK study PK Parameters in Single Dose Studies Mean PK Mice Rats Cynomolgus Monkeys Single-Dose Studies in Mice parameters (F, n=5, IV) (F, n=5, IV) (M, n=2; F, n=2; IV) (Study Report NRT0012), 0.5 mg/kg 0.25 mg/kg 0.1 mg/kg 0.5 mg/kg 2 mg/kg Rats (Study Report AUC0-last 4.22 4.08 1.92 8.05 32.1 NRT0013), and Monkeys (mg•h/mL) AUC0-inf 4.37 4.12 2.03 8.13 32.2 (Study Reports (mg•h/mL) NRT0003/NRT0004) Cmax 7.28 5.57 2.78 11.7 42.5 (mg/mL) t1/2 (h) 0.420 0.609 0.563 0.621 1.20 CL 0.040 0.228 2.39 2.83 3.26 (mL/min) Vss (mL) 1.37 10.6 107 131 182 F = female, M = male, IV = intravenous, AUC0-inf = area under concentration-time curve from time zero to infinity; AUC0-last = area under concentration-time curve from time zero to last observation; C0 = concentration at time zero; Cmax = maximum observed concentration; CL = clearance; IV = intravenous; t1/2 = half-life; Vss = volume of distribution at steady state.

Toxicology

General Toxicology

A 13-Week Repeat-Dose (3X weekly) Intravenous Bolus Toxicity, Toxicokinetics, and Pharmacodynamics Study with CAT-8015 in Cynomolgus Monkeys with a 6-Week 32 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Recovery Period / Study Report 20009858

Key Findings: • Main target organs of toxicity were the heart, nervous system, liver, skin, and kidney. • Minimal to moderate degeneration of heart tissue was observed in cynomolgus monkeys at the mid and high dose. • At the high dose, gliosis in the brain, axonal degeneration in the spinal cord, and body tremors were observed. Conducting laboratory and location: (b) (4) GLP compliance: Yes

Methods Dose and frequency of dosing: 0, 0.135 (LD), 0.405 (MD), or 1.35 (HD) mg/kg, 3 times per week for 13 weeks Route of administration: Intravenous Formulation/Vehicle: 0.65% (w/v) NaCl, 0.62 mM citrate, 6.25 mM sodium phosphate, 1.00% (w/v) sucrose, 2.00% (w/v) glycine, 0.0210% (w/v) polysorbate 80, pH 7.4 Species/Strain: Cynomolgus monkey Number/Sex/Group: 5/sex/group Age: 5.5 to 7.5 years of age (males) 4.3 to 9.2 years of age (females) Satellite groups/ unique design: None Deviation from study protocol affecting interpretation of results: No

Observations and Results: changes from control Parameters Major findings Mortality - One MD female was euthanized on Day 5; one HD female was euthanized on Day 35; one HD female was euthanized on Day 37; one HD female was euthanized on Day 63; one HD male was euthanized on Day 63 Clinical observations included decreased activity, lethargy, hunched appearance, low food consumption, favoring legs, tremors in feet and/or legs, toes in flexion, poor coordination, and/or general body tremors, weight loss, sloughing of the skin on digits of the hands and/or feet, atrophied legs, and enlarged axillary lymph nodes Clinical chemistry findings included increased AST, ALT, ALP, LDH, and glycosuria; decreased albumin Hematology findings included decreased platelets and red cell mass Coagulation findings included prolongations of PT and APTT Microscopic findings included: myocardial degeneration, necrosis and/or hemorrhages in the heart, increased injection site inflammation and/or hemorrhage, decreased size of lymphoid follicles within the spleen, mesenteric and mandibular lymph nodes, and

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Peyer’s patches, degeneration/regeneration, diffuse rarefaction, or necrosis of hepatocytes, Kupffer cell hypertrophy, renal tubular epithelium degeneration/regeneration, hypercellular gray matter in the brain characterized by gliosis, axonal degeneration in the lumbar spinal cord, epithelial cell apoptosis and/or necrosis, epidermal and mucosal ulcers and erosions of the oral cavity and skin of the arm, thorax, and dorsum. Clinical Signs Clinical findings

Body Weights HD: ↓13.5%/↓7.5% (M/F) Ophthalmoscopy Unremarkable ECG Unremarkable Hematology % Mean differences vs. concurrent controls (Day 86)

Clinical Chemistry % Mean differences vs. concurrent controls (Day 86)

Urinalysis Unremarkable

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Gross Pathology Gross pathology findings

Organ Weights MD: Kidney ↑32% (M); Lung ↑29% (M) HD: Brain ↑49% (M); Heart ↑23% (M); Kidney ↑98% (M); Liver ↑44%/↑20% (M/F); Lung ↑72% (M) Histopathology Heart: Degeneration; Myocardium; multifocal/Degeneration; Epicardial adipose tissue; Adequate battery: Yes focally extensive/Infiltrate, Mixed Cell; Epicardium; focally extensive Summary data are Injection site: Hemorrhage; Subcutis/Hemorrhage; Myofiber/Infiltrate, Mixed Cell; presented here. Full Subcutis/Infiltrate, Mixed Cell; Subcutis; Myofiber/Hyperkeratosis; tables of group Epidermis/Degeneration; Keratinocyte; Epidermis/Degeneration; incidences and Myofiber/Degeneration; Adipose tissue; Subcutis severities of test Kidney: Fibrosis; multifocal/Degeneration/Regeneration; Tubular epithelium/Atrophy; article-related Cortex; Medulla/Hypertrophy / Hyperplasia; Tubular epithelium; multifocal microscopic findings Liver: Infiltrate, Neutrophil; multifocal/Mineralization/Rarefaction, Cytoplasm; are presented below Hepatocyte; Centrilobular; focally extensive/Degeneration/Regeneration; Hepatocyte; diffuse/Extramedullary Hematopoiesis/Pigment; Sinusoidal cell/Hypertrophy; Ito cell/Hypertrophy; Ito cell; focally extensive/Hypertrophy, Kupffer Cell

ADA analysis Majority of animals (40/41) including controls had anti-drug antibodies, possibly due to prior exposure to Pseudomonas exotoxin. Systemic exposure and pharmacodynamic response measured as CD3-/CD20+ B cells may have been impacted by anti-drug antibodies. ADA = anti-drug antibodies; LD = low dose; MD = mid dose; HD = high dose.

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Table 4 Non-reproductive Microscopic Findings in the Monkey at the End of Dosing (Study Report 20009858)

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Table 5 Non-reproductive Microscopic Findings in the Monkey at the End of Recovery (Study Report 20009858)

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Table 6 Reproductive Microscopic Findings in the Monkey (Study Report 20009858)

A Pilot Dose-escalation, Range-finding Study of Moxetumomab Pasudotox and CAT-3888 in Cynomolgus Monkeys / Study Report ACY00039

Cynomolgus monkeys (2/sex) were administered moxetumomab pasudotox in a dose escalation (0.12, 0.36, 1.2, 2.4, and 4.8 mg/kg on Days 1, 3, 5, 8, and 11, respectively) via slow bolus IV injection. No mortality was observed. Clinical observations included dry, flaky skin and/or erythema of the arms and legs (ankles), hunched posture, thin appearance, and lethargy. Decreases in red blood cell count, hemoglobin, and hematocrit were observed. Increases in absolute reticulocyte counts were noted. ALT, AST, LDH, BUN, and triglycerides were increased and albumin was decreased.

A Study to Determine Potential Toxicity of 2-cycles of Moxetumomab Pasudotox and CAT 3888 when Administered in Cynomolgus Monkeys via IV with a 28-day Recovery Period / Study Report ACY00040

Cynomolgus monkeys (5/sex/group) were administered vehicle, 0.135, 0.405, or 1.35 mg/kg of moxetumomab pasudotox via slow bolus IV injection on Days 1, 3, 5, 15, 17, and 19.

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

No mortality was observed. Clinical signs included dry flaky skin with peeling and mild skin erythema. WBCs and neutrophils were increased. Hemoglobin was reduced. Albumin was decreased, and there were elevations in ALT, ASP, and LDH.

Genetic Toxicology

Not conducted per ICH S6.

Carcinogenicity

Not conducted per ICH S6, ICH S1, and ICH S9.

Reproductive and Developmental Toxicology

Fertility and Early Embryonic Development

Not conducted per ICH S9.

Embryo-Fetal Development

Reproductive and developmental toxicity studies were not conducted with moxetumomab pasudotox per ICH S5(R3). The draft ICH harmonized guideline S5(R3) Detection of Toxicity to Reproduction for Human Pharmaceuticals indicates that if the female patient population is post-menopausal, there is no utility in evaluating any of the reproduction stages. Hairy cell leukemia incidence rates are ~4-fold greater among men than women and the median age of diagnosis in women (63 years of age based on a SEER-17 analysis of data from 1978–2004) occurs post-menopause (10).

Based on its mechanism of action, cytotoxic nature, and findings in animal toxicology studies, moxetumomab pasudotox exposure is expected to cause embryo-fetal toxicity including B cell lymphocytopenia. In the human fetus, CD22-postive B cells are found in different tissues but are largely absent prior to 14 weeks of gestation (11, 12). Though CD22 knock-out mice are grossly normal and fertile (13) , B cells have a reduced lifespan and an increased rate of apoptosis. Studies in the monkey suggest the fetal nervous system and tissues and organs with rapidly dividing cell populations could be sensitive to moxetumomab pasudotox exposure.

The Applicant did not submit data that characterize fetal exposure. Theoretically, several characteristics of moxetumomab pasudotox may reduce fetal exposure: 1) moxetumomab pasudotox is approximately 63 kDa and has an isoelectric point of approximately 5.0 (i.e., acidic protein with negative charge at physiologic pH); 2) moxetumomab pasudotox is a disulfide- stabilized Fv, lacking an Fc region that would bind the neonatal Fc receptor (FcRN); 3) the toxin domain is genetically fused to the Fv; and 4) moxetumomab pasudotox has a short half-life (1-2 hours). Whether other mechanisms play a role is not certain.

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NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

6 Clinical Pharmacology

Executive Summary

The clinical pharmacology review focus on the appropriateness of the proposed dose regimen of moxetumomab pasudotox for the treatment of adult patients with relapsed or refractory hairy cell leukemia (R/R HCL) who received at least two prior systemic therapies, including treatment with a PNA.

The efficacy and safety of moxetumomab pasudotox in this population is supported by results from the pivotal Phase 3 trial (Study 1053) with additional data provided from Phase 1 trial 1001. In the pivotal trial, treatment with moxetumomab pasudotox at the recommended dosage achieved a durable CR rate of 30.3% (95% CI: 20.3%, 41.3%) per BICR in 80 heavily pre- treated patients with R/R HCL. The effectiveness of the treatment is supported by the significant reduction of CD19+ B cell from baseline. The maximum reduction of 89% was observed after the first three doses in this trial. Exposure-response (E-R) analyses indicates that high PK exposure area under the curve (AUC) is correlated with high rate of response including durable CR, CR and overall response rate (ORR). E-R analyses for safety supports the proposed dose regimen with appropriate labeling for safety monitoring and risk mitigation.

The Office of Clinical Pharmacology has reviewed the information contained in BLA 761104. This BLA is approvable from a clinical pharmacology perspective. The key review issues with specific recommendations and comments are summarized below.

Review Issues Recommendations and Comments

Evidence of An open-label, single-arm pivotal Phase 3 trial provides primary evidence. effectiveness Pharmacodynamics analysis of CD19+ B cell reduction and exposure-response analyses for durable CR, CR and ORR provide supportive evidence. General dosing The recommended dose regimen of moxetumomab pasudotox is 0.04 mg/kg (40 instructions µg/kg), administered as an IV infusion over 30 minutes on Days 1, 3, and 5 of each 28-day cycle. Patients should continue treatment for a maximum of 6 cycles, or until disease progression, or unacceptable toxicity. Dosing in patient No dose modification is needed for body weight, age, race (White, Non-white), subgroups (intrinsic gender, immunogenicity screen positive (anytime), neutralizing anti-drug and extrinsic factors) antibody positive (anytime), baseline spleen size (cm) and baseline bone marrow involvement (% infiltration by leukemia based on central review).

Data supports that no dose modification is needed for patients with mild to severe hepatic impairment, and mild or moderate renal impairment. Although not studied, significant changes in PK are not expected for patients with severe 43 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

renal impairment, as moxetumomab pasudotox has a molecular weight above 60 KDa.

Immunogenicity In Study 1053, 59% (45/76) of the patients tested positive for anti-drug antibody (ADA) prior to any treatment with moxetumomab pasudotox. Subsequently, 70 of 80 patients treated with moxetumomab pasudotox (4 patients not tested at baseline were subsequently tested) tested ADA positive at any visit and were subsequently tested for neutralizing antibody (nAb). The results showed that 67 of 70 subjects were nAb-positive. Among these 67 nAb-positive patients, 98.5% (66/67) had ADA specific to the PE38 binding domain, and 53.7% (36/67) also had ADA specific to the CD22 binding domain. ADA titers increased in 55 of 67 patients who were nAb-positive by a median of 640-fold (range: 2- to 20480- fold) when compared to the baseline values. Patients who tested positive for ADA had decreased systemic moxetumomab pasudotox concentrations.

Labeling Generally acceptable. A statement related to the increase of ADA titers was added to section 6.2. A statement describing the effect of immunogenicity on PK was added to section 12.3. The review team made recommendations for specific content and formatting changes.

There are no postmarketing requirements or postmarketing commitments required from a clinical pharmacology perspective.

Summary of Clinical Pharmacology Assessment

Pharmacology and Clinical Pharmacokinetics

Moxetumomab pasudotox is a 63 KDa recombinant cytotoxin targeting the B cell-specific surface antigen cluster of differentiation 22 (CD22). It is composed of an immunoglobulin light chain variable domain and a heavy chain variable domain genetically fused to a truncated form of Pseudomonas exotoxin 38 (PE38), with high affinity to CD22 (Kd = 6 nM). The PE38 domain can catalyze the ADP-ribosylation of protein synthesis elongation factor 2, which results in cell death.

Following the administration of multiple doses of moxetumomab pasudotox at the recommended dosing schedule in patients with R/R HCL, concentrations of moxetumomab pasudotox increased proportionally within the dose range of 5 to 50 µg/kg. Concentrations increased from the first to the third dose during the first cycle, likely related to the depletion of malignant B cells expressing CD22. This finding is consistent with the observation of high PK exposure in patients with low baseline CD19+ (a surrogate of CD22+) B cell counts. Based on population PK (popPK) analysis, the geometric mean (%CV) for clearance after the first dose 44 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

(CL1) was 24.7 L/h (116%), the corresponding value for clearance of subsequent doses (CL2) was 3.8 L/h (109%). The significant decrease of CL suggests that moxetumomab pasudotox undergoes target-mediated drug disposition in humans. The geometric mean (%CV) was 6.5 L (37.4%) for central volume of distribution (V1). The observed terminal half-life (t1/2) ranged from 1 to 3 hours, much shorter than that of monoclonal antibodies.

Patients treated with moxetumomab pasudotox had a high prevalence of ADA and nAb against the PE38 domain and/or CD22 binding domain. In Study 1053, 59.2% patients were tested positive for ADA at baseline (all specific to the PE38 domain). The ADA prevalence rate was 87.5% (70/80 patients) at any visit following treatment. nAb were detected in 67 of these 70 ADA-positive patients. Among these 67 patients who tested nAb positive, the ADA were 98.5% (66/67) specific to the PE38 binding domain and 53.7% (36/67) specific to the CD22 binding domain. ADA titers increased from a median of 80 at baseline to 320, 2400, and 19200 in Cycles 2, 3 and 5, respectively. Patients who tested positive for ADA had decreased systemic moxetumomab pasudotox concentrations (see section 19.3.3). Exploratory analyses showed that the subset of patients who had ADA titers greater than the median at Cycle 5 had less pharmacodynamic effect on CD19+ B cell and lower efficacy (durable CR) as compared to patients who tested negative for ADA or had ADA titers below the median. Although patients with high ADA titers had lower durable CR (20% vs 30% for the overall population), 20% durable CR still constitutes clinical benefit for these heavily pretreated patients with R/R HCL. Additionally, the E-R relationship for durable CR was not statistically significant indicating that there may not be a clinically meaningful benefit from increasing exposure. Regarding safety, the presence of ADA did not appear to have an association with the incidence or severity of adverse reaction.

General Dosing and Therapeutic Individualization

General Dosing

The proposed dose regimen of moxetumomab pasudotox is 0.04 mg/kg (40 µg/kg), administered as an IV infusion over 30 minutes on Days 1, 3, and 5 of each 28-day cycle. Patients should continue treatment for a maximum of 6 cycles, or until disease progression, or unacceptable toxicity occurs.

Therapeutic Individualization

No therapeutic individualization for intrinsic or extrinsic factors is recommended.

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NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

Mean terminal elimination The terminal phase half-life (CV%) was 1.4 hours (25.2%) at steady state (Cycle 2 half-life Day 1) at the recommended dose. Metabolism Primary metabolic Not evaluated. As a recombinant protein, moxetumomab pasudotox is expected pathway(s) to be degraded into small peptides and amino acids via catabolic pathways.

Inhibitor/Inducer Not evaluated. As a large recombinant protein, moxetumomab pasudotox is not expected to be an inhibitor or inducer of drug metabolism enzymes or transporters.

Excretion Primary excretion pathways No evaluated. As a recombinant protein, moxetumomab pasudotox is expected to (% dose) ± SD be degraded into low-molecular-weight peptides and amino acids via catabolic pathways. Its molecular weight is slightly above the cutoff value of 60 kDa for renal excretion so renal clearance is not expected.

Clinical Pharmacology Questions

Does the clinical pharmacology program provide supportive evidence of effectiveness?

Yes, there is supportive evidence of effectiveness from PK/pharmacodynamics and exposure- efficacy analyses.

In Study 1053, total peripheral blood CD19+ B cell counts (including normal B cells and HCL cells) were quantified since moxetumomab pasudotox interferes with detection of cellular CD22. The change of CD19+ B cells normalized by baseline following moxetumomab pasudotox treatment up to 181 days post end of treatment (EOT) is shown in Figure 5.

Figure 5. Median Baseline Normalized CD19+ B Cell Counts Over Time (Study 1053)

Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Figure 2.7.2.2.2.1-10

The results indicate that a maximum reduction (89%) of CD19+ B cell population from baseline was achieved around Day 8 following the first three doses of moxetumomab pasudotox. Median baseline-normalized CD19+ B cell values remained statistically reduced from baseline at all subsequent time points up to- and including Day 176 (EOT for subjects receiving all doses of 47 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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moxetumomab pasudotox). On Day 357 (181 days post EOT), median baseline-normalized CD19+ B cell values were similar to baseline levels. The change of CD19+ B cells over the course of moxetumomab pasudotox treatment showed the pharmacological effect of the drug that is associated with the effectiveness in patients with R/R HCL.

In the dose-finding Phase 1 Trial 1001, efficacy of moxetumomab pasudotox in patients with R/R HCL were investigated at doses of 5, 10, 20, 30, 40, or 50 μg/kg on Days 1, 3, and 5 of every 28-day cycle. Although none of the three patients treated at dose of 5 µg/kg achieved complete response (CR), E-R analysis with logistic regression showed a positive relationship between probability of CR and PK exposure (cumulative AUC during the first cycle) (p=0.02) within this dose range. Based on the overall effectiveness and safety profile, the 50 μg/kg dosing regimen was selected for the pivotal trial. This dose is biologically equivalent to 40 µg/kg of material used in Study 1053.

In Study 1053, within the exposure range of recommended dose of 40 µg/kg, notable exposure- response relationships were observed between AUC on Day 1 in Cycle 2 and all three efficacy endpoints – durable CR, CR and ORR (Figure 6). The exposure was a significant predictor for ORR (p=0.00059) while it was not statistically significant for Durable CR or CR.

Figure 6. Relationships between PK exposure (AUC on Day 1 Cycle 2) and durable CR, CR or ORR (Study 1053)

Source: Reviewer’s analysis

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Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

In summary, clinical pharmacology analyses provide supportive evidence of the effectiveness of moxetumomab pasudotox for the treatment of patients with R/R HCL.

Is the proposed dosing regimen appropriate for the general patient population for which the indication is being sought?

Yes. The proposed dosing regimen is generally supported by the E-R relationships in efficacy and safety. See the previous question for E-R in efficacy.

For safety, moxetumomab pasudotox was shown to have an acceptable adverse event (AE) profile at dose levels up to 50 μg/kg (biologically equivalent to 40 µg/kg used in pivotal trial) without reaching the maximum tolerated dose (MTD) in Phase 1 Study 1001. In the E-R analysis for safety based on pooled data from studies 1001 and 1053 (AUC was adjusted for different bioactivity between the two trials), there was no correlation between the incidence of AE of special interest (AESI) hemolytic uremic syndrome (HUS) and exposure (adjusted AUC on Day 1 Cycle 1) (Figure 7). However, the incidence of AESI capillary leak syndrome (CLS) and Grade ≥ 3 treatment emergent AE (TEAE, 30%) were correlated with adjusted AUC, which supports the proposed dose regimen with close monitoring patients for signs and symptoms of adverse events.

Figure 7. Correlation between PK exposure (AUC on Day 1 Cycle 1) and adverse events (Study 1053 and 1001)

Source: Reviewer’s analysis (aAUC: adjusted AUC where AUC from Trial 1001 was adjusted for the drug substance’s lower bioactivity)

Effect of Immunogenicity on Efficacy and Safety The durable CR rate was lower in patients with ADA titers greater than the median titer of 10240 in Cycle 5 compared to those with ADA titers below the median (Figure 8). This result could be partially explained by the observation that patients with high ADA titers had lower Cmax (see detail in section 19.4.2). However, the E-R relationship for durable CR was not 49 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

Reference ID: 4319411 NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

statistically significant, indicating that there is no assurance that increasing exposure will result in a clinically meaningful increase in durable CR. The E-R relationship for ORR was statistically significant (p=0.00059) but there was no difference in ORR rates between subjects with ADA titer ≤10240 and those with ADA titer >10240. Moreover, increasing the dose for patients with high ADA titer may not be able to achieve adequate PK exposure due to the presence of high concentration of nAbs and triggering of more ADA production. There are also safety concerns such as severe infusion related reaction and hypersensitivity associated with further dose increases in later cycles with the presence of higher ADA titer. Although patients with high ADA titer had lower durable CR (20%), these heavily pre-treated patients with R/R HCL still benefit from the treatment.

Figure 8. Relationship between ADA Titer and Efficacy Endpoints in Study 1053

Source: Applicant’s Clinical PopPK Modeling and Exposure-Response Analysis Report, Figure 6.7.6-1, page 61

Lastly, as shown in Table 7, ADA positivity did not have a significant effect on the safety profile of moxetumomab pasudotox.

Table 7. Subgroup Analysis of Safety Parameters–Immunogenicity (Study 1053)

Safety ADA ADA ADA-positive CD22 PE38 Titers > Parameter Positive at Always Patients who Specificity Specificity Median of Any Time Negative are nAb Positive at Positive Any Patients Who (n=70) (n=10) Positive at Any Time of Time of are Any Visit Patients Who Patients Who ADA+/nAb+ (ADA+/nAb+) are are (n=32) (n=67) ADA+/nAb+ ADA+/nAb+ (n=36) (n=66)

HUS/HUS-like 5 (7.1%) 1 (10.0%) 5 (7.5%) 1 (2.8%) 5 (7.6%) 1 (3.1%) CLS 7 (10.0%) 0 7 (10.4%) 4 (11.1%) 7 (10.6%) 1 (3.1%) Both HUS/HUS-like and 4 (5.7%) 0 4 (6.0%) 1 (2.8%) 4 (6.1%) 0 CLS Infusion-related reaction 7 (10.0%) 0 7 (10.4%) 5 (13.9%) 7 (10.6%) 4 (12.5%) Severe 0 0 0 0 0 0 hypersensitivity reactions to include anaphylaxis and serious allergic reactions 50 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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Treatment related TEAE 22 (31.4%) 2 (20.0%) 21 (31.3%) 10 (27.8%) 21 (31.8%) 6 (18.8%) (≥ Grade 3) Creatinine increased 19 (27.1%) 4 (40.0%) 19 (28.4%) 6 (16.7%) 18 (27.3%) 4 (12.5%) Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Table 2.7.2.4-2

Is an alternative dosing regimen or management strategy required for subpopulations based on intrinsic patient factors?

No. In the popPK analysis, various intrinsic factors were assessed as PK covariates, including body weight, age, race subtype (White, Non-white), gender, immunogenicity screen positive (anytime), neutralizing ADA positive (anytime), baseline spleen size (cm) and baseline bone marrow involvement (% infiltration by leukemia based on central review). None of these intrinsic factors had any significant effect on PK.

In the popPK analyses, mild hepatic impairment had no effect on PK. Although there were no data from subjects with moderate and severe hepatic impact available for the analyses, dose adjustment is not recommended for patients with hepatic impairment because metabolism of moxetumomab pasudotox is presumed to occur via catabolic degradation not by drug metabolism enzymes in liver.

Similarly, mild and moderate renal impairment did not show any difference in exposure (Figure 9) and no dose adjustment is indicated for these subgroups of patients. For subjects with severe renal impairment, significant change of PK is not expected based on available data from patients with mild and moderate renal impairment and the high molecular weight of moxetumomab pasudotox which is slightly above the cutoff value of 60 KDa for renal clearance.

Figure 9. Comparison of AUC by Renal Function (Study 1053, population PK analysis)

Source: Reviewer’s analysis

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NDA/BLA Multi-Disciplinary Review and Evaluation BLA 761104, Lumoxiti, Moxetumomab pasudotox

7 Sources of Clinical Data and Review Strategy

Table of Clinical Studies

Table 8 Clinical Trials Relevant to this BLA Trial Trial Design Regimen/ Treatment No. of Study No. of Identity (Endpoints) Schedule/Route Duration/ Patients Population Centers and Follow Up Enrolled Countries Uncontrolled studies to support efficacy and safety CD-ON-CAT- Phase 3, 40 µg/kg by IV Maximum 80 Relapsed or USA 35 8015-1053 multicenter, infusion over 30 ±10 of 6 cycles refractory France 8 (Study open-label, minutes on Days HCL; Italy 8 1053; single- 1,3, and 5 every 28 age ≥18 years GB 6 ongoing) arm days Germany 6 (efficacy, Poland 3 safety, PK Spain 3 and IM) Belgium 3 Canada 2 Serbia 2 Czech 1 Republic Ireland 1 Israel 1

Norway 1 Studies to support safety CAT-8015- Phase 1, 5, 10, 20, 30, 40, or Two cycles 49 Relapsed or USA 47 1001 open-label, 50 μg/kg IV beyond CR, refractory Non-US 2 (complete) multicenter, infusions progression HCL; interpatient (30 min) on Days 1, , initiation age ≥18 years dose- 3, and 5 of each 28- of alternate escalation day cycle cancer and dose therapy, expansion unacceptabl (safety, anti- e toxicity, tumor or activity, PK, developme IM and nt of nAbs pharmacodyn amics) CAT-8015- Phase 1, 5, 10, 20, 30, 40 or Total of 10 11 Relapsed or USA 9 1002 single-arm, 50 μg/kg IV cycles until refractory B- Poland 2 (complete) multicenter, infusions progression cell leukemia interpatient (30 min) on Days 1, or until (CLL, PLL, 53 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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Trial Trial Design Regimen/ Treatment No. of Study No. of Identity (Endpoints) Schedule/Route Duration/ Patients Population Centers and Follow Up Enrolled Countries dose- 3, and 5 of each 28- patient is SLL); escalation day cycle (Process 1 ineligible age ≥18 years (MTD, PK, and 2) pharmacodyna mics, efficacy, safety and IM) CAT-8015- Phase 1, 5, 10, 20,30, 40 or Total of 10 2 Relapsed or USA 2 1003 open- 50 μg/kg IV cycles, patients refractory (complete) label, single- infusions progression enrolled NHL arm, (30 min) on Days 1, or until at Age ≥18 multicenter, 3, and 5 of each 28- patient is 5 μg/kg years interpatient day cycle (Process 1 ineligible dose- and 2) escalation (MTD, PK, pharmacodyn amics, efficacy, safety and IM) MI-CP218 Phase 1/2, 20, 30, 40, 50, or 60 Until Arm A: Relapsed or USA 23 (Complete) open μg/kg IV infusions progression CLL, refractory label, single (30 min) on Days 1, or DLBCL, B-cell CLL or arm, 3, and 5 of a 28-day patients MCL, NHL multicenter, cycle (Process 2) became n=19 (DLBCL, FL, dose ineligible Arm B: MCL); escalation FL, n=4 age ≥ 18 and years expanded cohort (MTD/OBD, PK, pharmacodyn amics, efficacy, safety and IM) Source: FDA synopsis of individual studies included in the BLA CLL=chronic lymphocytic leukemia, DLBCL=diffuse large B-cell leukemia, FL=follicular lymphoma, GB=Great Britain, IM=immunogenicity, IV=intravenous, MCL=mantle cell lymphoma, MTD=maximum tolerated dose, NHL=non-Hodgkin lymphoma, OBD=optimal biologic dose, PK=pharmacokinetics, PL=prolymphocytic leukemia, SLL=small lymphocytic leukemia. 54 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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Review Strategy

The key materials used for the review of efficacy and safety included: • BLA 761104 • IND 115709 • Relevant published literature • Relevant information in the public domain

The efficacy review was primarily based on analyses of Study 1053. This trial provided efficacy data for 80 patients with HCL who received the proposed marketing dose of moxetumomab pasudotox and evaluation of the primary endpoint by BICR.

The Phase 1 study of HCL patients (Study 1001) and two Phase 1 studies of patients with non- Hodgkin lymphoma (NHL) (listed in Table 8)were used in the analysis of safety. The safety review emphasis was placed on the primary HCL adult population from studies 1053 and 1001. No integrated analysis of efficacy was conducted due to differences in the study design, doses, primary endpoint, and endpoint assessment in Study 1053 and Study 1001.

Data sources included applicant study reports, protocol and amendments, statistical analysis plan and amendments, datasets, and literature referenced for Study 1053 and the integrated summary of safety.

Clinical data were provided in the Clinical Data Interchange Standards Consortium (CDISC), Foundational Standards SDTM (Study Data Tabulation Model), and ADaM (Analysis Data Model Implementation). Define files were also submitted for the variables and the corresponding SAS programs for the primary ADaM data derivation to document the analysis results. The reviewers could duplicate the analysis results based on the Applicant’s submitted datasets.

Electronic datasets were located at: \\CDSESUB1\evsprod\BLA761104\0001\m5\datasets

Section 8.1 contains a review of efficacy from Study 1053. The statistical reviewer conducted the efficacy analyses independent of the Applicant’s results except where indicated. Both the statistical and clinical reviewers provided commentary on the results. SAS version 9.4 was used to provide results of the primary efficacy analysis.

Summaries of clinical trial data and statistical analysis by the clinical reviewer were performed using JMP 12.1.0 (SAS Institute, Inc., Cary, NC) and JMP Clinical 6.1. MedDRA Adverse Events Diagnostic 1.3 (MAED) (FDA, Silver Spring, MD) was also used to look for safety signals. The analyses of safety presented in Section 8.2 were those of the clinical reviewer using MAED and

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JMP. Unless otherwise stated, all tables and figures in section 8.2 (safety) were created by the clinical reviewer. .

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8 Statistical and Clinical and Evaluation

Review of Relevant Individual Trials Used to Support Efficacy

Study CD-ON-CAT-8015-1053

Trial Design

Study 1053 was an international multicenter, open-label, single-arm study of moxetumomab pasudotox designed to evaluate the efficacy of moxetumomab pasudotox in subjects with relapsed or refractory HCL.

Figure 10 Study 1053 Flow Diagram

Source: Figure 9.1-1 Study Flow Diagram cd-on-cat-8015-1053-clinical-study-report

An individual subject was considered to have completed the study if the subject was followed through the Day 181 post-end of treatment visit, regardless of the number of doses of investigational product received.

The study enrolled subjects ≥18 years of age with a histologically confirmed diagnosis of HCL or HCL-V who received at least 2 prior systemic therapies, including 2 courses of a PNA or 1 course of either rituximab or BRAF inhibitor following a single prior course of PNA.

Study Treatment: Approximately 80 subjects received treatment with moxetumomab pasudotox (40 μg/kg) by IV infusion over 30 ± 10 minutes on Days 1, 3, and 5 of each 28-day cycle for up to 6 cycles, until documentation of CR, PD, initiation of alternate therapy, or unacceptable toxicity (Figure 10).

Patients with platelet counts ≥ 100 x 109/L were to receive low dose aspirin (81 mg daily or local 57 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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standard dose) to prevent renal insufficiency. Patients also received 1 liter of 5% dextrose 0.45% NaCl, (recommended over 2-4 hours) prior to the beginning and after the end of each moxetumomab pasudotox infusion. On Days 0-8 of the cycle, patients were expected to drink at least 3 liters of fluid/day.

Premedications were administered 30-90 minutes prior to every moxetumomab pasudotox infusion as follows:

• Hydroxyzine 10-25 mg (dose to be determined by the investigator) • Acetaminophen 650 mg • Ranitidine 150 mg orally

After the end of each infusion, patients were recommended to receive acetaminophen 650 mg orally every 6 hours x 4 doses and hydroxyzine 10-25 mg orally every 8 hours for 2 doses.

Adequate Pneumocystis carinii pneumonia prophylaxis was recommended for patients receiving corticosteroids ≥ 10 mg of prednisone daily or equivalent, CD4 lymphocyte count < 0.2 x 109/L, or at the discretion of the investigator. Viral prophylaxis was also required for subjects receiving chronic corticosteroids or with lymphopenia.

Non-steroidal anti-inflammatory medications, other than aspirin, for prophylaxis of renal insufficiency, were not permitted during the study through 7 days after the last dose of moxetumomab pasudotox.

Key Inclusion Criteria: A need for therapy based on at least one of the following criteria: • neutrophils < 1.0 × 109/L • platelets < 100 × 109/L • hemoglobin < 10 g/dL • symptomatic splenomegaly Adequate organ function as defined below: • total bilirubin ≤ 1.5 mg/dL, unless consistent with Gilbert’s syndrome • -AST- and -ALT ≤ 3× upper limit of normal (ULN) and alkaline phosphatase < 2.5× ULN • serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 60 mL/min as estimated by the Cockcroft-Gault equation

Key Exclusion Criteria: • History of both thromboembolism and known congenital hypercoagulable conditions • Uncontrolled pulmonary infection or pulmonary edema • Oxygen saturation at rest < 88% measured by pulse oximetry or partial pressure of oxygen ≤ 55 mmHg • Serum albumin < 2g/dL 58 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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• Absolute neutrophil count (ANC) < 1.0 × 109/L or platelet count < 50 × 109/L, unless judged by the investigator to be due to underlying disease • Less than 50% of predicted forced expiratory volume (FEV) or < 50% of predicted diffusing capacity for carbon monoxide, corrected for hemoglobin concentration and alveolar volume • History of thrombotic microangiopathy or thrombotic microangiopathy/ HUS • Corrected QT interval (Friderica) elevation > 500 msec • Retinal or choroidal detachment identified during the screening ophthalmologic evaluation

Response Assessments: Bone marrow examination and radiographic disease assessment were performed at screening, EOT, and 6 months post EOT. If during treatment and prior to completion of 6 cycles of therapy blood counts were consistent with CR for at least 4 weeks, then an interim disease assessment could be performed at the discretion of the investigator. If a CR without minimal residual disease (MRD) is documented, then treatment could be discontinued. For any other response, treatment was continued to complete 6 cycles of therapy with the full disease assessment repeated at EOT.

The Applicant’s schedule of procedures and assessments for Study 1053 is listed below.

Table 9 Study Calendar for Cycle 1 and Subsequent Cycles

Day 8 Day 15 Day 21 Evaluation/Intervention Screening Pre-cycle Day 1 Day 3 Day 5 (±1D) (±2D) (±2D) Informed consent, X demographics, medical history, height, β-HCG Adverse events and concurrent X X X X X X X X medications Physical exam, pulse oximetry, query X X X X X for visual symptoms Ophthalmologic exam X 12-lead ECG (analyzed by central X X X X vendor) CBC with differential (smear X X X with Schistocyte count X X X X X [selected timepoints]) Urinalysis X X HBsAg, HBcAB, HepC, Hepatitis B Viral DNA load (if needed), HLA, C3, X C4, CH50, serum and urine protein electrophoresis, PFTs (if needed)

Sodium, potassium, chloride, bicarbonate, glucose, BUN, X X X X X X X X creatinine, calcium, magnesium, phosphorous, AST, ALT, total bilirubin, direct bilirubin, LDH, albumin, Alk Phos

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Day 8 Day 15 Day 21 Evaluation/Intervention Screening Pre-cycle Day 1 Day 3 Day 5 (±1D) (±2D) (±2D) Total protein, triglycerides, cholesterol, GGT, PT, PTT, X X fibrinogen, serum amylase, serum lipase, uric acid, fT4, TSH, CK, IgG Peripheral blood flow cytometry X X Peripheral blood for disease B-cell X clone detection Lymphocyte enumeration X X X CT or MRI abdomen X BM biopsy & aspirate (flow X cytometry/sequencing) Clinical response assessment X Vital signs X X X X X X X Orthostatic blood pressure (BP) X X X X X Weight X X X Performance status X X Pharmacokinetics X X

Immunogenicity evaluation X Moxetumomab pasudotox dosing X X X Source: Table 10-1 cd-on-cat-8015-1053-16-1-1 -protocol-and-protocol-amendments BM bone marrow, BUN blood urea nitrogen, CT computerized tomography; DNA deoxyribonucleic acid, ECG electrocardiogram, GGT gamaglutamyl transferase, HCG human chorionic gonadotropin, HBsAg hepatitis B surface antigen, HBcAB hepatitis B surface antibody, LDH lactate dehydrogenase, MRI-magentic resonance imaging, PT prothrombin time, PTT partial thromboplastin time, fT4-free thyroxine, TSH thyroid stimulating hormone, CK creatinine kinase, IgG immunoglobin G.

Table 10 Study Calendar for End of Treatment and Follow -up From end of treatment assessment Every month Every 3 181D 12 18 Yearly for 6 months months (+ 2W) months months thereafter (if in CR) for 24 (± 1M) (± 1M) (± 1M) (± 1W) months (± 2W) History and physical exam X X X X X Vital signs including pulse oximetry X X X X X Performance status X X X X X Concurrent medications X X X b X X Adverse events X Ophthalmologic exam X

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12-lead ECG (analyzed by central X vendor) Imaging with CT or MRI of abdomen X X X BM biopsy and aspirate (flow X X cytometry/sequencing) Clinical response assessment X X X X CBC with differential (no peripheral X X X X X X X Chem 7 (sodium, potassium, X X X X X chloride, bicarbonate, glucose, BUN, creatinine) Mineral panel (calcium, X X X X X magnesium, phosphorous, Hepaticl i panel ) (AST, ALT, total X X X X X bilirubin, direct bilirubin, Alk Phos) Uric acid, LDH, total protein, triglycerides, cholesterol, GGT, PT, X X PTT, fibrinogen, quantitative immunoglobulins, CK, CRP, serum ferritin TSH, fT4, serum amylase, serum X X lipase, haptoglobin, urinalysis Immunogenicity evaluation X Lymphocyte enumeration, peripheral blood flow X X X X X cytometry

Peripheral blood for disease B-cell X X clone detection Source: Table 10-2 cd-on-cat-8015-1053-16-1-1 -protocol

Study Endpoints

The primary efficacy endpoint of this study is durable complete response (CR) based on CR assessed per BICR. Hematologic remission (namely the blood counts needed for CR, without transfusions or growth factors) must have been maintained for > 180 days. Durable CR rate defined as the proportion of subjects with durable CR was calculated and the 95% CI of durable CR was estimated using the Clopper-Pearson exact method. Clinical Reviewer comment: The primary endpoint in Study 1053 is durable CR rate as defined in the protocol and is a novel clinical endpoint for drug approval in HCL. Previous approvals in HCL of cladribine and pentostatin were based on CR rates and an improved duration of CR. The durable CR rate can be considered a more stringent definition of CR as it requires patients in CR maintain hematological counts required for CR for >180 days. Additionally, as presence of cytopenia (as defined in Study 1053 is an indication for treatment (to prevent associated complications); durable CR rate can be considered as meaningful clinical benefit in this patient population.

Secondary endpoints are CR, time to CR, duration of CR, duration of hematologic remission from onset of hematologic remission, time to hematologic remission, objective response 61 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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(OR), time to OR, duration of OR, progression-free survival (PFS), and time to treatment failure (TTF).

Statistical Analysis Plan

The primary objective of this study is to determine the rate of durable complete response (CR) in multiply relapsed HCL with moxetumomab pasudotox. To meet the primary endpoint, patients were required to meet standard criteria for CR by analysis of blood, bone marrow and imaging, and maintain a hematologic remission, namely the blood counts needed for CR, for >180 days.

Sample Size Considerations

The sample size estimation in this study assumed that the historical durable CR rate in this population is ≤ 13%. This is based on previous studies of rituximab. The target durable CR for moxetumomab pasudotox was assumed to be at least 28%. Using the exact binomial test, a total of 77 subjects was expected to provide 90% power to detect a difference between 28% and 13% durable CR rates at a 2-sided significance level of 0.05. Furthermore, with 77 subjects, a two-sided 95% CI would have a width of +/-10% from the observed proportion when the expected proportion is 28%.

The intention-to-treat (ITT) population included all subjects who have been entered into the study and received treatment with moxetumomab pasudotox. The ITT population is the primary population for the efficacy analysis.

The efficacy evaluable population included all subjects who have received at least 1 dose of moxetumomab pasudotox and have a baseline and at least one postbaseline disease assessment. The efficacy evaluable population is secondary population for efficacy analysis.

The primary efficacy summaries are based on BICR assessment; efficacy results by investigator’s assessment are also presented.

Statistical Analysis Methods For the binary endpoints: durable CR, CR, OR, and hematologic remission, the proportion of subjects with these events were calculated and 95% CI were estimated using the Clopper- Pearson exact method. For the time-to-event endpoints: time to CR, time to OR, time to hematologic remission, PFS, and TTF results were summarized by Kaplan-Meier method.

Key Protocol Amendments

The original protocol was dated 14Feb2013. The Study was initially sponsored by the National Cancer Institute (NCI) and was transitioned to MedImmune upon starting Protocol Amendment 4 (12Aug2014). The study was revised a total of 9 times between activation and the data cutoff date of 24 May 2017. Key protocol revisions are summarized as follows: 62 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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Amendment 1, CTEP amendment A (26Mar2013) • Exclusion criterion added for subjects with clinically significant ophthalmologic findings during screening Amendment 2, CTEP amendment B (01Nov2013 and 20Feb2014) • Included provision for dexamethasone to be used as secondary prophylaxis for infusion- related reactions (IRR) at the investigator’s discretion • Subjects with Grade 4 CLS and Grade 3 HUS to be taken of off treatment instead of off study Amendment 3, CTEP amendment C (09Jun2014) • Eligibility criteria modified to clarify that subjects with HCL-V are eligible for enrollment Amendment 4 (12Aug2014) • Added optional interim disease assessment to be performed at the discretion of the investigator during treatment and prior to completion of 6 cycles of therapy • Included instructions stating treatment should be suspended for HUS of any grade until resolution of all laboratory abnormalities and should only be resumed if the maximum grade was ≤ 2 and after consultation and agreement with the sponsor Amendment 5 (02Oct2014) • Added that subjects should not begin a subsequent cycle of moxetumomab if there is active infection requiring treatment Amendment 8 (06Jan2017) • Requirements for CR ± MRD that need to be present was changed to require no evidence of leukemic cells in the peripheral blood and/or by routine H/E staining of bone marrow • Added censoring rules for duration of hematologic remission separate from duration of CR

The majority of subjects (54 [67.5%]) were enrolled under Protocol Amendment 7. The other subjects were enrolled under Protocol Amendments A (4 [5.0%]), B (5[6.3%]), 5 (4[5.0%]) and 6 (13[16.3%]). Under Protocol Amendments A and B, the maximum number of treatment cycles was not established. One subject enrolled in the study prior to implementation of the maximum number of treatment cycles as 6 and received 7 cycles of treatment. Additionally, for Protocol Amendments A and B, the Day 181 disease assessment was 181 days after start of CR as opposed to 181 days after EOT in later versions of the protocol (Source: cd-on-cat-8015-1053- clinical-study-report Table 10.1-2)

Study Results

Compliance with Good Clinical Practices

The Applicant provided attestation in Module 5 (Study 1053 CSR) that this study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.

Financial Disclosure

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The Applicant submitted financial disclosure information from all investigators for this trial. A summary of financial disclosures for the studies included in the submission is provided in Appendix 19.2. There were no clinical investigators with disclosable financial arrangements in relation to Study 1053.

Patient Disposition

Eighty-nine subjects were screened and 9 subjects failed screening due to not meeting inclusion/exclusion criteria (6 subjects) or other reasons. A total of 80 subjects were treated with moxetumomab pasudotox at 32 sites.

The first subject received the first dose of moxetumomab pasudotox on 02May2013 and the last subject was dosed on 30May2016. As of the data cutoff date of 24May2017 enrollment has been completed and no subjects remain on study treatment. The median duration of follow-up at the time of data cutoff date May 24, 2017 was 16.7 months (min 2.1 months, max 48.8 months).

Patient disposition in Study 1053 is shown in Table 11. As of 24May2017, 30 subjects discontinued prior to 6 cycles of treatment as of 24May2017. The most common reasons for treatment discontinuation were achievement of MRD/negative CR by flow cytometry assessed by investigator and adverse events. Two (2.5%) subjects did not complete treatment due to disease progression, and 3 (3.8%) subjects did not complete treatment for other reasons (1 subject had lack of benefit, 1 subject had lack of response, and 1 subject had stable disease/was refractory to treatment).

Deaths were reported in 3 (3.8%), two (2.5%) subjects withdrew consent, 1 (1.3%) subject was lost to follow-up, and 24 (30.0%) subjects discontinued study participation for other reasons.

Table 11 Study 1053-Patient Disposition N % Patients enrolled and received treatment 80 Patients who completed 6 cycles of treatment 50 62.5 Patients who did not receive 6 cycles of treatment 30 37.5 Adverse event 12 15.0 Complete response without MRD 12 15.0 Other 3 3.8 Progressive disease 2 2.5 Death 1 1.3 End of Study Status Patients ongoing in follow -up 50 62.5 Discontinued Study 30 37.5 Other 24 30.0

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Withdrawal of consent 3 3.8 Lost to follow-up 1 1.3 Source: Clinical reviewer analysis of ADSL dataset Study 1053

Among the 24 patients with reason for discontinuing study listed as “other”, the most common reasons were starting alternative therapy (11/30) or disease progression (10/30).

Protocol Violations/Deviations

A total of 13 (16.3%) subjects had important protocol deviations. The most common category of important protocol deviations pertained to safety assessments (8 [10.0%] subjects). Safety reporting to the Sponsor was delayed in 2 subjects. One subject (PID (b) (6) ) did not meet the protocol-defined inclusion criterion 1 (HCL with need for treatment based on hematology lab values and/or symptomatic splenomegaly). Day 181 disease assessments were not completed per protocol in 2 cases.

Table 12 Important Protocol Violations/Deviations Moxetumoman pasudotox Important Protocol Violations/Deviations N=80 Any subject with important protocol deviations 13 (16.3%) Inclusion and exclusion criteria 1 (1.3%) Study drug 3 (3.8%) Assessment – safety 8 (10.0%) Lab/Endpoint data 2 (2.5%) Informed consent 3 (3.8%) Other 2 (2.5%) Source: Table 10.2-1 CSR Study 1053

Reviewer comment: The important protocol violations/deviations identified by the Applicant do not appear to impact the interpretation of study results.

Demographics and other characteristics

Demographic characteristics of patients in Study 1053 are summarized in Table 13. The median age was 60 years (min, max: 34, 84 years) and the majority of subjects were male (78.8%, 63/80) and white (90.0%, 72/80).

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Table 13 Demographic Characteristics- ITT Population Parameter Moxetumomab pasudotox N = 80 Age, years Median 60 Min, Max 34, 84 Age Group (years), n (%) <65 49 (61.3) >=65 31 (38.8) Sex, n (%) Female 17 (21.25) Male 63 (78.75) Race, n (%) White 72 (90.0) Asian 1 (1.3) Black or African American 1 (1.3) Native Hawaiian or Pacific Islander 0 Other 3 (3.8) Missing1 3 (3.8) Region, n (%) US 35 (43.8) Non-US 45 (56.3) ECOG performance status, n % 0 49 (61.3) 1 29 (36.3) ≥2 2 (2.5) Missing 0 Source: FDA reviewer analysis 1 Data on race and/or ethnicity were not collected in XX country because of local regulations.

Reviewer Comment: The demographics of the Study 1053 is representative of the HCL population in the US with a 4:1 ratio of men to women and the median age at diagnosis is approximately 55 years old(14).

Other Baseline Characteristics

Baseline disease characteristics are summarized in Table 14.

The majority of patients had a diagnosis of classical HCL. Subjects’ hematologic parameters were generally below lower limits of normal. The most common cytopenia present in the enrolled patients was a platelet count ≤ 100 x 103/µL in nearly 84% (67/80) of the patients. Approximately 68% of the patients enrolled had neutrophil counts < 1 x 103/uL. Median 66 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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neutrophil count was 0.81 x 103/ µL (range: 0.13-6.21).

Table 14 Baseline Disease Characteristics-ITT Population Moxetumomab pasudotox Parameter N = 80 Spleen size by BICR (cm), n (%) < 14 cm 46 (57.5) ≥ 14 cm 28 (35.0) Missing 6 (7.5) < 17 cm 60 (75.0) ≥ 17 cm 14 (17.5) Missing 6 (7.5) HCL type, n (%) HCL 77 (96.3) HCL Variant 3 (3.8) Time from initial diagnosis to study entry (months) Median 133.33 Min-Max 7.3-367.7 Time from last prior treatment to study entry (months) Median 25.0 Min-Max 2.0-111.4 Hemoglobin (g/dL), n (%) <10 26 (32.5) ≥10 54 (67.5) 3 Platelets (10 /µL), n (%) <100 67 (83.8) ≥100 13 (16.2) 3 Neutrophils (10 /µL), n (%) <1.0 54 (67.5) ≥1.0 26 (32.5) Source: FDA reviewer analysis

Table 15 Study 1053-Prior HCL Therapy Moxetumomab pasudotox Parameter N = 80 Prior systemic therapies Median (range) 3.0 (2-11) Number of Lines, n (%) 2 Prior Lines 19 (23.8) 3 Prior Lines 22 (27.5) 67 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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Moxetumomab pasudotox Parameter N = 80 >3 Prior Lines 39 (48.8) Number of lines of prior PNA therapy, n (%) <2 10 (12.5) ≥2 70 (87.5) Prior HCL Treatment, n (%) Purine Nucleoside analog 80 (100) Both cladribine and pentostatin 32 (40.0) Pentostatin only 3 (3.8) Cladribine only 45 (56.3) Rituximab 60 (75.0) Monotherapy 41 (51.3) Combination with PNA 23 (28.8) Patients refractory to PNA, n (%) 39 (48.8) PNA monotherapy 29 (36.3) PNA+ Rituximab 15 (18.8) Prior BRAF inhibitor, n (%) 14 (17.5) Source: FDA Reviewer Analysis Reviewer Comment: The baseline disease characteristics and prior therapies of patients enrolled on Study 1053 reflect a real-world population of patients with relapsed HCL(7, 15). With few exceptions patients had cytopenias or enlarged spleen (≥14 cm) necessitating treatment initiation. The trial enrolled a heavily pretreated population; 75% received 3 or more prior therapies and all patients had received therapy with PNA. Although rituximab is not approved for HCL, 75% of the patients had received rituximab either as a single agent or in combination with a purine analog. Only three subjects included on Study 1053 were diagnosed with HCL-V. This is not unusual as HCL-V is an uncommon disorder accounting for only 10% of all HCL cases.

Treatment Compliance, Concomitant Medications, and Rescue Medication Use

The CSR for Study 1053 included a statement that moxetumomab pasudotox was administered by study site personnel who monitored compliance.

The most frequently used concomitant medication groups (> 50% of patients) were analgesics, antihistamines for systemic use (97.5% each), blood substitutes and perfusion solutions, drugs for acid-related disorders (96.3% each), antithrombotic agents (72.5%), anti-bacterials for systemic use (68.8%), corticosteroids for systemic use (58.8%), and antivirals for systemic use (53.8%). Generally, corticosteroids were given prophylactically and not in relation to AESI.

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The most common concomitant medication was paracetamol (97.5%, 78/80) followed by acetylsalicylic acid (64%, 51/80). Except in one patient, acetylsalicylic acid was reported to start within a week of study start or during study treatment. The most common indication for use of acetylsalicylic acid as concomitant medication was prophylaxis. The median platelet count prior to start of acetylsalicylic acid was 115.5 x 103/µL (30.0-313.0).

Review of concomitant medications did not reveal reports of transfusions or growth factor use that impacted assessment of primary endpoint.

Efficacy Results – Primary Endpoint

The durable CR rate assessed by BICR in the ITT Population was 30.0% (24/80 subjects; 95% CI: 20.3%, 41.3%). Thirty-three patients achieved CR.

The durable CR rate assessed by investigator in the ITT Population was 47.5% (38/80 subjects; 95% CI: 36.2%, 59%). Forty-one patients achieved CR.

Fourteen patients were determined as durable CR by investigator, but non-CR by BICR. Number of discordance between BICR and Investigator’s assessment is presented in Table 16.

Table 16 Concordance of Durable CR between BICR and investigator’s assessment BICR Investigator Y N Total Y 24 14 38 N 0 42 42 Total 24 56 80 Source: FDA reviewer analysis BICR = blinded independent central review; CR = complete response

Statistical Reviewer comment: The main reasons for the discordances: the investigator determined CR earlier than the BICR, and there was not enough time to reach the durable CR criterion by the data cutoff date per BICR; some patients did not achieve a CR per BICR due to non-evaluable bone marrow.

Reviewer comment: For the majority of patients, discordance was due to a lack of evaluable bone marrow or low levels of bone marrow involvement (less than 2%) but who otherwise met the criteria for CR. Additionally, there was a difference in estimation of CR by investigator and BICR. Clinical response assessments, performed at the start of each treatment cycle and at each follow-up visit after the Day 181 post EOT assessment, consisted minimally of hematologic parameter evaluations. Per protocol, investigators could monitor the presence of leukemic cells in peripheral blood using a peripheral blood smear and/or flow cytometry.

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Furthermore, investigators may have assessed spleen, liver, and lymph nodes by physical examination. According to the statistical analysis plan, both investigator-reported disease response and clinical response assessments were considered in determining the investigator’s best overall response. Three patients (Patient (b) (6) ) were reported by investigators as having a CR based on clinical response assessment during treatment, but were downgraded by the investigator to progressive disease, stable disease, and partial response (PR), respectively, based on disease response assessment at EOT.

Sensitivity Analyses for Primary Efficacy Endpoint

Two pre-specified sensitivity analyses using different censoring rules were conducted to determine the robustness of the methodology used to determine duration of hematologic remission in the ITT population. The durable CR rates from sensitivity analyses 1 and 2 were both 30% (95 CI: 20.3%, 41.3%). The outcome of the sensitivity analyses appears to support the primary efficacy results. Additional sensitivity analysis of durable CR based on CR determined by the investigator were also conducted in the same manner as described for durable CR per BICR.

Data Quality and Integrity

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The sponsor incorporated a strategy to assure data quality and integrity. The sponsor assured the data quality through monitoring of investigational sites, provision of appropriate training for study personnel, and use of data management procedures. Each electronic case report form were reviewed for completeness and accuracy with data sources. The overall quality and integrity of the application was acceptable.

Efficacy Results – Secondary and other relevant endpoints

Secondary endpoints are CR, time to CR, duration of CR, duration of hematologic remission from onset of hematologic remission, time to hematologic remission, OR, time to OR, duration of OR, PFS, and TTF.

Analyses of all secondary efficacy endpoints related to disease assessment were performed based on BICR (if available) and investigator assessment data. The analyses of secondary efficacy endpoints except for PFS and TTF were performed in the ITT Population as primary, and as supportive in the Efficacy Evaluable Population. Analyses of PFS and TTF were performed in the ITT Population only.

Complete Response (CR), Time to CR, and Duration of CR: Thirty-three (41.3%, 95% CI: 30.4%, 52.8%) subjects had CR assessed by BICR, and 41 (51.3%, 95% CI: 39.8%, 62.6%) subjects had CR by investigator’s assessment in the ITT Population. The median time to CR was 5.9 (95% CI: 5.7, 6.5) months and 4.7 (95% CI: 2.8, 5.7) months for subjects assessed by BICR and investigator’s assessment in ITT population, respectively. The median of Duration of CR was not reached in both assessments.

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Table 17 Complete Response, Time to Complete Response and Duration of Complete Response by BICR and Investigator’s Assessment – ITT Population Moxetumomab pasudotox N = 80 Parameter BICR Investigator’s Assessment Subjects with CR, n (%) 33 (41.3%) 41 (51.3%) Time to CR (months) Median 5.9 4.7 95% CI (5.7, 6.5) (2.8, 5.7) (Min, Max) (1.8, 13.2) (1.0, 24.5) Duration of CR (months) Median NR NR 95% CI (10.2, NE) (NE, NE) (Min, Max) (0.0+, 39.6+) (0.0+, 45.7+) Source: FDA reviewer analysis ITT = intent to treat; min = minimum; max = maximum; NE = not estimable. NR = not reached Objective response (OR), Time to OR, and Duration of OR: Objective response was determined by BICR for subjects in the ITT Population. Time to response defined as the time from the start of moxetumomab pasudotox administration to the first documentation of response (CR or PR). The median time to objective response was 5.7 months (95% CI: 5.7, 5.9). Duration of OR was defined as the time from the first documentation of OR (CR or PR) to the date of relapse. With a median duration of follow-up of 16.7 months, the median duration of objective response was not reached. Fourteen subjects lost objective response.

Objective response was also determined by investigator’s assessment for subjects in the ITT Population. The median time to objective response was 4.5 months (95% CI: 2.8, 5.6). With a median duration of follow-up of 16.7 months, the median duration of objective response was not reached.

Table 18 Objective Response per BICR and Investigator Assessment – ITT population Moxetumomab pasudotox Parameter N = 80 BICR Investigator’s Assessment Subjects with OR, n (%) 60 (75%) 63 (78.8 %) Time to OR (months) Median 5.7 4.5 95% CI (5.7, 5.9) (2.8, 5.6) (Min, Max) (1.8, 12.9) (0.9, 8.0) Duration of OR (months) Median NR NR 95% CI (12.6, NE) (16.5, NE)

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(Min, Max) (0.0+, 43.4+) (0.0+, 45.7+) Source: FDA reviewer analysis NE = not estimable; NR = not reached; OR = objective response Objective response rate (ORR) was defined as the proportion of subjects with a best response of CR or PR. The ORR assessed by BICR in the ITT population was 75% (60 subjects; 95% CI: 64.1%, 84.0%). Additionally, 12 (15.0%) subjects had stable disease and 2 (2.5%) subjects had progressive disease. The ORR by investigator’s assessment in ITT population was 78.8% (63 Subjects; 95% CI: 68.2%, 87.1%). Additionally, 9 (11.3%) subjects had stable disease and 3 (3.8%) subjects had progressive disease. Table 19 Disease Response Assessed by BICR and investigator assessment – ITT Population Moxetumomab pasudotox Parameter N = 80 BICR Investigator’s Assessment Complete response n (%) 33 (41.3%) 41 (51.3%) 95% CI* (30.4%, 52.8%) (39.8%, 62.6%) Partial response n (%) 27(33.8%) 22 (27.5%) 95% CI* (23.6%, 45.2%) (18.1%, 38.6%) Objective response n (%) 60 (75.0%) 63 (78.8%) 95% CI* (64.1%, 84.0%) (68.2%, 87.1%) Source: FDA reviewer analysis BICR = blinded independent central review; CI = confidence interval; ITT = intent to treat *Two-sided CI was calculated using the exact probability method based on the binomial distribution. Best Overall Response Comparison Between BICR and Investigator’s Assessments: Best Overall Response assessed by BICR and Investigator were concordant at rate of 65% (52/80). Of 33 patients with BICR-assessed CR, 29 also had investigator-assessed CR. Twelve patients with investigator-assessed CR were not reported as CR by BICR due to missing disease response assessments in BICR. Discordance between BICR and investigator assessment are presented in Table 20. Table 20 Best Overall Response Comparison – Investigator’s Assessment vs BICR – ITT Population BICR Investigator’s Assessment CR PR SD PD NE CR 29 9 3 - - PR 4 16 2 - - SD - 2 3 2 2 PD - - 3 - NE - - 1 - 4 Source: FDA reviewer analysis PD = progressive disease; PR = partial response; SD = stable disease; NE = not evaluable

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Hematologic Remission: Laboratory values for hemoglobin, neutrophils, and platelets were key variables used to determine hematologic remission. Sixty-four (80.0%) subjects (95% CI: 69.6, 88.1) achieved hematologic remission (Table 21). The median time to hematologic remission was 1.1 months (mix, max; 0.2, 12.9 months). With a median duration of follow-up of 16.7 months, the median duration of hematologic remission from onset of hematologic remission was not reached. Fifty-seven out of 64 subjects remained in hematologic remission 6 months after the onset of hematologic remission. Hematologic remission is programmatically derived based on laboratory values therefore there is no difference in values by BICR and investigator’s assessment.

Table 21 Hematologic Remission from Onset of Hematologic Remission – ITT Population Parameter Moxetumomab pasudotox N = 80 Hematologic remission n (%) 64 (80.0%) 95% CI (69.6, 88.1) Time to hematologic remission (months) Median* 1.1 95% CI (1.0, 1.2) (Min, Max) (0.2, 12.9) Duration of hematologic remission from onset of hematologic remission (months) Median* NR 95% CI (17.2, NE) (Min, Max) (0.3, 48.2+) Source: FDA reviewer analysis *Kaplan-Meier estimate; NE = not estimable; NR = not reached

Time to hematologic remission for subject with CR and Duration of hematologic remission from onset of CR: For the 33 subjects with CR assessed by BICR, the median time to hematologic remission was 1.0 month (95% CI: 1.0, 1.1) and the median duration of hematologic remission from onset of CR was not reached. For the 41 subjects with CR assessed by the investigator, the median time to hematologic remission was 1.0 month (95% CI: 1.0, 1.2), and the median duration of hematologic remission from onset of CR was not reached. Table 22 Hematologic Remission for Subjects with Complete Response per BICR and Investigator’s Assessment – ITT Population Moxetumomab pasudotox Parameter N = 80 BICR Investigator’s Assessment Number of subjects with CR 33 41 Time to hematologic remission for subject with CR (months)

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Median 1.0 1.0 95% CI (1.0, 1.1) (1.0, 1.2) (Min, Max) (0.3, 2.2) (0.2, 2.2) Duration of hematologic remission from onset of CR (months) Median NR NR 95% CI (NE, NE) (NE, NE) (Min, Max) (0.0+, 39.6+) (0.0+, 45.7+) Source: FDA reviewer analysis NE = not estimable; NR = not reached

Progression-free Survival: Progression-free survival (PFS) was defined as the time from the start of moxetumomab pasudotox administration to the date of the first occurrence of relapse, PD, or death. The median PFS per BICR was not reached in the ITT Population (95% CI: 15.1, NE; min, max: 0.0+, 48.5+ months). The median PFS per investigator assessment was 21.1 months in the ITT Population (95% CI: 12.7, NE; min, max: 0.0+, 48.5+ months).

Time to Treatment Failure: Time to treatment failure (TTF) was defined as the time from the start of moxetumomab pasudotox administration to the date of the first of relapse, PD, initiation of alternative anticancer therapy, or death due to disease or disease-related complication. The median TTF assessed by BICR was not reached for subjects in the ITT Population (95% CI: 15.1, NE; min max: 0.0+, 48.5+ months). The median TTF by investigator’s assessment was not reached for subjects in the ITT Population (95% CI: 13.9, NE; min, max: 0.0+, 48.5+ months).

Statistical Reviewer comment: Time-to-event endpoints are difficult to interpret in a single-arm trial.

Dose/Dose Response

All patients in Study 1053 received the same dose 40 µg/ kg of moxetumomab pasudotox. Durability of Response

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Table 17 shows the median of Duration of CR was not reached in both investigator and BICR assessments. Table 18 shows the median duration of objective response was not reached in both assessments.

Persistence of Effect

No patients were retreated with moxetumomab pasudotox following its discontinuation.

Efficacy Results – Secondary or exploratory Clinical Outcome Assessment endpoints

No secondary clinical outcome assessments, such as patient-reported outcomes, were included in this trial.

Additional Analyses Conducted on the Individual Trial

Analyses of durable CR rates were consistent among the demographic subgroups based on gender, race, and region. For the five subgroups reviewed, the only notable comparisons were for subgroup of age and MRD. Subjects aged 65 years or older has lower durable CR rate compared to subjects less than 65 years. Subjects who were MRD negative had higher durable CR rate compared to who were MRD positive.

Figure 11 Forest Plot of Durable CR Assessed by BICR – ITT population

Durable CR Rate (95% CI)

Gender Male(n=63) 34.9 (23.3, 48.0)

Female(n=17) 11.8 (1.5, 36.4)

Age

<65 (n=49) 44.9 (30.7, 59.8)

>=65 (n=31) 6.5 (0.8, 21.4)

Race Caucasion (n=72) 31.9 (21.4, 44.0)

Non-Caucasian (n=2) 0.0 (0.0, 84.2)

Region

U.S. (n=35) 42.9 (26.3, 60.6)

Non U.S. (n=45) 20.0 (9.6, 34.6)

MRD Nagative (n=33) 69.7 (51.3, 84.4)

Positive (n=46) 2.2 (0.1, 11.5)

0 25 50 75 100 Durable CR Rate Source: FDA reviewer analysis

Reviewer Comment: The durable CR rates were consistent across most subgroups except for the age subgroup. The Applicant noted that lower durable CR rates among patients ≥65 years was partially explained by the fact that 8 patients in this age group had CR assessed by BICR, and 4 76 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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patients had late confirmed CR and thus had the potential for durable CR post data cutoff date. An IR was sent requesting an updated efficacy data with late confirmed CR. The 4 patients with the late confirmed CR achieved durable CR as of updated data cutoff 28 March 2018. Upon follow up, 6 of 31 (19.4%; 95% CI:7.5%-37.5%) patients ≥65 years and older had achieved durable CR. An information request was sent to the Applicant requesting additional information regarding the reasons for late confirmation of CR. In 2 patients, PR was reported at the EOT assessment due to non-evaluable bone marrow samples.

The application included assessment of MRD based on BICR of immunohistochemistry for 5 biomarkers (CD20, Annexin A1, DBA.44, PAX5 and CD79a) primarily in the bone marrow. (b) (4)

The Center for Device and Radiological Health (CDRH) was consulted to assess the quality of the MRD data submitted as well as the validity of the reported results.

The CDRH reviewer identified several issues including: • use of multiple local tests with unknown protocols and performance characteristics • lack of comparability of testing metrics between the various local tests • use of non-uniform markers across study subjects with MRD assessment in Study 1053 • lack of detail on scoring criteria for using the 4 additional biomarkers

The CDRH reviewer concluded that the MRD results included in the submission were uninterpretable.

This reviewer concurs with the CDRH reviewer’s assessment; the lack of consistent approach and centralized protocol for staining and interpretation calls into question the interpretability of the results. (b) (4)

Durable CR rate by BICR by prior cancer therapy was analyzed in the ITT population. There was no notable difference for the primary endpoint by prior cancer therapy groups.

Figure 12 Forest Plot of Durable CR Assessed by BICR, prior cancer therapy – ITT population

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Source: FDA reviewer analysis

Integrated Review of Effectiveness

Assessment of Efficacy Across Trials

Study 1001 was submitted as a supportive study to this application. It was a multicenter, dose- escalation and dose-finding Phase 1 study, which used a 3+3 design with an expanded MTD cohort, to assess safety and antitumor activity of moxetumomab pasudotox at the MTD (or recommended Phase 2 dose). Among the 32 patients treated at the highest dose level of 50 μg/kg, the observed CR rate was 59% with an ORR of 91%. No dose limiting toxicity was observed, and the MTD was not established. Study 1001 supports the dose and regimen for moxetumomab pasudotox for treatment of patients with HCL (Clinical Pharmacology Section 6.3.2). The primary endpoint was to find the MTD and safety. Durable CR was not assessed as an endpoint. The BICR analysis was not part of the study protocol and was added subsequently as a change in planned analysis. We do not consider this study for efficacy results analysis.

Study CAT-8015-1053 is the only trial supporting the efficacy of moxetumomab pasudotox in patients with R/R HCL.

Integrated Assessment of Effectiveness

The Applicant has proposed the indication “For the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies, including treatment with a purine nucleoside analog (PNA)”. The clinical development program

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consisted of one Phase 3 trial (Study 1053) which enrolled 80 patients with relapsed HCL and Phase 1 dose-escalation and safety study which enrolled 49 patients with relapsed HCL. For the purposes of establishing efficacy, FDA considered only the 80 subjects who were documented to have relapsed HCL, treated at the recommended 40 µg/kg dose, and had BICR assessment of the primary endpoint of durable CR rate (Section 8.1.1.).

Efficacy Endpoints

The primary efficacy endpoint of this study is durable CR based on CR assessed per BICR. Hematologic remission (namely the blood counts needed for CR, without transfusions or growth factors) must have been maintained for > 180 days. This frequency of efficacy assessments was considered adequate.

There was no hypothesis testing planned, but the protocol indicated that if the lower bound of the 95% CI is above 13% (or equivalently, the binomial exact test one-sided p-value <0.025), it will be concluded that the durable CR rate in the subject population is significantly higher than the historical control value of 13% and considered clinically meaningful. FDA’s analysis of the primary endpoint included 80 subjects with R/R HCL; the durable CR rate for the Phase 3 trial was 30.0% (95% CI: 20.3%, 41.3%) as determined by BICR, which met the Applicant’s prespecified definition for clinical meaningfulness. Hence, this was a positive trial.

FDA has used CR supported by durability of response to grant regular approval for cladribine and pentostatin for the treatment of patients with HCL. Durable CR as defined in Study 1053 required that patients who attain CR maintain hematological counts required for CR for ≥180 days. In patients with relapsed HCL, where treatment is recommended to prevent complications arising from worsening cytopenias, these durable CR results are particularly meaningful. Moreover, Study 1053 showed high rates of CR and the median duration of response was not reached.

Study 1053 enrolled 80 patients with R/R HCL, which represents an adequate number of patients for evaluation of benefit in this rare disease. All patients on Study 1053 had received prior PNA treatment, with 87.5% of patients having received 2 or more prior lines of PNA treatment and 48.8% of patients classified as refractory to PNA. There were a notable number of patients exposed to rituximab (75.0%) and BRAF inhibitor. This heavily pretreated group was representative of the real world HCL population. The durable CR rate per BICR results from 80 patients treated with moxetumomab pasudotox in Study 1053 provides demonstration of a treatment effect of moxetumomab pasudotox in patients with R/R HCL who received at least two prior systemic therapies, including treatment with a PNA.

Review of Safety

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Safety Review Approach

The Applicant provided a summary of safety with integrated safety of moxetumomab evaluated for the Pivotal HCL Population, Primary HCL Population and total safety population as defined below:

Pivotal HCL Population (Study 1053; N = 80): This population consists of all patients in the pivotal Phase 3 study who received at least 1 dose of moxetumomab pasudotox at the intended dose level of 40 μg/kg administered on Days 1, 3, and 5 of each 28-day cycle for a maximum of 6 cycles.

Primary HCL Population (Study 1053 [pivotal Phase 3] and Study 1001 [Phase 1]; N = 129): This population consists of all patients in the 2 HCL studies who have received at least 1 dose of moxetumomab pasudotox at any dose level. This pooled population is considered representative of the target HCL indication. Both studies had an open-label, single-arm design with treatment being administered on Days 1, 3, and 5 of each 28-day cycle. The majority of patients (33/49) were treated at the 50 µg/kg dose. In a Type C meeting held November 2012 the Agency stated the planned dose adjustment of 50 mcg/kg/dose of Process 2 to 40 mcg/kg/dose of Process 3 was reasonable (DAARTS Type C Meeting Minutes 11/16/2012).

Adult Population (All 5 adult sponsored studies; N = 165): This population consists of all patients in the pooled adult studies who have received at least 1 dose of moxetumomab pasudotox at various dose levels (all administered on Days 1, 3, and 5 of each 28-day cycle) and treatment durations, and across multiple hematologic malignancy indications. The Sponsor considered that the safety profile of moxetumomab pasudotox in adult patients with R/R HCL would be similar to that in adult patients with other R/R hematologic B-cell malignancies.

This reviewer placed the emphasis of moxetumomab safety review on safety data from Study 1053. Pooled safety data from the two trials of moxetumomab monotherapy in the HCL population formed the basis for safety consideration analysis of submission specific concerns. Common treatment emergent adverse events (TEAEs), significant adverse events (AEs), AEs leading to treatment discontinuation, laboratory tests and AESI were presented for the Pivotal HCL Population and Primary HCL Population.

Data from the pooled Adult Population (including NHL trials) was analyzed to evaluate rare safety signals and AESI to support labelling recommendation. Relevant safety data are summarized in Section 8.4.

Studies in patients with acute lymphoblastic leukemia (both adult and pediatric) were not considered relevant for evaluation of safety due to differences in the disease biology and differences in the dose studied in these studies.

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Review of the Safety Database

Overall Exposure

Clinical trials included for pooled safety analysis are shown in Table 23. All trials including Study 1053 were single-arm trials.

Table 23 Safety Population

Study Indication Primary HCL Pivotal HCL Adult Population Population Population (N = 129) (N = 80) (N = 165) Uncontrolled 1053 HCL 80 (62.0%) 80 (100%) 80 (48.5%) trial for this Uncontrolled 1001 HCL 49 (38.0%) -- 49 (29.7%) trial for this Uncontrolled 1002 CLL, PLL, or SLL -- -- 11 (6.7%) trials in other 1003 NHL -- -- 2 (1.2%) indications CP218 B-cell CLL or -- -- 23 (13.9%) NHL Source: FDA reviewer analysis

The overall exposure across the three safety population groups are shown in Table 24. Overall, the extent of exposure was generally similar across the 3 adult populations, with the median duration of exposure being approximately 5 months. A higher percentage of patients were exposed for 6 cycles in the Pivotal HCL Population (82.5%) compared with the Primary HCL Population (69.0%) and Adult Population (58.2%).

Table 24 Overall Exposure-Safety Population Pivotal HCL Primary HCL Adult Population N=80 N=129 N=165 Duration of Exposure (Cycles)

Median 6 5 4 Min, Max 1,7 1,16 1,16 Number of n % n % n % Cycles 1 4 5.0 5 3.9 23 14.0 2 6 7.5 14 10.9 21 12.7 3 3 3.8 16 12.4 18 10.9

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4 6 7.5 18 14.0 23 13.9 5 6 7.5 13 10.1 14 8.5 6 54 67.5 58 45.0 59 35.8 7 1 1.3 2 1.6 3 1.8 8 0 0 2 1.6 2 1.2 9 0 0 0 0 1 0.6 16 0 0 1 0.8 1 0.6

Duration of exposure (months) Median 5.65 4.93 4.27 Min, Max 0.92,6.7 0.92,16.2 0.16,16.2 Number of n % n % n % months < 1 month 1 1.3 1 0.8 3 1.8 >= 12 months 0 0 1 0.8 1 0.6 1 to < 2 months 8 10.0 14 10.9 35 21.2 2 to < 6 months 58 72.5 97 75.2 108 65.5 6 to < 9 months 13 16.3 16 12.4 17 10.3 9 to < 12 0 0 0 0 1 0.6 months Source: FDA Reviewer Analysis

Relevant characteristics of the safety population:

Demographic information for patients analyzed for safety is summarized in Table 25

Table 25 Demographics-Safety Population Parameter Pivotal HCL Primary HCL Total Adult Population Population Population N = 80 N=129 N=165 Age, years Median 60 59.00 60.00 Min, Max 34, 84 34.0, 84.0 34.0, 84.0 Age Group (years), n (%) <65 49 (61.25) 89 (69.0) 109 (66.1) >=65 31 (38.75) 40 (31.0) 55 (33.3) Sex, n (%) Female 17 (21.25%) 25 (19.4) 32 (19.4)

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Male 63 (78.75%) 104 (80.6) 133 (80.6) Race, n (%) White 72 (90.0) 118 (91.5) 150 (90.9) Asian 1 (1.3) 1 (0.8) 1 (0.6) Black or African 1 (1.3) 1 (0.8) 5 (3.1) American Native Hawaiian or 0 2 (1.6) 2 (1.2) Other Pacific Islander Other1 3 (3.8) 4 (3.1) 4 (92.6) Missing 3 (3.8) 3 (2.3) 3 (2.5) Region, n (%) US 35 (43.8) 82 (63.6) 116 (70.3) Non-US 45 (56.3) 47 (36.4) 49 (29.7) ECOG performance status, n % 0 49 (61.3) 71 (55.0) 72 (43.6) 1 29 (36.3) 54 (41.9) 61 (37.0) ≥2 2 (2.5) 4 (3.1) 9 (5.5) Missing 0 0 23 (13.9)2 Source: FDA Reviewer Analysis

In the Primary HCL Population, demographic and baseline disease characteristics were generally representative of the target patient population. Most patients were male (80.6%) and White (93.7%), with a median age of 59.0 years (range, 34.0 to 84.0 years). Most patients (96.9%) had a baseline ECOG PS score of 0 or 1. At baseline, patients’ hematologic parameters were generally below the normal limits with prominent thrombocytopenia and neutropenia. A majority of patients had baseline platelet counts < 100 × 103/μL (82.9%) and baseline neutrophil counts < 1 × 103/μL (65.9%) (Source: Applicant’s Table 2.7.4.1.3.1-2 Summary of Clinical safety). Demographics and baseline characteristics in the Pivotal HCL Population was similar to the Primary HCL Population.

Adequacy of the safety database:

The size of the safety database is adequate to provide a reasonable estimate of adverse reactions that may be observed with moxetumomab in a patient population. Because the data are all from single-arm trials, the contribution of the underlying disease and patients usual state of health to adverse reactions is difficult to estimate. Long-term toxicities of moxetumomab cannot be assessed adequately, since most patients had exposure of ≤6 months of treatment. The duration of treatment recommended in patients with HCL is a maximum of 6 cycles. Lack of long term toxicity data is not a limitation. The demographics of the patients included in the safety pool in Table 25 are representative of patients with HCL and B-cell malignancies enrolled in clinical trials in the US. The duration of treatment is adequate to allow assessment of adverse

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reactions over time. All studies except Study 1053 were complete. Patients in Study 1053 had completed treatment; the last patient’s last dose was 21 October 2016 and the end of the AE reporting period was in end of 2016.

Adequacy of Applicant’s Clinical Safety Assessments

Issues Regarding Data Integrity and Submission Quality

The quality of the safety data submitted was adequate to allow substantial primary review. The Applicant provided analysis-ready datasets for each individual study as well as an integrated dataset reporting AEs in patients treated with moxetumomab pasudotox included in the safety analysis. The Applicant also provided narratives for all patients with AEs resulting in death, SAEs, AEs leading to discontinuation of the study, and AESI.

Categorization of Adverse Events

Adverse events and severe adverse events were defined per guidelines E6(R1). Adverse events were coded using Medical Dictionary for Regulatory Activities (MedDRA) and assigned grades based on the NC Common Terminology Criteria for Adverse Events (CTCAE) v4.0. TEAE was defined as any AE that occurred on or after the date of initial receipt of study treatment. TEAEs observed through 30 days after the last dose of moxetumomab pasudotox were included in all AE summary tables. AEs and SAEs were summarized by system organ class (SOC) and preferred term (PT) according to severity and relationship to moxetumomab. The FDA compared the verbatim adverse event term with the coded MedDRA preferred term for all adverse events reported in Study 1053 and did not identify any irregularities.

The Applicant identified the following as AESI and important safety risks: HUS/HUS-like/TMA events, CLS, hepatic function abnormality (potential Hy’s law cases), ocular events, pulmonary edema, nephrotoxicity (including blood creatinine increased, severe infections (including opportunistic infections), tumor lysis syndrome (TLS), CRS, severe hypersensitivity (including anaphylaxis and acute allergic reaction) and IRR. IRR were later classified as adverse drug reactions by the Applicant. Pre-specified preferred terms used to identify AESI were listed in a separate document called Adverse Events of Special Interest Characterization and Adjudication Charter. Grouped summary tables of certain MedDRA preferred terms were produced. For each ‘grouped’ term, the number (%) of subjects experiencing any of the specified terms will be presented by the highest NCI CTCAE grade. Time to onset of first AE or CTCAE Grade 3 or 4 for each grouped term and preferred term within each group were also produced, where appropriate.

Any grouping of preferred terms done by the sponsor or FDA reviewer will be noted in relevant sections or tables of this review. In general, rates of adverse events where summarized by individual PTs except for AESI reported in 8.1.9 which were summarized using grouped terms.

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Analysis of standardized MedDRA queries was also performed using MAED, and no additional safety signals were identified beyond those discussed below.

Routine Clinical Tests

See Table 9 for a description of the frequency of clinical assessments for the studies conducted in patients with HCL in Study 1053. The frequency of clinical assessments in the other studies included in the safety pool varied, but is adequate to assess the risks of serious safety events.

Safety Results

Deaths

Deaths in patients with HCL are summarized in Table 26. Overall, the number of patients who died on the HCL studies was small. Fatal AEs were reported in three patients in the Primary HCL Population. All fatal AE-related deaths were in Study 1053. One patient died due to a fatal AE of septic shock within 30 days of receiving moxetumomab pasudotox in the Primary HCL Population.

Table 26 Deaths- HCL Population

Pivotal HCL Population Primary HCL Population N = 80 N = 129

n % n % Deaths 4^ 5.0 8 6.2 ≤ 30 days post-last dose 1 1.3 1 0.8

> 30 days post-last dose 3 3.8 7 5.4

Due to AE 3* 3.8 3 1.6 Source: FDA reviewer analysis *In one patient AE started 30 days after start of study drug. ^ One patient died after he came off study for diagnosis of glioblastoma

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Patient deaths in the Primary HCL population is summarized in Error! Reference source not found..

Table 27 Patient Deaths -HCL Population

Patient ID Age Study Number Days Death Grade 5 Reviewer (PID) in Day of of Doses Since Last Due to AE Assessment years Death Received Dose Until Disease Death (Yes/No ) Study 1053 (b) (6) 70 130 15 7 No Septic Agree shock 79 69 3 65 No Pneumonia Cannot rule out CLS 73 64 1 64 Yes Sepsis Cannot rule syndrome out CLS Study 1001 (b) (6) 74 525 15 411 Yes -- Agree 65 86 6 54 Yes -- Agree 63 590 9 530 Yes -- Agree 65 1239 12 1151 Yes -- Agree

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Subject (b) (6) was a 70-year-old male. He completed 5 cycles of treatment. He had Grade 3 neutropenia at baseline that gradually worsened on study. On Cycle 5 Day 7, the patient was hospitalized for septic shock (due to Staphylococcus) and rhabdomyolysis; he died 4 days later (129 days after starting study medication and 6 days after the last dose) due to septic shock.

Subject (b) (6) was a 79-year-old female. She completed 1 cycle of treatment. On Cycle 1 Day 26, the patient was hospitalized for a Grade 3 infection (unknown origin). The patient was discharged after 3 days but then was hospitalized again for Grade 3 infection (unknown origin). Thirty days after the last dose of study drug, the patient experienced an SAE of pneumonia. Sixty-eight days after starting study medication and 64 days after last dose of study medication, the patient died. The primary cause of death was pneumonia. The source of infection was not identified. Despite broad spectrum antibiotics patient died 65 days after last dose of moxetumomab pasudotox. This patient had received dexamethasone for CLS. Three days after last dose (C1D8) admitted with grade 3 acute kidney injury was thought to be tumor lysis. CLS can present as multi-organ dysfunction or sepsis without known cause. In this patient, CLS as a cause of death cannot be ruled out.

Subject (b) (6) was a 73-year-old male. He had Grade 4 neutropenia at baseline and was hospitalized during screening. He received one dose of moxetumomab pasudotox. The same day, he experienced SAEs of Grade 3 febrile neutropenia and Grade 3 pneumonia. Three days after the first and only dose of moxetumomab pasudotox, he experienced a SAE of Grade 4 sepsis syndrome. However, this patient had CLS-related signs including pleural effusion, hypoalbuminemia and abdominal distension. Patient developed multiorgan dysfunction and sixty-three days after the first and only dose of study medication, the subject died. The primary cause of death was sepsis syndrome but CLS as related cause of death cannot be completely ruled out.

Serious Adverse Events

Serious adverse events were reported in 26.4% (34/129) of patients in the Primary HCL Population. The majority of these SAEs, 35.0% (28/80) were in the Pivotal HCL Population. HUS (6, 7.5%), CLS (4, 5.0%) and pyrexia (5, 6.3%) were the most common SAEs (at least 5% of patients) reported in the Pivotal HCL Population. Other SAEs reported (2 patients each) in the pivotal study included febrile neutropenia, hypoxia, IRR, and upper respiratory tract infection.

HUS, CLS and IRR are discussed in Section 8.1.9.

Dropouts and/or Discontinuations Due to Adverse Effects

Overall summary of TEAEs leading to discontinuations and modifications is shown in Table 27. In the Primary HCL Population, 15 patients (11.6%) had at least 1 AE that resulted in permanent discontinuation of moxetumomab pasudotox; 12 were in the Pivotal HCL Population.

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The overall incidence of AEs resulting in dose delay, omission or interruption was numerically lower in the Primary HCL Population (15.5%) compared with the Pivotal HCL Population (23.8%). This is because a more complete collection of reasons for dose delay within a treatment cycle was only collected in Study 1053. Dose interruptions and reasons for dose interruptions were based on reported events and not programmatically derived.

Table 27 Summary of TEAEs Leading to Discontinuations and Treatment Modifications Adverse event Pivotal HCL Population Primary HCL population N=80 N=129 n (%) n (%) AE leading to permanent drug 12 15.0 15 11.6 discontinuation AE leading to treatment 19 23.8 20 15.5 omission/interruption or delay AE leading to treatment delay 12 15.0 12 9.3 AE leading to treatment interruption 3 3.8 3 2.3 AE leading to treatment omission 5 6.3 5 3.9 Source: FDA reviewer analysis

TEAEs leading to treatment discontinuation is shown in Table 28.

Table 28 TEAEs Leading to Treatment Discontinuation Preferred Term Pivotal HCL Population Primary HCL Population N=80 N=129 n % n % Hemolytic uremic 4 5.0 6 4.7 syndrome Capillary leak syndrome 2 2.5 2 1.6 Blood creatinine increased 2 2.5 2 1.6 Pneumonia 1 1.3 1 0.8 Chills 1 1.3 1 0.8 Glioblastoma 1 1.3 1 0.8 Memory impairment 1 1.3 1 0.8 Renal failure 1 1.3 1 0.8 Respiratory tract infection 1 1.3 1 0.8 Sepsis syndrome 1 1.3 1 0.8 Vomiting 1 1.3 1 0.8 White blood cell count 0 0 1 0.8

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decreased

HUS was the most common PT term reported in patients whose treatment was discontinued, followed by CLS and nephrotoxicity-related AEs (blood creatinine decreased and renal failure). AEs resulting in dose delays, omissions, or interruptions in > 1 patient each were pyrexia (3 patients, 3.8%), and blood creatinine increased and dyspnea (2 patients, 2.5% each); all in the Pivotal HCL Population.

Significant Adverse Events

NCI CTCAE Grade 3 and 4 (severe) adverse events are provided in Table 29.

Treatment Emergent Adverse Events and Adverse Reactions

Treatment emergent adverse events in the HCL population is shown in Table 29. In the Pivotal HCL Population, 79 patients (98.8%) had any AE. The most common (≥ 30% of patients) AEs were edema (53.0%), nausea (35.0%), fatigue (33.8%), headache (32.5%), and pyrexia (31.3%). The most common Grade 3-4 AEs were lymphocyte count decreased (20%), anemia (10%) and hypophosphatemia (10%).

Table 29 Safety Analysis-Common TEAEs (>10% in the Pivotal HCL Population) Preferred Term Pivotal HCL population Primary HCL Population N=80 N=129 All Grades Grade 3/4 All Grades Grade 3/4 n % n % n % n % Edema *^ 42 53.0 0.0 0.0 69 53.5 0.0 0.0 Nausea 28 35.0 2.0 2.5 46 35.7 2.0 1.6 Fatigue 27 33.8 0.0 0.0 41 31.8 0.0 0.0 Headache 26 32.5 0.0 0.0 45 34.9 0.0 0.0 Pyrexia 25 31.3 1.0 1.3 49 38.0 3.0 2.3 Hypocalcemia 19 23.8 0.0 0.0 32 24.8 1.0 0.8 Hypophosphatemia 19 23.8 8.0 10.0 30 23.3 11.0 8.5 Constipation 18 22.5 0.0 0.0 26 20.2 0.0 0.0 ALT^increased 17 21.3 1.0 1.3 50 38.8 4.0 3.1 Diarrhea 17 21.3 0.0 0.0 24 18.6 0.0 0.0 Anemia 17 21.3 8.0 10.0 17 13.2 8.0 6.2 Hypoalbuminemia*^ 17 21.3 0.0 0.0 54 41.9 1.0 0.8 Lymphocyte count 16 20.0 16.0 20.0 27 20.9 26.0 20.2 decreased AST^ increased 15 18.8 0.0 0.0 46 35.7 0.0 0.0 Chills 15 18.8 0.0 0.0 27 20.9 0.0 0.0 Vomiting 15 18.8 1.0 1.3 19 14.7 1.0 0.8 Arthralgia 13 16.3 0.0 0.0 19 14.7 0.0 0.0 Hypokalemia 13 16.3 2.0 2.5 17 13.2 2.0 1.6

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Pain in extremity 12 15.0 0.0 0.0 17 13.2 0.0 0.0 Back pain 12 15.0 1.0 1.3 16 12.4 1.0 0.8 Hypertension 12 15.0 6.0 7.5 14 10.9 6.0 4.7 Myalgia 11 13.8 0.0 0.0 39 30.2 1.0 0.8 Decreased appetite 11 13.8 0.0 0.0 14 10.9 0.0 0.0 Face edema 11 13.8 0.0 0.0 13 10.1 0.0 0.0 Blood creatinine 9 11.3 0.0 0.0 22 17.1 0.0 0.0 increased^ Hyponatremia 9 11.3 3.0 3.8 21 16.3 5.0 3.9 Platelet count 9 11.3 5.0 6.3 18 14.0 12.0 9.3 decreased Dyspnea 9 11.3 0.0 0.0 17 13.2 1.0 0.8 White blood cell 8 10.0 7.0 8.8 33 25.6 28.0 21.7 count decreased Hyperglycemia 8 10.0 1.0 1.3 27 20.9 1.0 0.8 Cough 8 10.0 0.0 0.0 17 13.2 0.0 0.0 Dizziness 8 10.0 0.0 0.0 17 13.2 0.0 0.0 Insomnia 8 10.0 0.0 0.0 13 10.1 0.0 0.0 ^ Adverse reactions proposed by the Applicant for inclusion in the Label *Includes preferred terms. Edema: edema peripheral, edema, localized edema, face edema, periorbital edema, peripheral swelling; Hypoalbuminemia: hypoalbuminemia and blood albumin decreased Source: FDA reviewer analysis Reviewer Comment: The Applicant excluded a high proportion of common adverse events not considered adverse drug reactions based on internal review. The review process included assessment of investigator relatedness, background rates in the target population, temporal association, rechallenge responses, and biological plausibility (Module 2.5, Applicant’s Summary of Clinical Safety Section 2.7.4.2.1.7). Determining causality or relatedness in the absence of a comparator arm is problematic and cannot be accurately ascertained. The Applicant should include TEAEs occurring in ≥ 20% or greater patients in the Pivotal HCL Population regardless of relatedness in the label.

Laboratory Findings

The Applicant provided summaries of change from baseline values over time and change in toxicity grade from baseline to worst treatment and EOT emergent Grade for hematology laboratory tests. Change from baseline values over time and change in toxicity grade from baseline to worst treatment were summarized for select chemistry tests (AST, ALT, albumin and serum creatinine). Any Grade and Grade 3 or 4 worsening in hematology and chemistry toxicity during treatment for all lab tests were summarized. The Applicant noted the following important observations with respect to laboratory findings (Module 2.5 Summary of Clinical Safety Section 2.7.4.3):

Hematology Laboratory tests

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• In the Primary HCL Population, median hemoglobin, platelet, and neutrophil levels were higher than baseline levels both at the last record before the data cutoff and during treatment. See • Figure 13, Figure 14, and Figure 15. • Of the patients in the Primary HCL Population with any grade worsening in hematology variables, any worsening to Grade 3 or 4 was most commonly (> 30% of patients) observed for lymphocyte count decreased (65.9%), WBC count decreased (54.7%), and neutrophil count decreased (36.7%). Most Grade 3 or 4 hematologic abnormalities resolved. • In the Primary HCL Population, change from baseline in toxicity grades of key hematology parameters showed very few patients with shifts from normal or mild at baseline to moderate or severe either on treatment or at EOT. For all hematology parameters, patients who had worsening grades on treatment generally improved by EOT.

Figure 13 Mean Change and Standard Deviation from Baseline in Hemoglobin

Figure 14 Mean Change and Standard Deviation from Baseline in Absolute Neutrophil Count

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Figure 15 Mean Change and Standard Deviation from Baseline in Platelets

Source: Integrated summary of safety, Figures Figure 2.3

Overall, the observations in the Primary HCL Population were similar to those reported in the Pivotal HCL Population with the exception of the higher incidence of Grade 3 or 4 lymphocyte count decreased in the Primary HCL Population (65.9%) compared with the Pivotal HCL Population (55.0%) and Adult Population (55.5%). Reviewer Comment: Most hematology parameters improved during and after treatment with moxetumomab pasudotox likely reflecting control of underlying disease with treatment.

Clinical Chemistry

Analyses and detailed discussion in changes in serum electrolytes and creatinine in chemistry variables are discussed in Section 8.1.9.

The Applicant noted that very few patients had any worsening to Grade 3 or 4 in chemistry variables (Table 2.7.4.3.2.1-2 Summary of Clinical Safety). Any worsening to Grade 3 or 4 was most commonly (> 5% of patients) observed for hyperglycemia (6.2%), and ALT increased and hyponatremia (5.5% each). Analysis of hypophosphatemia lab variable was not conducted by the Applicant.

During treatment, 2-grade or higher shifts from baseline in hypoalbuminemia occurred in 33 patients (25.6%): 30 patients (23.3%) worsened from normal to Grade 2, 2 patients (1.6%) worsened from normal to Grade 3, and 1 patient (0.8%) worsened from Grade 1 to Grade 3. At the EOT, 2-grade shifts in hypoalbuminemia were experienced by 2 patients (1.6%); an additional 4 patients (3.1%) worsened from Grade 1 to Grade 2 at EOT.

Vital Signs

Changes in vital signs were reported in the individual study CSRs. Vital signs were monitored

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more frequently in Study 1053 than Phase 1 Study 1001 in the HCL population. The Applicant reported that overall changes from baseline to post-baseline visits were generally small and not considered clinically meaningful (Section 2.7.4.4.1.1 Summary of Clinical Safety).

Electrocardiograms (ECGs) and QT

ECG monitoring was not standardized across the clinical development program of moxetumomab and only done at screening in the NHL trials and as clinically indicated. ECG results are presented individually for the HCL studies.

In the pivotal study, centrally-read ECGs were collected between 30 to 60 minutes after end of infusion on days 1 and 5 in the first cycle. In addition, planned ECGs were also done before each cycle and EOT. The Applicant reported they were no clinically meaningful changes from baseline to EOT for central ECG parameters. The Applicant concluded that within the context of a limited ECG assessment, moxetumomab pasudotox administered at 40 μg/kg to patients with HCL did not result in clinically meaningful changes in QTcF, QTcB, or QT intervals.

ECG monitoring was sporadic in the Phase 1 1001 HCL trial. For patients in Study CAT-8015- 1001 who had at least 1 post baseline measurement, the Applicant reported that overall mean changes from baseline values to the last record on study were not clinically significant for the ECG parameters analyzed (PR interval, QRS duration, QT interval, heart-rate-corrected QT interval, and ventricular rate).

The Applicant also reviewed the cardiac adverse events in subjects in the safety population. None of the ECG abnormalities reported as AEs were serious, and none of the events led to discontinuation of study drug (Section 2.2.4.4.2.1 Applicant’s Summary of Clinical Safety).

QT

No formal QT evaluation was done for moxetumomab pasudotox as it is a large targeted molecule. The Applicant reported on patients meeting criteria for notable QT/QTc interval in central ECG in Study 1053 (Table 2.7.4.4.2.1-1 Summary of Clinical Safety). Two patients (2.7%) had a QTcF value exceeding 500 ms. Two patients with ventricular arrhythmias were reported in Study 1053.

The FDA Interdisciplinary Review Team (IRT) for QT Studies reviewed the data from Study 1053 and clinical cardiac events in the safety population. QT-IRT team concluded that the clinical data did not suggest a significant risk for QT prolongation (Finalized - BLA-761104 QT-IRT Review (CONSULT REV-QTIRT-01 Date: 04/04/2018).

Immunogenicity

In Study 1053, the presence of ADA was assessed in patients prior to the start of Cycles 1, 2, 3, and 5, and at EOT. Titers and the specificity of ADA (CD22 or PE38) were subsequently

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determined for patients with positive neutralizing ADA. Following moxetumomab pasudotox treatment, 48 (65.8%) of 73 patients developed treatment-emergent ADA against moxetumomab pasudotox. The ADA prevalence rate was 87.5% (70/80 patients) with nAbs against moxetumomab pasudotox detected in 83.8% (67/80) of patients. Among these 67 patients who tested nAb positive, 98.5% (66/67) had ADA specific to the PE38 binding domain, and 53.7% (36/67) had ADA specific to the CD22 binding domain. ADA titers were also measured for patients with positive nAb results. ADA titers progressively increased after multiple dosing with median titers in Cycles 2, 3, and 5 of 320, 2400, and 19200, respectively. The clinical pharmacology reviewer concluded that ADA positivity did not have a significant effect on the safety profile of moxetumomab pasudotox Table 7.

Analysis of Submission-Specific Safety Issues

Capillary Leak Syndrome

CLS is characterized by capillary permeability that facilitates the movement of protein-rich fluid from the intravascular to the interstitial space. Accumulation of protein-rich fluid in the interstitial space causes systemic pitting edema, effusions of the thoracic and abdominal cavities, noncardiogenic pulmonary edema, and/or acute respiratory distress syndrome in the lung, gastric, muscle edema, which can rarely lead to rhabdomyolysis, hypotension, and, in some cases, hypovolemic shock with multiple-organ failure. Volume resuscitation can increase the intravascular volume and thus improve blood pressure and renal function. Volume resuscitation also expands the interstitial volume and thus potentially worsens systemic edema, increases effusions, and worsens pulmonary, gut, and muscle edema(16).

The Applicant instituted a search strategy to identify additional potential AESI related to CLS from TEAE data and laboratory, vitals and body weight data (Source: Applicant’s Appendix 2.7.4.8. Summary of clinical safety.

To meet criteria for an adjudicated CLS event, the following events must have occurred at or around the same time: • Reported AE of ≥ Grade 2 hypotension was required. Reduced BP in vital signs was Insufficient. • Hypoalbuminemia (based on reported AE and/or laboratory data) was required. • Evidence of hemoconcentration (based on reported AE and/or laboratory data) supported a finding of CLS but was not required. Events of CLS that had been previously reported as AESI by the investigator were not reviewed in this adjudication.

In the Primary HCL Population, 17 of 129 patients (13.2%) had at least 1 AESI in the group CLS. The events reported were investigator-reported CLS in 16 patients and Sponsor-adjudicated CLS in 1 patient. In the Pivotal HCL Population, the Applicant reported 8.8% (7/80) had at least 1 AESI in the group CLS (Table 2.7.4.2.1.6-7 Summary of Clinical Safety). All events reported were

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investigator-reported CLS. Two patients reported with Grade 4 CLS (both in the Pivotal HCL Population) had treatment discontinued due to CLS. Three patients were reported to have life threatening CLS; including two patients with Grade 4 CLS listed above and one patient with Grade 2 CLS. The median time to onset of CLS was similar for the Primary HCL Population and Pivotal HCL Population (34.0 and 37.0 days, respectively). The median time to resolution was 12.0 in the Primary HCL Population but longer (36.0 days) in the Pivotal HCL Population.

The most common (in > 1 patient) CLS-associated symptoms reported by investigators in the Pivotal HCL Population were edema (4 patients), and blood albumin abnormal, respiratory failure, and weight abnormal (2 patients each).

Selected narratives for patients with CLS

PID (b) (6) was a 41-year-old male with received 4 prior lines of therapy. On Cycle 2 Day 4, subject experienced Grade 4 CLS (life threatening) and Grade 3 respiratory infection. Symptoms of Grade 4 CLS included Grade 4 respiratory failure. The subject was admitted to intensive care with symptoms of sweating dyspnea and hypoxemia and required mechanical ventilation, corticosteroids, and IV fluids. The subject also received broad spectrum antibiotics and frusemide. The CLS event was reported as resolved and subject was discharged from the hospital.

PID(b) (6) was a 58-year-old female with past medical history of duodenal ulcer. The subject had received three prior lines of therapy for HCL. The subject received concomitant medication to mitigate risk of renal insufficiency (IV fluids and acetylsalicylic acid lysine), medications for prophylaxis of allergic reaction, tumor lysis, and opportunistic infections. On Cycle 1 Day6, the Grade 2 CLS was reported. Symptoms of CLS included Grade 2 dyspnea, Grade 2 eyelid edema, and Grade 2 mild pulmonary overload. The subject was treated with albumin, furosemide, and oxygen. The subject was discharged one week later and the event resolved 10 days after start of the event. In Cycle 2, patient received dexamethasone for CLS prophylaxis. On Cycle 2 Day 3 the subject experienced another event of Grade 2 CLS (life threatening). Reported symptoms included Grade 2 albumin decreased, Grade 2 temperature increased and Grade 2 fatigue. BP was reported as 98/62 mmHg. The subject was treated with furosemide, albumin, methylprednisolone and prednisone for CLS. At the time of CLS the patient also reported AEs of Grade 1 myalgia and Grade 1 dyspnea. The event of CLS was reported as resolved and no action was taken for the study drug.

PID(b) (6) was a 73-year-old male with past medical history of arteriovenous malformation (lung), herpes zoster and cerebral hemorrhage. The subject received 3 prior line of therapy for HCL. On cycle 2-day 9 subject experienced Grade 2 CLS. Symptoms for CLS included Grade 2 edema, Grade 2 albumin decreased, Grade 2 hypotension, and Grade 3 creatinine increased. The subject was on enoxaparin prophylaxis started for AE of blood creatinine increased. Subject discontinued study on the same day CLS was reported but cause of study discontinuation was reported as HUS (also reported concurrently in the patient). CLS was reported as resolved in the

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narrative. At the time of study discontinuation, the symptoms of CLS including Grade 2 edema and Grade 2 hypoalbuminemia were still ongoing and CLS was reported as not resolved in the integrated summary of safety dataset.

The FDA conducted an independent review of the safety data to identify subjects with possible CLS using the following approach:

1. The FDA reviewed narratives from subjects determined as having CLS by the investigator and as determined by the Applicant’s adjudication process, available literature regarding the signs and symptoms of CLS produced by other agents (e.g. denileukin diftitox, filgrastim and peg filgrastim) and CLS events labelled in the prescribing information for the same drugs and used this information to devise an algorithm to identify cases of CLS-like using the integrated summary of safety dataset. 2. FDA applied this algorithm to the Primary HCL population (data generated by Jinzhong Liu, PhD).

Table 30 FDA criteria for Identifying Cases of Possible CLS Category Preferred Term

Report of any Group I Report of any 1 of the following AEs from Group II and 1 from Group III, or IV or V Report of any 1 of the following AEs from Group II and 1 from Group III, or IV or V Group I Capillary leak syndrome Group II Hypoalbuminemia Blood albumin decreased Group III Hypotension Group IV Abdominal distension Acute respiratory distress syndrome Ascites Fluid overload Fluid retention Edema Edema peripheral Pericardial effusion Peripheral swelling Pleural effusion Pulmonary congestion Pulmonary edema Weight increased Group V Respiratory failure Dyspnea Source: FDA reviewer analysis

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3. The FDA reviewed available supportive information (concomitant adverse event reports, laboratory data, and narratives, where available) for these subjects. The maximum grade of possible or probable CLS was determined by the FDA as the maximum grade of the component adverse event(s).

Using this approach, we identified 40% (52/129) of patients with CLS or CLS-like symptoms in the Primary HCL Population and 25% (20/80) in the Pivotal HCL Population. We identified 3 patients had Grade 3-4 possible or probable CLS and additional 6 patients in the Primary HCL Population (3 in the Pivotal HCL Population) with CLS related AEs that were not resolved. Reviewer comments: CLS has several overlapping signs and symptoms with other frequent adverse events seen in patients with HCL and those receiving moxetumomab pasudotox (e.g. infection, hypoalbuminemia). CLS requires a high degree of clinical vigilance and experience to recognize. Literature reports suggests that many cases of capillary leak are unrecognized and labeled as culture-negative sepsis or are attributed to an alternate pathophysiology such as hypoalbuminemia(16). The frequency of CLS in patients with HCL treated with moxetumomab pasudotox, appears to be at least 13% (the frequency of CLS as reported by the Applicant) and probably no higher than 40% (the frequency of possible CLS as determined by the FDA’s algorithm). There were at least 2 fatal cases of CLS in a patient on Study 1053 (Table 26) and 3 life threatening cases of CLS reported in the HCL population. CLS can recur in multiple cycles in the same patient. The USPI should include rates of CLS using the FDA search strategy and the USPI include a boxed warning for CLS. The reviewer also recommends that the sponsor be asked to further evaluate risk of CLS through enhanced pharmacovigilance program.

Hemolytic Uremic Syndrome (HUS)

The Applicant instituted a search strategy to identify additional potential AESI related to HUS and an adjudication process to identify patients with HUS in the safety database.

To meet criteria for adjudicated HUS or adjudicated HUS-like event, the following events must have occurred at or around the same time: • HUS required the presence of ≥ 5 schistocytes/high power field. • HUS-like required the presence of schistocytes (as evidence of RBC destruction is an essential part of the triad) but the number may have been < 5 or may have been reported qualitatively (e.g., present, positive, few) rather than numerically. Schistocytes must have been increased from baseline to adjudicate a case as HUS-like. • Blood creatinine elevated above the ULN (based on reported AE and/or laboratory data) and increased from baseline was required. • Evidence of thrombocytopenia (based on reported AE and/or laboratory data) supported a finding of HUS but was not required.

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HUS or HUS like events in the HCL population is shown in Table 31. In the Primary HCL Population, 7.0% (9/129) had at least 1 AESI in the group HUS/HUS-like/TMA; of which 6 were reported in the Pivotal HCL Population. All HUS events in the Primary HCL Population were SAEs. Five patients (3.9%), had events of Grade 3 or 4 severity all in the Pivotal HCL Population.

Table 31 HUS or HUS- like AEs-HCL population Pivotal HCL Population Primary HCL population N=80 N=129 n % n % Hemolytic Uremic Syndrome TEAEs 7 8.8 9 7.0 AEs grade3/4 6 7.5 5 3.9 SAEs 6 7.5 9 7.0 Fatal TEAEs 0 0 0 0 AE leading to permanent drug 4 5.0 6 4.7 discontinuation AEs not resolved 0 0 0 0 Source: FDA reviewer analysis

Three patients with Grade 3 HUS and 3 patients Grade 2 HUS permanently discontinued treatment with moxetumomab pasudotox due to the events. In addition, the patient with Sponsor-adjudicated Grade 3 HUS discontinued treatment due to associated event of blood creatinine increased. One patient with Grade 2 HUS reported delay in treatment and one with Grade 4 HUS (life threatening) reported no action taken (see narrative). Life threatening HUS event was reported in one patient with Grade 2 HUS. None of the HUS AESI resulted in death. All 9 patients with HUS in the HCL population were reported as resolved. Only one additional case of sponsor adjudicated HUS was reported in the total adult population. The median time to onset was 34.5 days in the Primary HCL Population and 31.0 days in the Pivotal HCL Population.

The most common investigator reported PTs for HUS in the Pivotal HCL Population included blood creatinine increased (3 patients), blood pressure abnormal, anemia, hemolysis and renal impairment (2 patients each).

Six out of 7 patients in the Primary HCL Population (4.7%; 4 of whom were in the pivotal study) with investigator-reported HUS had concurrent investigator-reported CLS.

Selected narratives of patients with HUS

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PID (b) (6) Subject was a 43-year-old female with past medical history of Raynaud’s phenomenon, Gilbert’s syndrome, mitral valve prolapse and depression. Patient had received 2 prior therapies for treatment of HCL. The subject had received prophylaxis with acetylsalicylic acid and IV fluids. On Cycle 4 Day 8 subject experienced Grade 2 HUS and Grade 2 CLS. Reported symptoms for HUS included Grade 2 blood creatinine increased and Grade 2 platelet count decreased. Treatment was delayed due to AEs of HUS and CLS. A month after onset of HUS and CLS the events were considered resolved and the patient was discharged. Patient completed treatment one month after end of AE.

PID (b) (6) was a 66-year-old female with no reported past medical history. Patient experienced Grade 4 CLS on Cycle 1 Day 7. Patient was intubated and transferred to critical care unit. Fifteen days after start of study (Cycle 1 D16) patient was reported to have Grade 4 HUS (life threatening). Symptoms of AESI included neutropenia, renal dysfunction, thrombocytopenia, hemolysis, decreased haptoglobin, increased LDH and anemia. Blood films showed fragment 20/hpf. The subject received norepinephrine to maintain BP, IV fluids, oxygen, IV antibiotics, antifungals, plasma protein fraction, plasma exchange for renal impairment and multiple transfusions. Forty-four days after start of event of HUS and 53 days after start of CLS, the events were reported as resolved and EOT assessment was performed on the same day. Subject had received only 3 doses of moxetumomab and completed only 1 of planned 6 cycles. Action taken for AE of HUS and CLS was reported as permanently discontinued for CLS and none for HUS. Based on my review, treatment was discontinued due to HUS and CLS.

PID (b) (6) was a 71-year-old male with no reported prior medical history. Patient had received two prior lines of therapy for treatment of HCL. On Cycle 2 Day 1 after receiving 4 infusions the subject experienced Grade 2 HUS which was reported as an SAE. Reported symptoms of HUS included pyrexia, blood pressure changes and vomiting. Subsequently, the patient also had thrombocytopenia, increased LDH, increased creatinine. The patient was transferred to intermediate care for management of worsening symptoms. The HUS event was reported as life threatening. Thirty-eight days after start of event the subject was discharged home in stable condition.

PID (b) (6) (discussed in 8.1.10) experienced Grade 3 HUS on Cycle 2 Day 8, two days after AE of Grade 3 acute kidney injury. Symptoms reported for HUS included blood creatinine increased, decreased hemoglobin and presence of schistocytes. Creatinine reported was 4.28 mg/dL. On Cycle 2 Day 9 Grade 2 CLS was reported and HUS was reported as resolved. Patient had Grade 1 hematuria, Grade 1 hemoglobinuria and Grade 1 proteinuria. Patient’s creatinine level was 5.12 mg/dL. Patient discontinued study participation due to HUS on Cycle 2 Day 9. Patient had ongoing HUS related AEs at the time of study discontinuation. Reviewer comment: HUS is an important safety concern for patients treated with moxetumomab pasudotox. The Applicant instituted search strategy and adjudication process to identify additional potential AESI related to HUS in the safety database was reasonable. The protocol recommended IV fluid prophylaxis, oral fluid recommendations, close monitoring and

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treatment discontinuation guidelines likely mitigated the risks and prevented fatal HUS events. Despite the close monitoring, life threatening HUS events including events requiring intensive supportive care including plasma exchange were reported in the HCL population. Additionally, most patients with HUS also experienced CLS events. The management of patients with concurrent HUS and CLS can be particularly challenging. The proposed USPI includes Warnings and Precautions for HUS (b) (4)

One patient with Grade 2 HUS was reported to have a life-threatening event. The USPI should include a boxed warning for HUS. The treatment modification guidelines should (b) (4) state that moxetumomab pasudotox should be discontinued for any Grade HUS. Additionally, the USPI and patient medication guide should include signs and symptoms of HUS that require early reporting or monitoring.

Infusion-related reactions

IRR was identified initially as AESI and later classified as adverse drug reactions by the Applicant. The Applicant reported IRR defined by co-occurrence of 2 or more events of headache, dizziness, hypotension, myalgia, pyrexia, chills, nausea, and/or vomiting on the same day of study drug infusion. Based on this definition the Applicant reported IRR occurred in 24.8% (32/129) in the Primary HCL Population and in 25.0% (20/80) in the Pivotal HCL Population. Most of these events were of Grade 1 or Grade 2 severity; there were 2 patients (1.6%) in Primary HCL Population with Grade 3 events of IRR; both events occurred in the Phase 3 study. Among the reported AE of IRR study drug was interrupted in 1 patient, and no action was taken with study drug for the remaining patients. Reviewer comment: This reviewer does not agree with definition of IRR events for reporting as defined by the Applicant. Capturing and reporting any one infusion related AE occurring on the day of infusion will be important to communicate to the treating physician. This is consistent with the approach taken previously by the Agency for analyzing and reporting IRR. Based on the reviewer grouped PTs, IRR were identified in nearly 60% of the HCL population; 58.8% (47/80) in Pivotal HCL Population and 60.4% (78/129) in Primary HCL Population. Infusion reactions related TEAEs are shown in Table 32.

Table 32 IRR related TEAEs -HCL Population Adverse Event Pivotal HCL Population Primary HCL Population N=80 n=129 n % n % Nausea 14 17.5 26 21.4 Pyrexia 11 13.8 21 16.3 Chills 13 16.3 20 15.5 Headache 10 12.5 18 13.8

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Myalgia 5 6.3 18 14.0 Vomiting 9 11.3 12 9.3 Dizziness 4 5.0 10 7.8 Hypotension 3 3.8 9 7.0 Infusion related 7 8.8 7 5.42 reaction Hypertension 5 6.3 6 4.7 Dyspnea 4 5.0 5 3.9 Sinus tachycardia 3 3.8 5 3.9 Cough 2 2.5 3 2.3 Flushing 1 1.3 2 1.6 Wheezing 2 2.5 2 1.6 Feeling hot 1 1.3 1 0.8 Tachycardia 1 1.3 1 0.8 Source: FDA reviewer analysis

Most IRR were reported as Grade 1 or 2. Four patients in the HCL population (all in the Pivotal HCL Population) reported Grade 3 or 4 IRR. Four patients reported infusion related adverse events as serious AEs all in the Pivotal HCL Population (data not shown). No events of CRS or severe hypersensitivity reactions were reported as of the BLA DCO date of 24May2017.

Selected narratives for patients with IRR

PID (b) (6) was a 48-year-old male with past medical history of pulmonary embolism. Patient had received two prior treatments for HCL. Patient received premedications with histamine blockers (hydroxyzine and ranitidine) and paracetamol. On Cycle 5 Day 1, subject experienced Grade 1 non-cardiac chest pain and Grade 1 hypoglycemia. Infusion was temporarily interrupted. The subject received narcotic pain medications and hydrocortisone. Events resolved on the same day. On Cycle 5 Day 3, the patient experienced events of Grade 1 dysguesia and Grade 1 feeling hot despite receiving hydrocortisone as infusion prophylaxis prior to infusion. The medication was temporarily interrupted and events resolved. On Cycle 5 Day 5, the subject experienced Grade 2 infusion related reaction. The subject had received hydrocortisone prior to infusion. Infusion was temporarily interrupted and restarted after the event resolved. The subject completed Cycle 6 without additional occurrences.

PID(b) (6) was a 68-year-old male with no reported past medical history. Patient had received seven previous lines of therapy. Patient received protocol recommended prophylaxis for IRR. On Cycle 2 Day 1, the subject experienced Grade 1 infusion reaction with symptoms of chills and fever. The event was treated with repeat antihistamine. On Cycle 2 Day 3, the subject experienced Grade 2 infusion reaction with chills, fever, diarrhea and vomiting. Subject received treatment with antihistamine. Subject also had evidence of tachycardia, BP increase to 153/97 and respiratory rate of 24/min. On Cycle 2 Day 5, the subject experienced Grade 2 renal

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failure with increase in creatinine from 1.18 to 1.38 mg/dL. Renal failure resolved approximately 20 days after start of event. Subject had received IV dexamethasone for prophylaxis on Cycle 3 Day1. On Cycle 4 Day 3, subject experienced AE of Grade 2 renal failure. Renal failure was reported resolved at EOT. Reviewer Comment: Grade 3-4 IRR related AEs and serious AEs were reported primarily in Study 1053. The reason for this differential reporting in severe and serious AEs is not clear. Infusion reactions were recurrent and could occur as late as the fifth cycle of treatment. High rates of IRR were noted despite protocol mandated premeditations and recommended post-infusion medications. The Applicant has proposed inclusion of IRR in the Clinical Trials Experience Section 6.1 in the label. The Applicant should revise the label and include a revised rate of IRR in the Warnings and Precautions of the label to adequately convey the risk of IRR with moxetumomab.

Hepatic function abnormality

AESI of hepatic function abnormality were defined by the Applicant as any increase in ALT or AST ≥ 3 × ULN and concurrent (within 8 days) increase in bilirubin ≥ 2 × ULN. In addition, any serum AST and ALT elevations and any total bilirubin laboratory abnormalities were evaluated and reported.

Table 33 AESI of Hepatic Function Abnormality-HCL Population Pivotal HCL Population Primary HCL Population Laboratory Testa Total bilirubin n 80 129 Any abnormality 5 (6.3%) 8 (6.2%) ≥ 2 × ULN and ≤ 3 × ULN 4 (5.0%) 7 (5.4%) > 3 × ULN and ≤ 5 × ULN 1 (1.3%) 1 (0.8%) > 5 × ULN 0 0 ALT or AST n 80 127 Any abnormality 11 (13.8%) 24 (18.9%) ≥ 3 × ULN and ≤ 5 × ULN 10 (12.5%) 22 (17.3%) > 5 × ULN and ≤ 8 × ULN 3 (3.8%) 6 (4.7%) > 8 × ULN and ≤ 10 × ULN 0 1 (0.8%) > 10 × ULN and ≤ 20 × ULN 0 0 > 20 × ULN 0 0 n 80 127 Potential Hy’s lawb 1 (1.3%) 2 (1.6%)

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Source: Modified from Table 2.7.4.2.1.6-13 Summary of Clinical Safety Note: Percentages are based on the number of patients with at least 1 non-missing post-baseline result. a Derived from the worst case of post-baseline laboratory assessments up to and including 30 days following the last dose of moxetumomab pasudotox. b Potential Hy’s law is defined as AST ≥ 3 × ULN or ALT ≥ 3 × ULN and concurrent total bilirubin ≥ 2 × ULN (within 8 days of each other).

In the Pivotal HCL Population, 11 patients (13.8%) had any ALT or AST abnormalities and 5 patients (6.3%) had any total bilirubin abnormalities. None of the 11 patients with any AST or ALT abnormalities had AST or ALT > 8 × ULN. In the Primary HCL Population, 24 patients (18.9%) had any ALT or AST abnormalities and 8 patients (6.2%) had any total bilirubin abnormalities. None of the 24 patients with any AST or ALT abnormalities had AST or ALT > 10 × ULN. Two patients (PIDs (b) (6) and (b) (6) ), 1 each in Study 1053 and Study 1001, were considered to have met potential Hy’s law criteria.

Patient (b) (6) experienced transient Grade 3 ALT elevation and Grade 2 AST elevation after receiving 2 doses of study drug (i.e., Cycle 1, Day 5), which were followed a week later by Grade 2 bilirubin elevation (maximum 2.00 × ULN). The increase in bilirubin occurred during an SAE of HUS. Direct bilirubin (originating from liver) was not significantly elevated, indicating that indirect bilirubin (originating from hemoglobin catabolism) was the dominant form

Patient (b) (6) had ongoing Grade 1 hyperbilirubinemia and cholelithiasis at study entry (screening total bilirubin of 1.50 × ULN). ALT, AST, and bilirubin levels fluctuated on study with a maximum severity of Grade 2; the maximum total bilirubin reached a 1-time value of 2.00 × ULN on Cycle 3 Day 3 followed by a trend towards a decrease.

Reviewers Comments: Upon review of these two patient narratives, there were confounders. This reviewer agrees with the Applicant’s assessment that these two cases were not Hy’s law.

AST/ALT changes reported as TEAES are shown in Table 34. AEs of AST or ALT elevations were reported in 25% (20/80) of the Pivotal HCL Population and 41.8% (54/129) patients in the Primary HCL Population.

Table 34 TEAEs of AST/ALT Elevations-HCL population Pivotal HCL Population Primary HCL population N=80 N=129 n % n % AST/ALT elevated* TEAEs 20 25 54 41.8 AEs grade3/4 1 1.3 5 3.9 SAEs 0 0 0 0 Fatal TEAEs 0 0 0 0 AE leading to permanent 0 0 0 0

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drug discontinuation AEs not resolved or 2 2.5 5 3.9 recovered with sequelae *Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzymes increased and transaminase increased Source: FDA reviewer analysis

Transaminase elevations were more frequently reported in the Phase 1 study 1001 (34/49) compared to the Pivotal HCL Population (20/80). AST/ALT elevations were mostly Grade 1 or Grade 2 severity with Grade 3 events occurring in 4 patients, 3 in Study 1001 and 1 in Study 1053. The Applicant noted the discrepancy between the high rate of TEAEs of AST/ALT elevations in the Phase 1 1001 study and the pivotal Study 1053 was due to differences in reporting requirement for laboratory AEs for the two studies. Five patients with hepatic enzyme elevations, 3 patients in Study 1001 and 2 patients in Study 1053 had evidence of continuing elevations or reported evidence of recovery with sequalae. All five patients were reported to have Grade 1 toxicity. Among patients with Grade 3 events in the Phase 1 study, 3 recovered and could continue treatment but 1 patient discontinued treatment due to co-occurring Grade 3 HUS. No adverse events related to transaminase elevations were reported as serious in the safety database. None of the AST/ALT elevations led to dose changes or modifications. In 12 patients in the HCL population elevations in AST/ALT were in patients with reported AEs of CLS. In the remainder, AST/ALT elevations were most often recorded in patients with reported AEs of edema or hypoalbuminemia.

Changes in AST and ALT laboratory values during treatment AST and ALT levels increased during treatment with highest levels recorded during mid cycle. In general, the levels returned to baseline at the EOT. See Figure 16 and Figure 17.

Figure 16 Serum AST levels -Pivotal HCL population

Source: FDA reviewer analysis created in JMP Clinical Software

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Figure 17 Serum ALT Levels (U/L) -Pivotal HCL Population

Source: FDA reviewer analysis created in JMP Clinical Software

Change from baseline to worst on-treatment and EOT (AST/ALT)

ALT increased: During treatment 2-grade or higher shifts in ALT occurred in 8 subjects (10.0%) with normal ALT at baseline: 5 subjects (6.3%) worsened to Grade 2 and 3 subjects (3.8%) to Grade 3. Three subjects (3.8%) with baseline Grade 1 worsened to Grade 2. At the EOT no subjects had 2-grade or higher shifts in ALT. AST increased: During treatment 2-grade or higher shifts in AST occurred in 5 patients (6.3%) with normal AST at baseline: 4 subjects (5.0%) worsened to Grade 2 and 1 subject (1.3%) to Grade 3. At the EOT, no subjects had 2-grade or higher shifts in AST. (Source: Section 2.7.4.3.2.1 Summary of Clinical Safety). Reviewer comment: Hepatic transaminase enzyme elevations are frequent in patients treated with moxetumomab pasudotox. In non-clinical studies increases in clinical chemistry enzymes indicative of striated muscle and/or liver injury (ALT, AST, alkaline phosphatase, and lactate dehydrogenase) were noted. Histopathology evaluations in the 13-week toxicity study identified the liver (in addition to others) as target organ of toxicity (Source: Section 2.7.4.1.1.3 Summary of Clinical Safety). The association of elevated hepatic transaminases with AEs of edema, hypoalbuminemia and CLS suggest possible liver injury secondary to vascular congestion as a related cause. Information about possibility of hepatic enzyme elevation should be included in the USPI so that physicians are aware of this adverse reaction and how to manage it.

Nephrotoxicity

The Applicant used grouped PTs to derive incidence of nephrotoxicity in the safety database. The nephrotoxicity grouped terms defined by the Applicant included PTs for hemoglobinuria,

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hemoglobin urine present and hematuria which define a hemolytic process rather than nephrotoxicity. This reviewer defined grouped term for renal toxicity used to calculate the rates shown in Table 35 is included in the Appendix.

Renal toxicity was reported in approximately one third of patients in the HCL safety database; 33.3% (43/129) patients in the Primary HCL Population and 30.9% (51/165) in the safety population. No fatal renal toxicity events were reported. Adverse events related to renal toxicity were more common in the Phase 1 study 24/49 (49%) than in the Pivotal HCL Population 19/80 (23.9 %). Blood creatinine increased was the most common PT term reported; 9 (11.3%) in the pivotal trial and 22 (17.1%) in the HCL population. Majority of the AEs were reported as Grade 1 or 2. Grade 3 or 4 events were reported in 2 patients in the pivotal HCL study both with PT term acute kidney injury and 2 in the NHL studies.

Table 35 Adverse Events Related to Renal Toxicity-Safety Population Pivotal HCL Primary HCL Population population N=80 N=129 n % n % Renal Toxicity TEAEs 19 23.8 43 33.3 AEs grade3/4 2 2.5 2 1.6 SAEs 3 3.8 4 3.1 AE leading to discontinuation 3 3.8 0 0 AEs not resolved 4 5.0 13 10.1 Source: FDA reviewer analysis

Clinical laboratory changes in serum creatinine

Any grade worsening in creatinine was reported in nearly all patients in the pivotal study (96.3%, 77/80) and in the Primary HCL Population (95.3%, 123/129). Creatinine levels increased from baseline over the course of the study with the highest levels reported at EOT and last record on treatment. Creatinine increased (grading based on baseline serum creatinine value): During treatment, 2- grade or higher shifts from baseline occurred in 23 patients (28.5%) in the pivotal trial; 21 (26.3%) patients worsened from normal to Grade 2 and 2 (2.5%) patients worsened to Grade 3. At the EOT, 2-grade or higher shifts from baseline were experienced by 7 patients (8.8%) who worsened from normal to Grade 2. Nearly 70 % (55/80) patients continued to have 1-Grade shift from baseline at EOT. The results in the Primary HCL Population showed a similar trend. (Source: Table 2.7.4.3.2.1-3 Section 2.7.4 Summary of Clinical Safety).

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Grade 1 or 2 except for hypophosphatemia. Grade 3 or 4 hypophosphatemia was reported in 10% (8/80) patients in the Pivotal HCL Population and 8.5% (11/129) in the Primary HCL Population. No electrolyte abnormality was reported as an SAE. The median time to onset was 35 days (1-224).

Table 36 TEAEs of Electrolyte abnormalities-HCL population Preferred Term Pivotal HCL Population Primary HCL N=80 N=129 All Grades Grade 3 or 4 All Grades Grade 3 or 4 n % n % n % n % Any electrolyte 37 46.3 13 16.3 74 57.4 19 14.7 abnormality Hypocalcemia 19 23.8 0.0 0 32.0 24.8 1.0 0.8 Hypophosphatasemia* 20 25.0 8.0 10 32.0 24.8 11.0 8.5

Hyponatremia 9 11.3 3.0 3.8 21.0 16.3 5.0 3.9 Hypokalemia 13 16.3 2.0 2.5 17.0 13.2 2.0 1.6 Hypermagnesemia 2 2.5 0.0 0.0 15.0 11.6 1.0 0.8

Hypomagnesaemia* 5 6.3 1.0 1.3 15.0 12.4 1.0 0.8

Hyperkalemia 6 7.5 1.0 1.3 13.0 10.1 1.0 0.8 Hypernatremia 4 5.0 0.0 0 10.0 7.8 0.0 0 Blood bicarbonate 2 2.5 0.0 0 7.0 5.4 0.0 0 decreased Hypercalcemia 0 0 0.0 0 2.0 1.6 0.0 0 *Hypomagnesemia includes hypomagnesemia and blood magnesium decreased; hypophosphatemia includes hypophosphatemia and blood phosphorus decreased Source: FDA reviewer analysis

Changes in electrolyte laboratory values during treatment are shown in Table 37

Table 37 Changes in Electrolyte laboratory values Laboratory Pivotal HCL Population Primary HCL abnormality N=80 N=129

Any Grade Grade 3 or 4 Any Grade Grade 3 or 4

n % n % n % n %

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Hypercalcemia 5 6.3 0.0 0 10.0 7.8 1.0 0.8 Hyperkalemia 13 16.3 1.0 1.3 24.0 18.6 1.0 0.8 Hypermagnesemia 10 12.5 1.0 1.3 27.0 20.9 4.0 2.4 Hypernatremia 8 10.0 0.0 0 18.0 14.0 0.0 0 Hypocalcemia 43 53.8 0.0 0 66.0 51.2 4.0 2.4 Hypokalemia 20 25.0 2.0 2.5 26.0 20.1 4.0 3.1 Hypomagnesemia 18 22.5 1.0 1.3 36.0 27.9 2.0 1.2 Hyponatremia 33 41.3 7.0 8.8 50.0 38.8 7.0 5.4 Hypophosphatemia 42 52.5 11.0 13.8 62.0 48.1 17.0 13.2 Source: FDA reviewer analysis Reviewer Comment: High rates of serum electrolytes laboratory abnormalities were reported as adverse events in the HCL population and as changes in clinical laboratory values. Not all changes in laboratory electrolyte values were captured as adverse events on Study 1053 because of the requirement in adverse event reporting for laboratory abnormalities. Only those changes in laboratory values that required medical intervention by the investigator, or a finding judged by the investigator as medically significant were to be reported as an AE. Although the rates of grade 3 or 4 electrolyte abnormalities were low given the reporting requirements, nearly 50% of the electrolyte abnormalities required intervention or were considered clinically significant. Further analyses revealed that multiple electrolyte abnormalities occurred at the same time in the same patient. Hypoalbuminemia and edema peripheral were more often associated with adverse events of electrolyte abnormalities and 35% of patients with electrolyte abnormalities also reported adverse events related to nephrotoxicity or HUS. The reason for high rates of electrolyte abnormalities is likely multifactorial but could be related to either due to shifts in fluid or due to nephrotoxicity. The Applicant did not identify electrolyte abnormalities as a significant concern with moxetumomab pasudotox. Rates of hypophosphatemia either as adverse events or laboratory abnormalities were not identified or reported by the Applicant. The high rates of electrolyte abnormalities requiring intervention or considered clinically significant in the pivotal study, risk for nephrotoxicity and fluid requirements during moxetumomab administration warrants that physicians or caregivers are adequately aware of this toxicity in the post marketing setting. This reviewer recommends inclusion of risk for electrolyte abnormalities and recommendations for monitoring in the warnings and precautions section of the label.

Ocular Toxicity

Ocular AESI were defined by the Applicant as any clinically significant change (as determined by the investigator) in vision, retinal abnormalities, or choroidal disturbance that occurs during the course of each study. Based on this definition, the Applicant reported 8.5% (11/80) AESI of ocular events. Source: Section 2.7.4.2.1.6 Summary of Clinical Safety.

This reviewer analyzed all adverse events reported in under EYE DISORDER SOC to evaluate the extent of ocular toxicity with moxetumomab pasudotox. The majority of events occurred on

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Study 1053. Any grade eye disorders were reported in 30% (24/80) subjects in Study 1053. No events were reported in the 1001 Phase 1 study. All events were reported as Grade 1 or 2. No Grade 3 or 4 events were reported. The most common PT reported was vision blurred in 8.8% (7/80) on the pivotal trial. Visual events were reported as not resolved in 8 subjects: cataract (3), dry eye (3), vitreous floaters (1) and retinal degeneration (1). No adverse events in the Eye Disorder SOC was reported as a serious AE in the Primary HCL Population. Analysis of the adult safety population revealed one PT term of bilateral optic ischemic neuropathy was reported as serious AE. Treatment was permanently discontinued in the patient.

The FDA ophthalmology team in the Division of Transplant and Ophthalmology Products (DTOP) reviewed the safety data on ocular toxicity reported in the pivotal trial and safety database. The consult reviewer concluded that the monitoring and reporting of ophthalmic adverse events on the pivotal trial were not sufficient to adequately characterize the effect of moxetumomab pasudotox on the eye. It is not possible to determine whether ophthalmological assessments should be required for patients receiving moxetumomab pasudotox. The reviewer noted: “In several cases the Applicant has inaccurately characterized or classified the adverse events. The relative seriousness of each ocular event and the potential relationship of the ocular event to the drug product cannot be ascertained based on the reports from the investigator or applicant.”

The ophthalmology reviewer recommended the inclusion of ocular adverse events in the label under Clinical Trial Experience in adverse reaction section of the label: Ocular adverse reactions occurred at a frequency of 1 to 10% including: blurred vision, conjunctivitis, conjunctival hemorrhage, cataracts, ocular discomfort and/or pain, dry eye, ocular discharge, and ocular swelling/periorbital edema (Source: DAARTS, General Consult Review dated 06/07/2018). Reviewer Comment: This reviewer agrees with the consult reviewer’s recommendation. The ocular adverse events as recommended by the consult reviewer will be included in the USPI.

Fluid Retention

Grouped terms for edema were identified by the Applicant and reported as common TEAE in patients receiving treatment with moxetumomab pasudotox (Table 29). FDA identified several other PTs that could not be classified as edema but would reflect the risk of fluid retention that can occur during treatment with moxetumomab pasudotox. Based on the FDA grouped terms, fluid retention was reported in nearly 60% of the Primary HCL population and 62.5% of the Pivotal HCL Population. The most common PT term reported was edema peripheral. Only 1 patient with PT term of weight increased was reported as SAE due to hospitalization and 1 patient with pleural effusion was reported as Grade 3 or 4. Use of concomitant diuretics was reported in nearly 40% of patients in the Primary HCL and Pivotal HCL population.

TEAEs of fluid retention are shown in Table 38.

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Table 38 TEAEs of Fluid Retention -HCL Population Preferred Term Pivotal HCL Population Primary HCL Population N=80 N=129

n % n % Edema peripheral* 31 38.8 53 41.1 Edema* 4 5.0 17 13.2 Face edema* 11 13.8 13 10.1 Weight increased 6 7.5 13 10.1 Abdominal 10 12.5 10 7.8 distension Pleural effusion 5 6.3 8 6.2 Localized edema* 3 3.8 5 3.9 Peripheral swelling* 4 5.0 4 3.1 Pericardial effusion 1 1.3 2 1.6 Ascites 1 1.3 1 0.8 Fluid overload 1 1.3 1 0.8 Fluid retention 1 1.3 1 0.8 *PTs included in grouped term “edema” Source: FDA reviewer analysis

The median weight (kg) in the Primary HCL Population was 82.8 (42.4-152.8) and at the EOT 85.0 (50.9-155.8). In the Pivotal HCL Population median weight(kg) at baseline was 80.0 (42.4- 123.1) and at EOT 82.5 (51.0-128.5). Reviewer comment: High rates of fluid retention are reported in patients treated with moxetumomab pasudotox including fluid collections in body cavities. Generally, AEs were mild to moderate and resolved. The Applicant proposed inclusion of “edema” in the USPI. The rates of fluid retention should also be included in the USPI.

Severe Infections (Including Opportunistic Infections)

The Applicant identified AEs of severe infections as important potential risk.

The Applicant noted that in the Primary HCL Population,13.2% (17/129) had at least 1 AESI in the group severe infections (defined as Grade 3 or higher). PT reported in > 1 patient each were pneumonia (3 patients), and erysipelas, lung infection, and upper respiratory tract infection (2 patients, each). In the Pivotal HCL Population 17.5 % (14/80) reported severe infections. Fatal 111 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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AEs of pneumonia, septic shock, and sepsis syndrome were reported in 3 patients in the Pivotal HCL Population. These patient narratives are discussed in Section 8.1.8. One patient in the adult population (NHL trial) was confirmed at autopsy to have pneumocystis jirovecii pneumonia. Three patients, all in the Pivotal HCL Population permanently discontinued treatment with moxetumomab pasudotox due to events of Grade 5 pneumonia (fatal), Grade 3 respiratory tract infection, and Grade 4 sepsis syndrome (fatal). Reviewer comment: The HCL target population had preexisting neutropenia at study entry and various preexisting immune deficiencies resulting from underlying disease or previous anticancer therapies. Based on the report of AESI by the Applicant in the BLA, the risk of severe infections does not appear to be increased by treatment with moxetumomab pasudotox. Patients with evidence of ongoing or active infection were excluded from the HCL trials. There is insufficient data to determine if the rate of infections will be higher in HCL patients with active infection.

Other important risks

Pulmonary edema was reported in one patient in the Primary HCL Population. This patient was treated on Study 1053 and had Grade 2 pulmonary edema which developed 3 days after the first and only dose of the study drug. The rates of pulmonary edema were low in the overall adult population. Other important risks reported in the Summary of Clinical Safety included TLS, cytokine release syndrome and hypersensitivity. The Applicant noted that the incidence of TLS AESI was low (range, 0.8% to 1.3%) and consistent across the 3 adult populations. None of the events resulted in discontinuation of study drug or death, and all events resolved (Source: 2.7.4.1.2.6 Summary of Clinical Safety).

Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability

No COA measures were evaluated in the clinical trials of moxetumomab pasudotox in patients with primary HCL.

Safety Analyses by Demographic Subgroups

Safety analysis by Age subgroups in the Primary HCL Population is shown below in Table 39.

The incidence of treatment-related SAEs (7.9% vs 22.5%), AEs resulting in discontinuation of study drug (6.7% vs 22.5%), treatment-related AEs resulting in discontinuation of study drug (4.5% vs 15.0%) were higher in patients ≥ 65 years (n = 40) compared to those < 65 years (n = 89).

Table 39 Overall Safety by Age- Primary HCL population Adverse Event <65 years ≥65 years

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N=89 N=40 N (%) N (%) Any TEAE 88 (98.9) 40 (100) Any grade 3 or 4 66 (74.2) 30 (75.0) Serious AEs 21(23.6) 13 (32.5) Life threatening AEs 3 (3.4) 4 (10) AEs leading to permanent 6 (6.7) 9 (22.5) drug withdrawal Source: FDA reviewer analysis

Three patients died on study 1053. All three deaths were due to AEs and all in patients 65 years and older. Narratives are discussed in detail in 8.1.8

TEAEs by age is shown in Table 40.

Table 40 TEAEs by Age Subgroups -Primary HCL Population Preferred Term <65 >=65 5% N=89 N=40 difference

n % n % % Hypocalcemia 18 20.2 14 35.0 14.8 Weight increased 5 5.6 8 20.0 14.4 Capillary leak 8 9.0 8 20.0 11.0 syndrome Musculoskeletal 2 2.2 5 12.5 10.3 chest pain Atrioventricular 0 0.0 4 10.0 10.0 block first degree Dyspnea 9 10.1 8 20.0 9.9 Decreased appetite 7 7.9 7 17.5 9.6 Hypertension 7 7.9 7 17.5 9.6 Hemolytic uremic 3 3.4 5 12.5 9.1 syndrome Blood bilirubin 6 6.7 6 15.0 8.3 increased Febrile 4 4.5 5 12.5 8.0 neutropenia Blood creatinine 13 14.6 9 22.5 7.9 increased Dry eye 2 2.2 4 10.0 7.8 Vomiting 11 12.4 8 20.0 7.6 Acute kidney injury 0 0.0 3 7.5 7.5

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Renal failure 0 0.0 3 7.5 7.5 Hypermagnesemia 9 10.1 7 17.5 7.4 Hyperkalemia 7 7.9 6 15.0 7.1 Constipation 16 18.0 10 25.0 7.0 Abdominal 5 5.6 5 12.5 6.9 distension Infusion related 3 3.4 4 10.0 6.6 reaction Pyrexia 32 36.0 17 42.5 6.5 Cataract 1 1.1 3 7.5 6.4 Nasopharyngitis 1 1.1 3 7.5 6.4 Diarrhea 15 16.9 9 22.5 5.6 Pleural effusion 4 4.5 4 10.0 5.5 Hyponatremia 13 14.6 8 20.0 5.4 Abdominal pain 2 2.2 3 7.5 5.3 upper Hemoglobinuria 2 2.2 3 7.5 5.3 Nasal congestion 2 2.2 3 7.5 5.3 Pneumonia 2 2.2 3 7.5 5.3 Hemorrhoids 0 0.0 2 5.0 5.0 Hepatic enzyme 0 0.0 2 5.0 5.0 increased Injection site 0 0.0 2 5.0 5.0 reaction Renal impairment 0 0.0 2 5.0 5.0 Urinary retention 0 0.0 2 5.0 5.0 Source: Reviewer analysis

The analysis of serum creatinine values by age were reported in the pivotal trial. The baseline mean blood creatinine concentration was 0.85 mg/dL for subjects aged < 65 years and 0.89 mg/dL for subjects aged ≥ 65 years. The maximum blood creatinine concentration increased from baseline for both subjects aged < 65 years (1.13 mg/dL) and subjects aged ≥ 65 years (1.51 mg/dL); however, the magnitude mean change from baseline was numerically higher for subjects aged ≥ 65 years. The EOT blood creatinine concentration was numerically higher for subjects aged ≥ 65 years (1.12 mg/dL) compared to subjects < 65 years (0.98 mg/dL) (Source: Table 12.4.1.2-5Study 1053 Clinical Study Report).

Reviewer Comment: Patients ≥ 65 years of age generally had a higher incidence of HUS and CLS (important identified risks), and certain renal events, compared with patients < 65 years. The increased renal damage observed in the elderly could be explained by lower kidney reserve (i.e. lower creatinine clearance in elderly than younger patients with the same creatinine level) and pre-existing comorbidities. Elderly patients also reported a higher rate of weight increased events. Of note, a high volume of hydration was suggested in the CAT-8015-1001 and CD-ON-

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CAT-8015-1053 study protocols (nearly 4-5 L of fluid per day). All three deaths occurred in patients who were 65 years and older. Close monitoring will be required in older patients to minimize the risks associated with toxicity from moxetumomab treatment.

Renal impairment

No patients with severe renal impairment were enrolled on the HCL studies. In the Primary HCL Population, most patients had normal renal function (82 patients, 63.6%) or mild renal impairment (43 patients, 33.3%), and 4 patients had moderate renal impairment at baseline. All 4 patients were in Study 1053 and ≥65 years of age. The patients age, baseline creatinine clearance and AEs are listed below.

Table 41 Outcomes-Moderate Renal Impairment USUBJID Creatinine Age in TEAEs Best clearance years response (BICR) (b) (6) 42.0 82 Multiple AEs including hepatic enzymes mL/min increased but none grade 3 or higher except SD for nasal varices. 47.7 84 Multiple but no nephrotoxicity related AE CR mL/min 49.9 79 Died cause listed as sepsis? Cannot rule out Not mL/min CLS assessed 53.6 82 Had AE of nephrotoxicity CR mL/min Edema reported as not resolved. Source: FDA reviewer analysis

Of the 43 patients with mild renal impairment at baseline, 1 patient had a severe post-baseline renal impairment based on creatinine clearance rate and 2 patients had kidney failure. One patient with moderate renal impairment at baseline had a severe post-baseline renal impairment based on creatinine clearance rate. Among the 4 patients with severe post-baseline renal impairment based on creatinine clearance rate or kidney failure, 3 were patients with HUS and 1 was a 79-year-old patient with TLS who also experienced acute kidney injury. All 4 patients showed improvement in creatinine clearance rate to at least one category or better based on last record on study and/or follow-up values. All 4 patients were 64 years of age or older.

Additional subgroups analyses

The Applicant reported that incidence of AEs was generally comparable between patients with HCL in the US (n = 82) and non-US (n = 47) for all AE categories except Grade 3 or 4 AEs (87.8% vs 51.1%), which occurred at a notably higher rate in US versus non-US patients. This was

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primarily due to higher laboratory abnormalities reported as TEAEs in the Phase 1 1001 trial. Overall, the population of patients enrolled at non-US sites was rather small and nearly 2-fold smaller than the population of patients enrolled in the US (Section 2.7.4.5.2.1. Applicant’s Summary of clinical safety).

The incidence of AEs was generally similar for subgroup categories of sex, refractory to PNA therapy, and unfit for PNA. For the subgroups of race and ECOG performance status the numbers were too small to allow analysis (Section 2.7.4.5.1 Applicant’s Summary of clinical safety).

Specific Safety Studies/Clinical Trials

No special safety studies were submitted with this Application.

Additional Safety Explorations

Human Carcinogenicity or Tumor Development

A formal human carcinogenicity was not conducted for moxetumomab.

MAED SOC of neoplasms benign, malignant, and unspecified (including cysts and polyps) in the HCL population included 1 patient with basal cell carcinoma and squamous cell carcinoma and 1 patient with 1 event of glioblastoma. The spectrum and frequency of second primary malignancies identified in the HCL database are like that of the baseline patient population. Based on these data, no secondary cancer signal was identified.

Human Reproduction and Pregnancy

There are no data with moxetumomab pasudotox use in pregnant women to determine whether there is a drug-associated risk. Animal reproduction studies have not been conducted with moxetumomab pasudotox. It is unknown whether moxetumomab pasudotox can cause fetal harm when administered to a pregnant woman or if moxetumomab pasudotox has the potential to be transferred to the fetus. No data are available regarding the presence of moxetumomab pasudotox in human milk, the effects on the breastfed child, or the effects on milk production.

Pediatrics and Assessment of Effects on Growth

The Applicant was granted Orphan Designation for moxetumomab pasudotox for the treatment of patients with HCL and is therefore exempt from pediatric studies under the Pediatric Research Equity Act.

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Overdose, Drug Abuse Potential, Withdrawal, and Rebound

There has been no experience of over-dosage with moxetumomab pasudotox. There is no specific treatment for moxetumomab pasudotox overdose and symptoms of overdose have not been established.

There is no evidence of drug abuse with moxetumomab pasudotox from clinical studies. Moxetumomab pasudotox is unlikely to be abused due to its mode of action, physiological and pharmacological activity, lack of stimulant properties, and clinical setting of use.

Safety in the Postmarket Setting

Safety Concerns Identified Through Postmarket Experience

Moxetumomab pasudotox is not marketed in any country.

Expectations on Safety in the Postmarket Setting

The main safety concern that could pose a significant risk in the postmarket setting is CLS, and HUS. The risk was mitigated by guidance on monitoring, recommendations for fluids. The prescribing information and Medication Guide also convey the signs and symptoms of HUS and CLS to caregivers, patients and physicians.

Additionally, the safety profile of moxetumomab in patients with severe renal impairment is not known. The Applicant has recommended against use of moxetumomab pasudotox in patients with severe renal impairment. Minimal safety information is available in patients with moderate renal impairment. Close monitoring and early intervention is required in these patients.

Patients 65 years and older had higher rates of SAEs and treatment discontinuations. Additionally, several AEs including AEs related to electrolyte abnormalities, renal toxicity, weight gain, HUS and CLS were reported at higher rates in patients 65 years and older compared to patients younger than 65. Older adults also have comorbidities that may place them at an increased risk for adverse events related to moxetumomab pasudotox. Close monitoring and early intervention is required in these patients.

Integrated Assessment of Safety

The primary safety of moxetumomab pasudotox as monotherapy was evaluated in 80 patients with HCL in the Pivotal HCL Population, and comparable to the Primary HCL Population. The population of patients for the Pivotal HCL Population was representative of the expected demographic population for HCL with a median of 2 prior therapies and all patients received prior PNA therapy either alone or in combination with rituximab. Safety data from 129 patients (Primary HCL Population) supported the safety conclusions from the Pivotal HCL Population.

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Overall, 3 fatal AEs were reported in the HCL population. In the pivotal study, one patient died due to an AE of septic shock, one patient due to an AE of pneumonia, and one patient died due to an AE of sepsis syndrome and HCL. In the last 2 patients, cause of death due to CLS-like symptoms cannot be completely ruled out.

SAEs were reported in 2.4%-34.5% in the HCL population. HUS was the most frequently reported SAE. Other SAEs reported in >3 patients in the Pivotal HCL Population were SAEs of CLS and pyrexia.

Across the 2 adult HCL populations, the rate of treatment discontinuation due to related AEs was ≤ 10%. A markedly higher incidence of AEs resulting in dose interruption, delay, or omission was reported in the Pivotal HCL Population (23.8%) compared with the Primary HCL Population (15.5%) attributed to more complete collection of the reasons for dose interruption, delay and omission in the pivotal study.

AEs resulting in permanent discontinuation of moxetumomab pasudotox in > 1 patient each were HUS (6 patients, 4.7%), blood creatinine increased, and CLS (2 patients, 1.6% each). Treatment-related AEs resulting in permanent discontinuation of moxetumomab pasudotox in ≥ 1 patient each were HUS (6 patients, 4.7%), blood creatinine increased and CLS (2 patients, 1.6% each). With exception of one case of Grade 2 HUS in the Pivotal HCL Population, all patients who developed HUS were permanently discontinued.

TEAEs were reported in 98.8% to 99.4% of patients with most patients (range, 67.5% to 74.4%) experiencing Grade 3 or 4 AEs. The most common (≥ 30% of patients) AEs were edema peripheral (38.8%), nausea (35.0%), fatigue (33.8%), headache (32.5%), and pyrexia (31.3 %). Approximately two-thirds of patients (67.5%) had events of Grade 3 or 4 severity. Grade 3 or 4 AEs reported in ≥ 10% of patients were lymphocyte count decreased (20.0%), anemia, and hypophosphatemia (10.0% each). The AE profile of the Primary HCL Population was comparable to that of the Pivotal HCL Population with few exceptions. AEs related to abnormal laboratory values were reported in a lower rate in the Pivotal HCL Population compared to the Primary HCL Population due to differences in prespecified guidance on data collection among the individual studies.

HUS and CLS are primary safety concerns with moxetumomab pasudotox and merit boxed warning to adequately convey the risks of these AEs. The optimal management of CLS and HUS is not clearly defined but includes close monitoring for early diagnosis, treatment modifications (discontinuation for HUS) and supportive care. Other AEs that warrant close consideration include nephrotoxicity, IRR, electrolyte abnormalities, and elevated hepatic enzymes.

Statistical Issues

The major statistical issues are the discordance between BICR and investigator’s assessment in durable CR and best overall response. In general, there are more patients determined as

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9 Advisory Committee Meeting and Other External Consultations

This Application was not presented to the Oncologic Drug Advisory Committee nor any other external consultants.

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10 Pediatrics

The Applicant was granted Orphan Designation for moxetumomab pasudotox for the treatment of patients with HCL and is therefore exempt from pediatric studies under the Pediatric Research Equity Act.

The proposed indication, hairy cell leukemia, is not reported to occur in the pediatric population.

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11 Labeling Recommendations

Prescription Drug Labeling

The following summarizes the major changes to the moxetumomab pasudotox prescribing information proposed based on this review.

1 HIGHLIGHTS: Add boxed warning for HUS and CLS. Update common adverse reactions occurring in ≥20% of patients with adverse events reported (b) (4) . Remove “adult” from the indication statement. This disease is uncommon in the pediatric population.

2 DOSAGE AND ADMINISTRATION: (b) (4) revise recommendations for treatment discontinuation for HUS based on available evidence.

5 WARNINGS AND PRECAUTIONS: Revise rates of CLS AEs based on Agency’s grouped terms. Include electrolyte abnormalities, elevated hepatic enzymes and Infusion reactions with recommendations for management. Clarify monitoring for HUS to be consistent with that on study. Change “nephrotoxicity” to “renal toxicity” for easy readability.

6 ADVERSE REACTIONS: Include rates for AEs, all grades, and grade > 3 in the adverse drug reactions table occurring in ≥20% of patients in Study 1053. In a single-arm study, attribution of causality or relationship to study drug cannot be assessed. Include table listing serum chemistry abnormalities.

14 CLINICAL STUDIES: Include eligibility criteria for creatinine clearance to identify patients treated on Study 1053. Remove (b) (4) .

17 PATIENT COUNSELING INFORMATION: Revise section to be consistent with the updated Warnings and Precautions section.

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12 Risk Evaluation and Mitigation Strategies (REMS)

There are no additional risk management strategies needed beyond recommended labeling. The package insert will also include a Medication Guide and Instructions for Use.

Recommendations on REMS

Review of the application and of the findings from the review teams, the Division of Risk Management in the Office of Surveillance and Epidemiology agree that a REMS is not needed to ensure the benefits of moxetumomab pasudotox exceed its risk. Therefore, the subsequent sections are not applicable for this review and have been omitted.

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13 Postmarketing Requirements and Commitment

To further characterize the safety of moxetumomab pasudotox post approval in patients who are 65 years of age and older and in those with moderate renal impairment the Applicant will be required to conduct the following study:

PMR 3477-1 Conduct a study to provide evidence characterizing 1) the safety of moxetumomab pasudotox in patient who are 65 years of age and older and 2) the safety of moxetumomab pasudotox in patients who have moderate renal impairment. Submit interim and complete final reports and data of adverse events, including outcomes, management and discussion of potential mitigating strategies, with data collection 2 years post-approval and 5- years post approval respectively.

The timetable for submission is as follows:

Draft Protocol Submission: 10/2018 Final Protocol Submission: 01/2019 Interim Analysis Submission: 03/2021 Final Report Submission: 03/2024

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17 Division Director (Clinical)

Hairy cell leukemia (HCL) is a B-cell malignancy characterized by accumulation of mature B cell lymphoid cells with characteristic “hairy” projections in the peripheral blood, bone marrow and spleen. The cells typically express B-cell antigens such as CD19, CD20 and CD22. The purine analogues, cladribine and pentostatin are approved therapies for the treatment of HCL. These treatments are associated with high durable response rates. However, HCL is not curable and patients often relapse or develop refractory disease. Although re-treatment with PNA is possible, the depth of response lessens and the duration of remission tends to be shorter with each course of therapy, such that additional treatment options are needed for this patient population.

On January 29, 2018 Astra Zeneca submitted BLA 761104 for moxetumomab for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies, including treatment with a purine nucleoside analog (PNA). Moxetumomab is a CD22- directed cytotoxin composed of an immunoglobulin light chain variable domain (VL) and a heavy chain variable domain (VH) genetically fused to a truncated form of Pseudomonas exotoxin, PE38. The application was primarily supported by Study 1053, a single-arm, open-label study evaluating moxetumomab monotherapy in patients with relapsed or refractory HCL. All subjects had received prior treatment with a PNA, the median number of prior therapies was 3 (range 2-11). In total, 88% of patients had received two or more prior lines of PNA therapy. Although not approved for this indication, 75% of patients had received prior rituximab and 18% had received prior treatment with a BRAF inhibitor. The primary endpoint was the rate of durable CR as determined by BIRC. Among the 80 patients enrolled, the durable CR rate was 30.3% (95% CI: 20.3%, 41.3%) per BICR. The CR rate was 41.3% (95% CI: 30.4%, 52.8%) and the median duration of CR was not reached with a median follow-up of 16.7 months. A durable CR rate of 30% represents demonstration of adequate efficacy in this refractory patient population.

The most common adverse reactions (≥ 20%) observed in Study 1053 included: peripheral edema, hypoalbuminemia, increased alanine aminotransferase (ALT), pyrexia, nausea, headache, fatigue, hypocalcemia, hypophosphatemia, decreased lymphocyte count, constipation, diarrhea and anemia. There were three deaths due to adverse events in the trial: one due to sepsis, one death due to pneumonia and capillary leak syndrome (CLS) and one due to sepsis and CLS. Safety issues of CLS and hemolytic uremic syndrome (HUS) were identified. The prescribing information includes boxed warnings for CLS and HUS. Other warnings and precautions include: renal toxicity, infusion related reactions, and electrolyte abnormalities. A PMR was agreed upon, in which the Applicant would conduct a study to provide evidence characterizing 1) the safety of moxetumomab pasudotox in patients who are 65 years of age and older and 2) the safety of moxetumomab in patients who have moderate renal impairment.

Study 1053 provided substantial evidence of efficacy with demonstration of acceptable safety

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of moxetumomab for the treatment of relapsed or refractory hairy cell leukemia. While serious safety issues were identified, these safety issues can be adequate communicated in labeling. I agree with the recommendation of the review team for regular approval of moxetumomab for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies, including treatment with a purine nucleoside analog (PNA).

Nicole Gormley, MD Deputy Division Director, DHP (acting)

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18 Office Director (or designated signatory authority)

This application was reviewed under the auspices of the Oncology Center of Excellence (OCE) per the OCE Intercenter Agreement. The risk-benefit of moxetumomab pasudotox was also assessed by Drs. Gormley and Kanapuru, and I concur with their recommendation to approve this drug. My signature below represents an approval recommendation for the clinical portion of this application under the OCE. My signature below also represents the approval decision of this application under CDER.

Richard Pazdur, MD Office Director, OHOP (acting) Office Director, OCE

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19 Appendices

References

1. Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA: a cancer journal for clinicians. 2016. 2. Jones G, Parry-Jones N, Wilkins B, Else M, Catovsky D, British Committee for Standards in H. Revised guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant*. British journal of haematology. 2012;156(2):186-95. 3. Grever MR, Abdel-Wahab O, Andritsos LA, Banerji V, Barrientos J, Blachly JS, et al. Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia. Blood. 2017;129(5):553-60. 4. Grever MR. How I treat hairy cell leukemia. Blood. 2010;115(1):21-8. 5. Goodman GR, Burian C, Koziol JA, Saven A. Extended follow-up of patients with hairy cell leukemia after treatment with cladribine. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003;21(5):891-6. 6. Wierda WG, Byrd JC, Abramson JS, Bhat S, Bociek G, Brander D, et al. Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN. 2017;15(11):1414-27. 7. Divino V, Karve S, Gaughan A, DeKoven M, Gao G, Knopf KB, et al. Characteristics and treatment patterns among US patients with hairy cell leukemia: a retrospective claims analysis. Journal of comparative effectiveness research. 2017;6(6):497-508. 8. Nieva J, Bethel K, Saven A. Phase 2 study of rituximab in the treatment of cladribine- failed patients with hairy cell leukemia. Blood. 2003;102(3):810-3. 9. Tiacci E, Park JH, De Carolis L, Chung SS, Broccoli A, Scott S, et al. Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia. The New England journal of medicine. 2015;373(18):1733-47. 10. Dores GM, Matsuno RK, Weisenburger DD, Rosenberg PS, Anderson WF. Hairy cell leukaemia: a heterogeneous disease? Br J Haematol. 2008;142(1):45-51. 11. Bofill M, Janossy G, Janossa M, Burford GD, Seymour GJ, Wernet P, et al. Human B cell development. II. Subpopulations in the human fetus. J Immunol. 1985;134(3):1531-8. 12. Janossy G, Caligaris-Cappio F, Bofill M, Campana D, Janossa M. Development of B cell subpopulations in humans and its relevance to malignancy. Haematol Blood Transfus. 1985; 29:461-70. 13. Otipoby KL, Andersson KB, Draves KE, Klaus SJ, Farr AG, Kerner JD, et al. CD22 regulates thymus-independent responses and the lifespan of B cells. Nature. 1996;384(6610):634-7. 14. Grever MR, Blachly JS, Andritsos LA. Hairy cell leukemia: Update on molecular profiling and therapeutic advances. Blood reviews. 2014;28(5):197-203. 15. Saven A, Burian C, Koziol JA, Piro LD. Long-term follow-up of patients with hairy cell leukemia after cladribine treatment. Blood. 1998;92(6):1918-26.

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16. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney international. 2017;92(1):37-46.

Financial Disclosure

Covered Clinical Study (Name and/or Number): CD-ON-CAT-8015-1053

Was a list of clinical investigators provided: Yes No (Request list from Applicant) Total number of investigators identified: 168 Number of investigators who are Sponsor employees (including both full-time and part-time employees): 0

Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 0 If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: Significant payments of other sorts: Proprietary interest in the product tested held by investigator: Significant equity interest held by investigator in S Sponsor of covered study: Is an attachment provided with details Yes No (Request details from of the disclosable financial Applicant) interests/arrangements: Is a description of the steps taken to Yes No (Request information minimize potential bias provided: from Applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3) 0 Is an attachment provided with the Yes No (Request explanation reason: from Applicant)

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OCP Appendices (Technical documents supporting OCP recommendations)

Bioanalytical Method Validation and Performance

Bioanalytical Method for Detection of Moxetumomab pasudotox

Moxetumomab pasudotox plasma concentrations from Study 1053 were determined using validated sandwich enzyme-linked immunosorbent assays (ELISA). For samples from Study 1053, an anti-idiotypic mAb against the CD22-binding domain of moxetumomab pasudotox was coated on microtiter plates to capture moxetumomab pasudotox present in tested samples. Bound moxetumomab pasudotox was detected following sequential incubation steps with biotinylated IP-49 antibody (a mouse monoclonal antibody which detects the PE38 portion of moxetumomab pasudotox), streptavidin-horseradish peroxidase (HRP) conjugate, and TMB (3,3’5,5’ tetramethylbenzidine) substrate. The assay range was from 40 to 1,200 ng/mL in 100% plasma. The accuracy and precision shown in Table 42 were within acceptable ranges. No hook effect was observed at concentrations of up to 100,000 ng/mL of moxetumomab pasudotox. Assay selectivity was within acceptable ranges. Stability of moxetumomab pasudotox in K2- EDTA plasma was observed following storage at room temperature for 24 hours and following up to 6 cycles freeze/thaw from -70°C.

The ELISA method used for PK samples from 28 out of 49 patients Trial 1001 was similar to that used by Study 1053, except that a recombinant human CD22 was used as the capture reagent. The assay demonstrated linearity of dilution within the assay detection range with no hook effect at concentrations up to 35,000 ng/mL. The assay had acceptable accuracy and precision (Table 42) and matrix selectivity. Stability of moxetumomab pasudotox in K2-EDTA plasma was observed following storage at room temperature for 48 hours, frozen at - 70°C and -20°C for up to 743 days, and following up to 6 cycles of freeze/thaw from -70°C.

In addition, moxetumomab pasudotox concentrations were also assayed with a non-validated cell-based assay at the NCI for 42 out of 49 patients enrolled at the NCI in Trial 1001. This cell- based PK assay determined concentrations of moxetumomab pasudotox in human sodium- heparin plasma by measuring its cytotoxicity on CD22-positive cells (Raji). Known concentrations of moxetumomab pasudotox (0, 0.32, 1.6, 8, and 40 ng/mL) in cell medium were incubated with Raji cells to construct a standard curve. After 16 to 20 hours of incubation at 37°C, inhibition of protein synthesis by moxetumomab pasudotox (from diluted plasma samples) was determined by pulsing the cells for 4 to 6 hours with [3H]-leucine, harvesting the incorporated protein onto protein-binding filters, and determining counts per minute using a scintillation counter. The concentration of moxetumomab pasudotox in the diluted plasma sample was determined from DL50 (dilution of the plasma necessary for 50% inhibition of protein synthesis) with normalization between plates using the moxetumomab pasudotox standard curve.

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plasma concentrations is shown in Table 42.

Table 42. Bioanalytical Methods for Moxetumomab Pasudotox Concentration Determinations in Plasma LLOQ Assay Range Inter-assay Intra-assay Inter-assay Intra-assay Method Report No. a ng/mL ng/mL % RE % RE % CV % CV Range Range b Range b Range -9.5% to ELISA with antigen 244-0702 40.00 40.00 to 3.3% -10.6% to 9.0% to 1.7% to 8.6% capture (MedImmune) 1,200.00 -1.3% 15.9%

ELISA with an anti-ID 40.00 40.00 to -8.3% to -8.3% to 2.6% to 3.9% to 8.4% antibody capture AR6121 1,200.00 5.1% 5.1% 6.6% (MedImmune) Cell-based assay NCI 16.00 c ND ND ND ND ND Not validated

% CV = percent coefficient of variation; % Diff = % difference; ELISA = enzyme-linked immunosorbent assay; ID = idiotype; LLOQ = lower limit of quantitation; NCI = National Cancer Institute; ND = not determined; No. = number; (b) (4) ; % RE = percent relative error. % CV = standard deviation/mean concentration × 100% % Diff = ([mean found concentration – nominal concentration]/nominal concentration) x 100 % RE = (mean observed concentration/nominal concentration - 1) × 100%. aRefers to method validation report, located in Reports of Biopharmaceutic Studies bInter- and intra-assay ranges are reported as % RE as per the (b) (4) validation report and as % Diff as per the (b) (4) validation report. The formula used for % RE and % Diff is the same. cValue is estimated. Source: Applicant’s Summary of Biopharmaceutic Studies (M 2.7.1), Table 2.7.1.1.3.2-1

Bioanalytical Methods for Detection of Anti-Drug Antibodies and Neutralizing Antibodies

Anti-Drug Antibodies Clinical samples were screened for ADA using validated ELISA or electrochemiluminescent (ECL) assays. For the ELISA assay conducted at (b) (4) for Trial 1001, patient plasma was added to wells coated with moxetumomab pasudotox. After incubation and washing steps, moxetumomab pasudotox-bound patient antibodies were detected by addition of biotinylated- moxetumomab pasudotox followed by streptavidin-HRP, and subsequent addition of TMB substrate. For the ECL assay conducted by MedImmune in Hayward and then transferred to MedImmune’s Mountain View site for Trial 1053, samples and controls were pre-incubated with biotin-moxetumomab pasudotox and ruthenium-moxetumomab pasudotox to pre-form ADA immune-complexes, which were captured via biotin on streptavidin Meso Scale Discovery (MSD) plates. After removal of unbound materials, plate-bound ADA immune-complexes were detected by ruthenium-emitted ECL.

The summary of the validations of the both ADA assays are presented in Table 43. Cut-point normalization factor termed “X” was calculated as difference between the cut-point value (absorbance) and the absorbance of the negative control. Cut-point normalization factor 135 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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termed “CPF” was calculated as ratio of cut-point value (signal) of individual human drug-naïve plasma over negative control signal.

Table 43. Summary of Validation ADA Assay Parameters Assay Cross-validation at Mountain Parameter Validation at (b) (4) Validation at Hayward View Tested Validation 06-0591 V-IM-0040 V-IM-0040 Addendum 1 report no. Assay cut- point a b b X = 1.568 CPF 2.33 CPF 3.94 (normaliza- tion factor)

Detection c d d 6,354 ng/mL 17 ng/mL 42 ng/mL sensitivity Assay can detect Assay can detect ≥ 1,800 ng/mL PC in the Assay drug ≥ 655 ng/mL PC in the e presence of ≤ 125.78 ng/mL ND tolerance of moxetumomab presence of ≤ 500 ng/mL of f pasudotox moxetumomab pasudotox Intra-assay precision g ≤ 13% ≤ 13% ≤ 20% (% CV) Inter-assay precision h ≤ 61% ≤ 19% ≤ 20% (% CV) BLQ = below limit of quantitation; % CV = percent coefficient of variation; CPF = cut-point factor; LOD = limit of detection; ND = not determined; PC = positive control. Source: Applicant’s Summary of Biopharmaceutic Studies (M 2.7.1), Table 2.7.1.1.3.3-1

Neutralizing Antibodies Detection of neutralizing anti-drug antibodies (nAbs) was performed by either solid-phase ELISA or a cell-based assay. For samples from Phase 1 Trial 1001, nAb was assessed by inhibition of the binding of moxetumomab pasudotox to CD22 using a solid-phase ELISA performed at (b) (4) . Briefly, wells of ELISA plate were coated with recombinant human CD22, plasma samples were pre-incubated with 100 ng/mL biotinylated moxetumomab pasudotox then diluted 1:20 with assay buffer and added to the plate. Upon completion of binding, the microtiter plate was washed to remove all unbound components and incubated with streptavidin-HRP followed by a TMB substrate solution. If nAb was present in a sample, the signal was reduced (neutralized) in comparison with the signal in control plasma. Positive/negative samples were determined using the cut-point, percent signal neutralization greater or equal to 50%.

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Table 44. Summary of Validation nAb Assay Parameters Assay Validation at Cross-validation at Parameter (b) (4) Validation at Hayward NCI Mountain View Tested Validation 06-0592 V-IM-0039 V-IM-0039, Addendum 1 Not validated report no. Assay cut- point a a 50% CPF 1.3 CPF 1.18 50% (fixed CP or CPF)

Detection > 1000 c c b 280 ng/mL 165 ng/mL ND sensitivity ng/mL Assay can detect ≥ 494 ng/mL Assay drug PC in the presence of ≤ 64 ND ND ND tolerance ng/mL of moxetumomab pasudotox Intra-assay d e e precision < 9% ≤ 4.7% ≤ 20.5% ND (% CV) Inter-assay d f f precision < 19% ≤ 22.1% ≤ 23.6% ND (% CV) % CV = percent coefficient of variation; CP = cut-point; CPF = cut-point factor (ratio); LOD = limit of detection; NCI = National Cancer Institute; nAb = neutralizing antibody; ND= not determined; PC = positive control. Note: % CV = standard deviation/mean*100% a Cut-point was empirically assigned as 50% neutralization of moxetumomab pasudotox induced cytotoxicity by nAb present in serum sample (NCI) or moxetumomab binding to CD22 coated plates (b) (4) ) b Sensitivity was estimated to be greater than 1000 ng/mL based on the two PC antibodies (PL3 and PT7) tested at this concentration and returning negative results in the assay c Sensitivity was determined as concentration corresponding to the LOD signal. It was calculated by statistical analysis of individual samples used in cut-point determination at 5% false positive and 5% false negative rate. G09.4 was used as PC. d Precision (of biotinylated moxetumomab pasudotox) measurement is shown as the highest value from all validation samples e Intra-assay precision is shown as a highest value from all tested negative and positive controls fI nter-assay precision is shown as a highest value from all tested negative and positive controls Source: Applicant’s Summary of Biopharmaceutic Studies (M 2.7.1), Table 2.7.1.1.3.4-1

The presence of nAbs were also assessed with a validated cell-based assay at MedImmune for samples in Study 1053. The assay measured neutralization of moxetumomab pasudotox- induced cytotoxicity in the B-cell lymphoma cell line Raji. The assay detected nAbs to both domains of moxetumomab pasudotox: the CD22 binding and/or the PE38 domains. Using statistical analysis, the cut-point was determined to be 49% cell viability. The assay limit of detection based on a positive control antibody, clone G09.4, was 280 ng/mL. The assay detectable range was from 280 to 360,000 ng/mL. After method transferring to MedImmune’s Mountain View site, the assay was cross-validated with a new limit of detection was determined to be 165 ng/mL of the positive control antibody.

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A similar but non-validated cell-based assay was also used to detect the nAbs in samples from patients enrolled at NCI in Trial 1001.

The performance of the above validated methods to detect the nAbs are summarized in Table 44. The precision and sensitivity of these methods are acceptable.

Method for Titer Assessment

Titer assessment was only conducted for samples from Study 1053. The titer assay is a modification of the ADA screening assay where each ADA-containing sample is titrated in a series of step-wise (1:2) dilutions to identify the highest dilution providing detectable ADA. Briefly, serially diluted ADA-containing samples were pre-incubated with biotinylated and ruthenylated moxetumomab pasudotox reagents to form tri-complexes, which were captured via biotin on streptavidin MSD plates. After removal of unbound material, ECL signals produced by ruthenium in the immunocomplexes were measured on MSD Sector Imager. A surrogate ADA, anti-moxetumomab pasudotox anti-idiotypic antibody G09.4 spiked into negative control at 4 ng/mL (40 ng/mL in 100% matrix), was used as the assay positive control. The reciprocal of the maximal dilution for each sample was designated as the sample titer. This method was validated by MedImmune (report V-IM-0061) using surrogate ADA concentration range between 500 ng/mL and 20,000 ng/mL.

Method for Measurement of ADAs Specific to PE38 or CD22 Binding Domains

The bioanalytical methods used for the measurement of ADA specific to the CD22-binding domain (ADA1) or the PE38 domain (ADA2) of moxetumomab pasudotox in human plasma were validated and applied for samples from Trial 1053. The method is a validated bridging immunoassay, which detects both subtypes of ADAs (ADA1 and ADA2) by forming immune- complexes with biotin- and ruthenium-labeled moxetumomab pasudotox using MSD ECL technology.

Briefly, to determine whether an ADA-positive sample contains ADA1 and/or ADA2 subtype antibodies, each sample is tested using 3 assay conditions: 1) in the presence of ADA1-specific inhibitor D1 (moxetumomab pasudotox IgG, which shares the CD22-binding domain with moxetumomab pasudotox); 2) in the presence of ADA2-specific inhibitor D2 (LMB-9, which contains the PE38 domain of moxetumomab pasudotox); and 3) in the presence of both D1 and D2. Each sample and control were pre-incubated using 3 combinations of inhibitors followed by incubation with biotin- and ruthenium-labeled moxetumomab pasudotox to detect ADA immune-complexes as described in the ADA screening method. Samples with percent inhibition of the ADA-specific signal greater than the assay threshold or cut-point (Spec-CP) were determined positive for the specific ADA subtype. The detail of the method validation and performance of the method can be found in report V-IM-0068 and its Addendum 1.

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Bioanalytical Method for Pharmacodynamics Sample Analysis To assess the pharmacodynamic effects of moxetumomab pasudotox, cluster of differentiation 22 (CD22) expression cells were measured by flow cytometry. Soluble CD22 (sCD22) concentrations were also measured.

To determine CD22 expression levels, beads embedded with known quantifies of phycoerythrin (PE, a fluorochrome specific to CD22) molecules were analyzed on the instrument daily to generate a standard curve of PE molecule count vs. geometric mean fluorescence. For soluble CD22 quantification, a sandwich-based immunoassay method was used with plate coated with a 1 µg/mL solution of the mouse anti-human CD22 mAb (b) (4) . After overnight incubation with the samples and washing, a 1 mg/mL streptavidin-HRP solution was added. The immunoassay was developed by adding a 1:1 solution of tetramethylbenzidine:hydrogen peroxide for 12 minutes followed by the addition of 2N sulfuric acid to stop the reaction.

The above assays were developed by NCI for analysis of samples from Trial 1001 but not validated.

A validated bioanalytical flow cytometry assay was developed by (b) (4) to analyze the population percentages and absolute counts (cells/mm3) of T, B, and NK cells in whole blood specimens from Trial 1053. The details of the assay can be found in validation report ECTS07011-VR01-03.

Clinical Pharmacokinetics and Pharmacodynamics

Pharmacokinetics Assessment

In the Study 1053, the mean plasma concentration-time profiles of moxetumomab pasudotox following the first and third dose of Cycle 1 (Cycle 1 Day 1 and Cycle 1 Day 5) and first dose of Cycle 2 (Cycle 2 Day 1) are shown in Figure 19.

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Figure 19. Mean Concentration-time Profiles of Moxetumomab Pasudotox Following IV Administration in the First Two Cycles of Treatment – PK Population

Data below LLOQ (40 ng/mL; as shown by dotted horizontal line) are plotted at 1/2 LLOQ for illustrative purposes only. Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Figure 2.7.2.2.2.1-1

Following IV infusion, the mean concentration of moxetumomab pasudotox monoexponentially declines. Compared to PK exposure after the first dose (Cycle 1 Day 1), the mean concentrations were significantly higher on Cycle 1 Day 5 and Cycle 2 Day 1. After the third dose (Cycle 1 Day 5), Cmax levels were similar between dosing intervals as shown in Figure 20, suggesting steady state has been achieved after the third dose. This result is expected based on the observed short half-life (t1/2) of less than 2 hours (see Table 45) at steady state. The inter- subject variability in PK exposure among patients with HCL was moderate to high with the CV% of 54% and 88% for Cmax and AUC0-last (on Cycle 1 Day 5), respectively.

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Figure 20. Mean Peak Concentration Levels of Moxetumomab Pasudotox in HCL Subjects after Each Cycle

Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Figure 2.7.2.2.2.1-2

Table 45. PK Parameters Following Multiple IV Administration of 40 µg/kg Moxetumomab Pasudotox in Patients with HCL (Study 1053) Parameter (units) Cycle 1 Day 1 Cycle 1 Day 5 Cycle 2 Day 1 Tmax (hour) 0.567 (0.433 – 1.30) [75] 0.550 (0.417 – 2.45) [71] 0.583 (0.500 – 1.75) [69] Cmax (ng/mL) 192 (162) [75] 435 (233) [71] 379 (262) [69] AUC0-last (ng·hr/mL) 120 (261) [75] 820 (721) [71] 626 (610) [69] AUC0-3h (ng·hr/mL) 869 (200) [6] 856 (370) [54] 1030 (333) [37] a AUC0-inf (ng·hr/mL) NR 1300 (742) [49] 1470 (541) [22] a CL (mL/hr/kg) NR 44.6 (30.5) [49] 31.8 (13.7) [22] a t1/2 (hour) NR 1.38 (0.632) [49] 1.39 (0.351) [22] Notes: Values presented as mean (standard deviation) [n], except Tmax shown as median and range (min – max). Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Table 2.7.2.2.2.1-1

The average Cmax was approximately 2-fold higher on Day 5 compared to Day 1 of Cycle 1 (Table 45). The significantly lower exposure (Cmax and AUC) after the first dose is considered related to the presence of large amount of CD22+ B cells and target-mediated disposition at baseline. Upon multiple doses (Cycle 1, Day 5 and beyond), there was a reduction in the CD22+ B cell pool and subsequently elimination of associated target mediated drug disposition. Total peripheral blood CD19+ B cell counts (including normal B cells and HCL cells) were quantified since moxetumomab pasudotox interferes with detection of cellular CD22. As shown in Figure

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21, PK exposure was inversely related to the log of baseline CD19+ B cell counts during Cycle 1 Day 1 (Inset A, p < 0.01) and Cycle 1 Day 5 (Inset B, p < 0.01).

Figure 21. Relationship Between PK and Baseline CD19+ B cells in Subjects after First (Left) and Third Dose (Right) of Cycle 1 (Trial 1053)

Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Figure 2.7.2.2.2.1-3

When the PK exposure (Cmax) from Cycle 1 Day 1 were stratified by median baseline value (92.0 cells/mm3) of CD19+ B cells, as shown in Figure 22, after the first dose of Cycle 1, markedly higher Cmax values (median, 232 vs. 108 ng/mL) were associated with low baseline CD19+ B cell counts.

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Figure 22. Moxetumomab Pasudotox Exposure Comparison between CD19 Low and CD19 High Group at Baseline

Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Figure 2.7.2.2.2.1-4

The above results support the hypothesis that increase in concentrations after the first dose is related to the depletion of CD22+ (detected as CD19+) B cells and target-mediated drug disposition. In addition, the high inter-subject variability in PK can also be explained at least in part by the differences in baseline CD19+ B cells and the magnitude of B cell depletion post- treatment.

In the Phase 1 Trial 1001, PK data from 28 of 49 patients were determined used a validated ELISA assay. The mean concentration-time profiles of moxetumomab pasudotox following the first (Day 1) and third (Day 5) doses are shown in Figure 23. The mean Cycle 1 PK parameters from all 28 evaluable patients are summarized in Table 46. Similar to that observed in Study 1053, PK exposure on Day 5 were significantly higher than that after the first dose at the therapeutic dose in Cycle 1. PK exposure after the third dose in Cycle 1 (Day 5) did not increase dose proportionally from 5 to 20 µg/kg. However, a dose-proportional increase in PK exposures (AUC and Cmax) was observed across the 30 to 50 µg/kg dose range.

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Figure 23. Mean Concentration-time Profiles of Moxetumomab Pasudotox in Patients with HCL Following the First and Third Dose of Cycle 1 (Study 1001)

Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Figure 2.7.2.2.2.2-1

Table 46. Summary of Cycle 1 PK Parameters of Moxetumomab Pasudotox in Patients with HCL (Trial 1001) Cohort 5 µg/kg 10 µg/kg 20 µg/kg 30 µg/kg 40 µg/kg 50 µg/kg Day 5 Day 5 Day 5 Day 5 Day 5 Day 1 Day 5 n 3 3 3 3 4 12 12 Cmax 103 135 161 420 701 435 738 (ng/mL) (40.5) (49.1) (136) (384) (328) (260) (316) AUC0-last 179 90.2 93.2 909 1640 511 1920 (hiring/mL) (155) (52.3) (113) (861) (1270) (585) (1290) CL 13.3 68.9 66.3 18.7 45.5 106 33.3 (mL/kg/hr.) (47.6) (80.2) (37.5) t1/2 2.20 0.369 0.404 1.86 1.66 0.799 2.06 (hr.) (0.928) (0.755) (0.980) Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Table 2.7.2.2.2.2-1

The inter-subject variability in PK exposure among patients with HCL was moderate to high based on the CV% of 43% and 67% for Cmax and AUC0-last on Cycle 1 Day 5 at 50 µg/kg, respectively.

Pharmacodynamics Assessment

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In Study 1053, the change of CD19+ B cells normalized by baseline following moxetumomab pasudotox treatment up to 181 days post EOT is shown in Figure 5.

The results indicate that a maximum reduction (89%) of CD19+ B cell population from baseline was achieved around Day 8 following the first three doses of moxetumomab pasudotox. Median baseline-normalized CD19+ B cell values remained statistically reduced from baseline at all subsequent time points up to- and including Day 176 (EOT for subjects receiving all doses of moxetumomab pasudotox). On Day 357 (181 days post EOT), median baseline-normalized CD19+ B cell values were not significantly different, suggesting a return to baseline levels.

When the PD effect was stratified by the patient’s response, as shown in Figure 24, HCL subjects with best overall responses of CR or PR demonstrated longer durations of reductions in CD19+ B cells than HCL subjects with SD or PD. However, at Day 357 (181 days post EOT), median baseline-normalized CD19+ B cell values were similar among patients with CR, PR, and SD.

Figure 24. Median Baseline Normalized CD19+ B Cell Counts Over Time Stratified by Clinical Response Category (Trial 1053)

Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Figure 2.7.2.2.2.1-11

In Trial 1053, moxetumomab pasudotox treatment had much less effects on CD3+, CD4+, CD8+ T and NK cell populations. Although there were statistically significant reductions in median baseline-normalized quantities observed on Day 8 following the first 3 doses of moxetumomab pasudotox, baseline-normalized values from these cell populations either returned to or were statistically elevated above baseline levels at all subsequent visits.

Immunogenicity

In Study 1053, of the 76 subjects with baseline ADA results, 45 (59.2%) subjects tested positive for ADA (specific to PE38 domain) prior to any treatment with moxetumomab pasudotox. Following moxetumomab pasudotox treatment, the ADA prevalence rate was 87.5% (70/80 subjects) with neutralizing antibodies (nAbs) against moxetumomab pasudotox detected in 67 (83.8%) (of 80 subjects). Among these 67 subjects who tested nAb positive, 98.5% (66/67) had ADA specific to the PE38 binding domain, and 53.7% (36/67) had ADA specific to the CD22 binding domain. ADA titers were also measured for subjects with positive nAb results. Titers 145 Version date: February 1, 2016 for initial rollout (NME/original BLA reviews)

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were generally low at baseline (Cycle 1 Day 1) with the median titer of 80 (range, 10 to 6400). However, ADA titers increased with time and median titers in Cycles 2, 3 and 5 were 320, 2400, and 19200, respectively (see Figure 25). The ADA titers increased in 55 out of 67 patients who were nAb-positive by a median of 640-fold (range: 2- to 20480-fold) when compared to the baseline values.

Figure 25. ADA Titers in HCL Subjects with Positive Neutralizing ADA Results (Trial 1053)

Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Figure 2.7.2.2.2.1-6

Impact of Immunogenicity on PK Although the presence of ADA had no significant effect on PK during Cycle 1 and Cycle 2, the presence of ADA was associated with significant decrease in PK exposure (Cmax) at later cycles (Cycle 3 and beyond) (Figure 26), which is consistent with the exponential increasing titer levels at later cycles shown above. As demonstrated in Figure 26, ADA-positive subjects in Cycles 3 and 5 exhibited approximately 4- and 26-fold lower median Cmax, respectively, compared to ADA-negative subjects. These data indicate that the observed impact of ADA on PK was due to titer level and not directly related to time.

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Figure 26. Effect of Post-Baseline ADA Status by Cycle on PK Exposure in Subjects with HCL (Trial 1053)

Source: Applicant’s Summary of Clinical Pharmacology (M 2.7.2), Figure 2.7.2.2.2.1-8

In summary, there were high incidence of ADA following moxetumomab pasudotox treatment in patients with HCL. Neutralizing Abs against both PE38- and CD22-binding domain were detected. The presence of ADA, especially at later cycles (cycle 3 and beyond) significantly decrease the PK exposure Cmax. The high incidence of ADA is also related to the observed high inter-subject variability in PK.

Pharmacometrics

Population PK Analysis This Applicant’s population PK (popPK) and exposure-response (E-R) analysis included data from Trial 101 and Trial 1053 in adult HCL patients. A total of 123 patients were included in the analyses (with n=49 from study 1001 and n=74 from Study 1053). See Table 47 for the summary of studies included in the analyses.

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Table 47. Summary of studies included in the analysis

Source: Applicant’s Clinical PopPK Modeling and Exposure-Response Analysis Report, Table 6.1.2-1

The moxetumomab pasudotox PK was described with one-compartment model with linear elimination from the central compartment. Two parameters for clearance were utilized to distinguish early phase faster elimination (CL1) and later phase slower elimination (CL2) of moxetumomab pasudotox from the central compartment.

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Figure 27. Pharmacokinetics Model

Source: Applicant’s Clinical PopPK Modeling and Exposure-Response Analysis Report, Figure 5.2.1-1, page 20

From covariate analyses, none of the tested variables were identified as significant covariates although few covariates such as baseline spleen size, baseline ALT, baseline body weight showed some trends influencing clearance parameters or volume of distribution. Furthermore, baseline creatinine clearance did not show any trend with respect to random effect on CL1 or CL2. The range included the subjects with normal glomerular filtration rate (GFR) (79 out of 123 subjects), mild decrease in GFR (40 out of 123 subjects), and moderate decrease in GFR (4 out of 123 subjects). Thus, the base structure model was determined as the final model.

The Applicant’s popPK analyses including covariate testing were acceptable. However, its additional analysis to evaluate the effect of ADA titer was not aligned with its overall model development. The Applicant performed the additional analysis with data from Study 1053 only to evaluate the effect of ADA on moxetumomab pasudotox PK and concluded that nAb positive patients with ADA titer >10240 showed ~ 4-fold increase in CL2. However, robustness of this estimate is questionable. ADA titer was not identified as a statistically significant covariate with the pooled dataset which was utilized for the model development and therefore not included in the final model.

Reviewer’s comments: The Applicant reported approximately 4-fold difference in clearance between subjects with ADA titer ≤10240 and those with ADA titer >10240 based on its post-hoc analysis. However, the post-hoc analysis was not performed with the final model which was developed with the pooled dataset. It was performed with additional modeling with fixed parameter estimates from the final model on a subset of data (data from Study 1053). ADA was not identified as a significant covariate during the model development, which was also confirmed by the reviewer’s analysis that showed an increase in the objective function value (OFV) from 34295 to 34482 after adding ADA titer to the final model. Therefore, although the Applicant reported ~30-fold difference in Cmax on Day 1 Cycle 5 between subjects with ADA titer ≤10240 and those with ADA titer >10240 based on noncompartmental analysis (CSR for Study 1053) and 4-fold difference in steady-state CL based on its popPK analysis, the post-hoc analysis did not confirm the difference at that magnitude.

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Exposure-Response Analyses for Efficacy The Applicant performed exploratory analysis to assess the correlation between exposure and efficacy endpoints including durable CR, CR, and ORR based on data from trial 1053. Percentage of responders were compared between subjects whose exposure were above or below median during Cycle 2. As shown in Figure 28, higher rates for durable CR were observed from the subjects with exposures above median. Similar trends were observed for CR and ORR (figures not shown).

Figure 28. Exposure-Response Relationships Between Cmax or AUC and ORR (Trial 1053)

Source: Applicant’s Clinical PopPK Modeling and Exposure-Response Analysis Report, Figure 6.7.4-1, page 59

To confirm the Applicant’s findings, the reviewer conducted independent E-R analyses for these efficacy endpoints using logistic regression. As shown in Figure 29, notable exposure-response relationships were observed. The exposure was a significant predictor for ORR (p=0.00059 for AUC in Cycle 2). For Durable CR and CR, age and weight were statistically significant predictors rather than the exposure although the positive trends were observed. These trends were similar with exposures in other Cycles as well (figures not shown).

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Figure 29. Exposure-Response Relationships Between AUC in Cycle 2 and Durable CR, CR, and ORR (Trial 1053)

Source: Reviewer’s analysis

Furthermore, the distribution of AUC in patients by various responses also supported the efficacy of moxetumomab. As shown in Figure 30, higher AUC values were observed from subjects with better efficacy: AUC in subjects with Complete Response (CR) was greater than those with Partial Response (PR), AUC in subjects with PR was greater than those with Stable Disease (SD), and AUC is subjects with SD was greater than those with PD.

Figure 30. Distribution of AUC in Cycle 1, 2, and 5 Among Subjects with Various Responses (Trial 1053)

Source: Reviewer’s analysis (PD: Progressive Disease, SD: Stable Disease, PR: Partial Response, CR: Complete Response, N/E: Not evaluated)

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Overall, exposure-response relationships provided supportive evidence to support the efficacy of moxetumomab pasudotox.

To assess the ADA effect on efficacy, the Applicant also compared percentage of responders by ADA titer status. As shown in Figure 31, rates for CR and Durable CR in subjects with ADA titer >10240 were lower (36% and 20%, respectively) than those with ADA titer ≤10240 (46.9%, 38.8%) while no difference was observed for ORR between these two groups of subjects. Reviewer’s analysis also confirmed the Applicant’s analysis (results not shown).

Figure 31. Exposure-Response Relationships by ADA Titer (Trial 1053)

Source: Applicant’s Clinical PopPK Modeling and Exposure-Response Analysis Report, Figure 6.7.6-1, page 61

Exposure-Response Analyses for Safety The Applicant performed exposure-response analyses separately for data from Trial 1053 and those from Trial 1001 due to the known difference in bioactivity between drug substance used in these two trials. Bioactivity of the drug substance used in Trial 1001 was lower than that

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used in Trial 1053 and 50 µg/kg of the drug substance used in Trial 1001 was believed to be equivalent to 40 µg/kg of the drug substance used in Trial 1053. From the Applicant’s analysis, higher incidence of Capillary Leak Syndrome (CLS) was observed in subjects with higher exposure in Trial 1053 but no trend was observed in Trial 1001. In both Trials, the incidence of Hemolytic Uremic Syndrome (HUS) was very low so no exposure-response analysis for HUS was performed. None of subjects from Trial 1001 had any ≥Grade 2 elevation of serum creatinine. However, 31% of subjects showed such elevation in Trial 1053 and subjects with higher exposure showed higher incidence of ≥Grade 2 elevation of serum creatinine. Furthermore, subjects with higher exposure showed higher incidence of Grade 3 or 4 Treatment-Emergent Adverse Event (TEAE) in Trial 1001 but such a trend was not observed in Trial 1053.

Reviewer performed an independent analysis using pooled data from both trials. Considering the different bioactivity between drug substances used in these trials, an adjustment factor was utilized. Concentrations from Trial 1001 was adjusted by multiplying 0.8 and then exposure- response analyses for HUS, CLS, increased creatinine and TEAE were performed. As shown in Figure 32, significant exposure-response relationships for CLS and ≥Grade 3 TEAE were observed while those for HUS or ≥Grade 2 elevation of serum creatinine were not significant. The exposure utilized for the analyses was AUC on Day 1 in Cycle 1 and AUC in other Cycles also showed similar trends.

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Figure 32. Exposure-Response Relationships for Safety Endpoints (Trial 1053 and Trial 1001)

Source: Reviewer’s analysis (aAUC: adjusted AUC where AUC from Trial 1001 was adjusted for the drug substance’s lower bioactivity)

Additional Clinical Outcome Assessment Analyses

Not applicable

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Reference ID: 4319411 Signature Page 1 of 2 ------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/ ------

WANDA D NGUYEN 09/12/2018

BINDU N KANAPURU 09/12/2018

MATTHEW D THOMPSON 09/12/2018

JOHN K LEIGHTON on behalf of CHRISTOPHER M SHETH 09/12/2018

JOHN K LEIGHTON 09/12/2018

GUOXIANG SHEN 09/12/2018

JEE E LEE 09/12/2018

LIAN MA 09/12/2018

OLANREWAJU OKUSANYA 09/12/2018

BRIAN P BOOTH 09/12/2018

JIAXI ZHOU 09/12/2018

THOMAS E GWISE on behalf of YUAN L SHEN 09/12/2018

THOMAS E GWISE 09/12/2018

Reference ID: 4319411 Signature Page 2 of 2 NICOLE J GORMLEY 09/12/2018

RICHARD PAZDUR 09/12/2018

Reference ID: 4319411

Date: July 1, 2018 From: Kimberly Smith, Medical Officer, Division of Cardiovascular and Renal Products Through: Aliza Thompson, Team Leader Norman Stockbridge, Director Division of Cardiovascular and Renal Products To: Quyen Tran, Regulatory Project Manager, Division of Hematology Products Subject: Use of moxetumomab pasudotox in patients with moderate renal impairment and monitoring to mitigate the risk of renal toxicity

Background Moxetumomab pasudotox is a recombinant immunotoxin targeting the B cell-specific surface antigen CD22. It includes an immunoglobulin light chain variable domain (VL) and a heavy chain variable (b) (4) domain (VH) from the murine anti-CD22 monoclonal antibody genetically fused to a truncated form of Pseudomonas exotoxin. Following binding to CD22 on the surface of B cells, the complex is endocytosed and releases exotoxin, thereby inhibiting protein synthesis and resulting in cell death.

On November 30, 2017, the Division of Hematology Products (DHP) received a BLA for moxetumomab pasudotox for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies including treatment with a purine nucleoside analog. HCL is a rare, indolent, chronic B cell lymphoproliferative disorder characterized by the accumulation of small mature B lymphoid cells in the peripheral blood, bone marrow, and spleen. The median age of onset is 50 to 55 years of age. Acute or chronic renal insufficiency is not generally associated with the disease itself but can result from complications such as tumor lysis syndrome (TLS), sepsis, or treatment-related toxicity.

Immunotoxin therapies have been associated with Hemolytic Uremic Syndrome (HUS) and Capillary Leak Syndrome (CLS). HUS manifests as acute kidney injury (AKI), microangiopathic hemolytic anemia, and thrombocytopenia. Other symptoms can include pulmonary edema, hypertension, neurologic dysfunction, and cardiac abnormalities. The mechanism underlying immunotoxin-induced HUS is not well understood. CLS is a diagnosis of exclusion that manifests as hypotension, hypoalbuminemia, and hemoconcentration. Symptoms of CLS include fluid overload resulting in peripheral and pulmonary edema and weight gain. Immunotoxin-induced CLS is believed to result from toxin sequences that bind to vascular endothelial cells.

Primary support for the efficacy and safety of moxetumomab pasudotox for the treatment of HCL is provided by studies CD-ON-CAT-8015-1053 (CAT-1053) and CAT-8015-1001 (CAT-1001) in adults with relapsed/refractory HCL. Based on the renal safety findings in these studies, DHP has requested input from the Division of Cardiovascular and Renal Products regarding 1) whether the label should include a limitation of use for patients with moderate renal impairment and 2) whether there are any other measures that should be taken to mitigate the risk of adverse events related to renal impairment.

Materials Reviewed 1. Protocols for studies CAT-1053 and CAT-1001 2. Draft prescribing information submitted November 30, 2017 3. Summary of Clinical Safety

Reference ID: 4285471 Page 2 of 7

Study Designs CAT-1053 is an ongoing open-label, single-arm study in which 80 patients with relapsed or refractory HCL received moxetumomab pasudotox 40 µg/kg intravenously over a 30-minute period on Days 1, 3, and 5 of each 28-day cycle for up to 6 cycles until complete remission, progressive disease, initiation of alternative therapy, or unacceptable toxicity. Inclusion criteria included a serum creatinine ≤1.5 mg/dL or creatinine clearance (CrCL) ≥60 mL/min (Cockroft-Gault). The primary objective is to determine the rate of durable complete response in multiply relapsed HCL. As of the cutoff date for the Interim Clinical Study Report dated May 24, 2017, enrollment was complete with 80 subjects enrolled and receiving at least one dose of study drug. Fifty subjects have completed six cycles of treatment. None remain on treatment.

CAT-1001 was an open-label, single-arm, dose-escalation study in which 49 patients with relapsed or refractory HCL received moxetumomab pasudotox 5 to 50 µg/kg intravenously over a 30-minute period on Days 1, 3, and 5 of each 28-day cycle for up to 6 cycles until complete remission, progressive disease, initiation of alternate therapy, unacceptable toxicity, or the development of neutralizing antibodies. Exclusion criteria included a CrCL of ≤60 mL/min. Primary objectives included identification of the maximum tolerated dose and characterization of the toxicity profile of moxetumomab pasudotox. All subjects discontinued treatment before completion of 6 cycles, mostly because of the development of neutralizing antibodies.

For both studies, subjects were to receive intravenous fluids prior to and after each moxetumomab pasudotox infusion. For CAT-1053, subjects were expected to drink at least 3 liters of fluid/day on Days 0 to 8 of each cycle. For CAT-1001, subjects were encouraged to “drink plenty of fluids to maintain a steady and elevated urine output.”

For CAT-1053, serum chemistries were assessed at screening, pre-cycle, and on Days 1, 3, 5, 8, 15, and 21 of each treatment cycle. For CAT-1001, serum chemistries were assessed at screening, pre-cycle, daily on days 1 to 8, and on days 11, 14, 21, and 28 of each cycle. Adverse Events of Special Interest included HUS, CLS, and nephrotoxicity (including blood creatinine increased). In addition, the applicant implemented a process to identify potential cases of HUS or CLS based on adverse events and/or laboratory or diagnostic findings that may not have been identified and reported by the investigator.

Changes in serum creatinine were graded using the Common Terminology for Adverse Events (CTCAE Version 4.03): Grade 1 (>ULN-1.5xULN), Grade 2 (>1.5-3.0xULN), Grade 3 (>3.0-6.0xULN); and Grade 4 (>6.0xULN).

Overview of Select Safety Findings Overview Of the 129 subjects enrolled in CAT-1053 and CAT-1001 (“Primary HCL population”), 128 (99%) subjects had at least one adverse event and 34 (26%) had at least one SAE. Seven subjects died during the study related to underlying disease (n=5) or an AE (n=2; septic shock and pneumonia). The most common AEs were “edema peripheral” (41%) and hypoalbuminemia (40%). In addition, edema was reported for 17 (13%) subjects and face edema was reported for 13 (10%) subjects.

Changes in Renal Function Median baseline serum creatinine was 0.9 mg/dL. According to the applicant, at baseline, 82 (64%) subjects had a CrCl ≥ 90 mL/min (“normal renal function”), 43 (33%) had a CrCl of 60 to 89 mL/min (“mild renal impairment”), and four had a CrCl of 30 to 59 mL/min (“moderate renal impairment”).

As shown in Table 1, 37 (29%) subjects were reported to have a “nephrotoxicity”-related adverse event, most often blood creatinine increased (22 [17%]). All of the blood creatinine increased events were Grade

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1 or 2 in severity (increase of up to 3xULN) and all were reported as recovered except two: a subject with HUS and CLS ((b) (6) ) and one with an isolated Grade 1 (increase up to 1.5xULN) event ((b) (6) ).

Table 1: Nephrotoxicity Adverse Events in Primary HCL Population (N=129)

Source: Applicant, Summary of Clinical Safety, Table 2.7.4.2.1.6-2.

Two subjects were reported to have Acute Kidney Injury (AKI) events of Grade 3 severity: one subject with baseline CKD stage 3, TLS, and a severe urinary tract infection ((b) (6) ) and one subject with HUS ((b) (6) ). Four subjects had renal-related SAEs: an event of renal failure associated with the use of nephrotoxic antimicrobial agents that led to treatment discontinuation ( (b) (6) ), acute kidney injury in the setting of sepsis ((b) (6) ), a “blood creatinine increased” associated with CLS ((b) (6) ), and blood creatinine increased and hematuria associated with an HUS-like event that led to treatment discontinuation ((b) (6) ). One additional subject discontinued treatment for a renal-related AE, a nonserious event of “blood creatinine increased” associated with HUS ( (b) (6) ).

Of subjects without baseline creatinine abnormalities (Grade 0), 46 (37%) had a worst on-treatment grade of at least Grade 1 and 9 (7%) had a worst on treatment grade of Grade 2 or 3 (Figure 1). Both Grade 3 abnormalities were during SAEs of HUS ((b) (6) and (b) (6) ). One subject with a baseline Grade 1 abnormality had a worst on-treatment grade of Grade 2. At the end of treatment, 20 (16%) subjects had a toxicity grade worse than baseline. Four of these were Grade 2: one related to HUS ((b) (6) ), one in a subject with baseline CKD that was associated with sepsis ((b) (6) ), and two subjects who were treated for pneumonia with concomitant antibiotics and antifungal agents associated with nephrotoxicity before the development of serum creatinine elevations (b) (6) and (b) (6) ). One subject had severe HUS and CLS and required plasmapheresis and hemodialysis. We could not locate additional details regarding this case.

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Figure 1: Change in Creatinine Toxicity Grade – Worst on Treatment and End of Treatment Worst on Baseline Toxicity Grade Treatment 0 1 0 77 (63%) 0 1 37 (30%) 3 (75%) 2 7 (6%) 1 (25%) 3 2 (2%) 0 Total 123 (100%) 4 (100%) End of Baseline Toxicity Grade Treatment 0 1 0 103 (84%) 3 (75%) 1 16 (13%) 0 2 3 9(3%) 1 (25%) Total 122 (100%) 4 (100%) Source: Applicant, Summary of Clinical Safety, Table 2.7.4.2.1.6-12.

Mean serum creatinine trended higher over the course of the trial (Figure 1), although standard deviations at later timepoints are large. According to the applicant, at the end of treatment, serum creatinine levels remained elevated at 1.5- to 3x ULN in four (5%) subjects. In Study 1053, the median end of treatment CrCL was higher among subjects without HUS (89 mL/min, range: 42 to 195) compared to subjects with HUS (76 mL/min, range: 19 to 96).

Figure 2: Change from Baseline Over Time in Serum Creatinine

Source: Applicant, Summary of Clinical Safety, 2.7.4.3.2.1-1.

Capillary Leak Syndrome (CLS) CLS was reported for 16 (12%) subjects, and the applicant identified one additional case. An SAE of CLS was reported for four (3%) subjects. Two subjects permanently discontinued treatment because of CLS. All 17 subjects with CLS recovered with a median time to resolution of 12 days (range 1 to 53 days).

Hemolytic Uremic Syndrome (HUS) HUS was reported for eight (6%) subjects, and all were SAEs. The applicant identified one additional case. HUS was the most common event leading to study drug discontinuation (6 [5%]). All nine subjects with HUS were reported as recovered with the median time to resolution of 11.5 days (range 2 to 44 days).

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Monitor renal function prior to each infusion of TRADENAME, and as clinically indicated throughout treatment. Delay TRADENAME dosing in patients with Grade ≥ 3 elevations in creatinine, or upon worsening from baseline by ≥ 2 grades [see Dosage and Administration (2.3)].”

Consult Question Please assess the safety data for moxetumomab pasudotox related to CLS, HUS, edema, electrolyte abnormalities and nephrotoxicity events reported in the pivotal trial CAT-1053 (pivotal HCL population) and in the primary HCL population submitted in the integrated summary of safety. Please address specifically the following in your review:

1. Given the safety profile of moxetumomab infusion and the requirement for hydration, should the label include a limitation of use for patients with moderate renal impairment?

DCRP Response: In studies of patients with HCL and relatively preserved renal function (CrCl ≥60 mL/min), moxetumomab pasudotox treatment was associated with acute nephrotoxicity. The more clinically meaningful events (i.e., those reported as renal failure, SAEs, AEs leading to treatment discontinuation, and events requiring dialysis) were generally associated with other drug- induced complications including HUS, CLS, or TLS, sepsis, or concomitant administration of drugs that are known to be nephrotoxic. The events were largely reversible with discontinuation of treatment and supportive care. The applicant has proposed labeling that recommends monitoring of renal function before each dose and between treatment cycles and includes recommendations for stopping drug based on changes in renal function

Because of the entry criteria, the applicant has limited data in patients with a CrCl <60 mL/min; only four subjects had a baseline CrCl of 30 to <60 mL/min and no subject had a baseline CrCL of <30 mL/min. The proposed label states that moxetumomab pasudotox is not recommended in patients (b) (4) with severe renal impairment (CLcr ≤29 mL/min). We offer the following general comments on issues that that should be considered when deciding how to approach labeling for patients with reduced renal function. From a safety perspective, patients with reduced renal function may be more susceptible to renal-related toxicities, and they are likely to have less reserve if toxicity occurs. In addition, patients with low levels of renal function may not be able to handle the fluids administered concomitantly with the drug. However, whether use of the drug should be discouraged below some level of renal function depends on the balance of potential benefits and harms in the population and the ability to mitigate these harms via monitoring. If DHP believes moxetumomab pasudotox provides an important benefit relative to other available therapies for HCL, it may be reasonable to note the lack of data in patients with moderate to severe renal impairment and the potential for increased toxicity but not otherwise discourage use. If the label recommends against use below a certain level of renal function, the label should include a rationale for the statement.

2. Are there any other additional measures that should be taken to mitigate the risk of adverse events related to renal impairment and to ensure that the risks to subjects are reasonable?

We believe the applicant has proposed a reasonable strategy to monitor renal function and mitigate the risk of acute kidney injury.

Regarding the proposed Warning and Precaution for nephrotoxicity, we believe the proposed text should be revised to describe the context in which renal events were observed in the clinical studies (e.g., associated with HUS, CLS, sepsis, etc.) to give providers a better sense of the types of events observed and the settings in which they occurred.

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Finally, electrolyte-related adverse events were common, but the applicant has not proposed text in the label related to these findings. We recommend describing the electrolyte abnormalities in the label and recommending monitoring of relevant chemistry parameters.

Reference ID: 4285471 Signature Page 1 of 1 ------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/ ------

KIMBERLY A SMITH 07/01/2018

ALIZA M THOMPSON 07/02/2018

NORMAN L STOCKBRIDGE 07/02/2018

Reference ID: 4285471 MEMORANDUM

MEMO DATE: 05/01/2018

TO: To the file for BLA 761104

FROM: Matthew D Thompson, PhD, MPH Pharmacology-Toxicology Reviewer Division of Hematology Oncology Toxicology Office of Hematology and Oncology Products

THROUGH: Christopher M Sheth, PhD Pharmacology-Toxicology Supervisor Division of Hematology Oncology Toxicology Office of Hematology and Oncology Products

Recommendation AstraZeneca (Applicant) submitted BLA 761104 for moxetumomab pasudotox, also known as CAT-8015 and GCR-8015, a new biological (a CD22-directed immunotoxin) for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who received at least two prior systemic therapies, including treatment with a purine nucleoside analog. The Applicant submitted a waiver request for an embryofetal development (EFD) toxicity study and an enhanced pre- and postnatal development (ePPND) toxicity study for moxetumomab pasudotox. A recommendation for waiving the EFD and ePPND studies is based on the Guidance for Industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. S9 states that:

For biopharmaceuticals, an assessment in one pharmacologically relevant species should usually be sufficient. This assessment might be done by evaluating the toxicity during the period of organogenesis or study designs as described by ICH S6. Alternative approaches might be considered appropriate if scientifically justified. The alternative approaches might include a literature assessment, assessment of placental transfer, the direct or indirect effects of the biopharmaceutical, or other factors.

A study of fertility and early embryonic development is not warranted to support clinical trials or for marketing of pharmaceuticals intended for the treatment of patients with advanced cancer. Information available from general toxicology studies on the pharmaceutical’s effect on reproductive organs should be used as the basis of the assessment of impairment of fertility.

A pre- and postnatal toxicology study is generally not warranted to support clinical trials or for marketing of pharmaceuticals for the treatment of patients with advanced cancer.

Based on S9, the ePPND is not warranted for marketing of moxetumomab pasudotox for the relapsed or refractory HCL indication.

Based on our review of the Applicant’s scientific justification for waiving an EFD toxicity study, Pharmacology/Toxicology agrees with the Applicant's request to waive an EFD study with moxetumomab pasudotox for the relapsed or refractory HCL indication. The

Reference ID: 4256518 BLA # 761104 Reviewer: Matthew D Thompson, PhD, MPH

Pharmacology/Toxicology recommendation is primarily based on the first four considerations discussed below (see Pharmacology/Toxicology Comments): 1) the patient population; 2) the lack of adverse findings in reproductive organs/tissues in cynomolgus monkeys; 3) the lack of reproductive tissue cross reactivity; and 4) the biophysical properties of moxetumomab pasudotox. The remaining two considerations were only weakly supportive of the waiver request.

Background Drug Information Moxetumomab pasudotox is a CD22-directed immunotoxin. Moxetumomab pasudotox (approximately 63 kDa) is composed of an immunoglobulin light chain variable domain (VL) and a heavy chain variable domain (VH) genetically fused to a truncated form of Pseudomonas exotoxin, PE38. The VL and VH domains of moxetumomab pasudotox are derived from the murine anti-CD22 monoclonal antibody (b) (4) .

Figure 1. Moxetumomab Pasudotox Construct

(Excerpted from Applicant’s Submission)

Regulatory Background A Type C meeting occurred on December 14, 2016. The Applicant asked “Does the FDA agree with the Sponsor’s proposal to waive conduct of an embryofetal development toxicity study for moxetumomab pasudotox in the treatment of relapsed or refractory HCL patients?” The Agency responded “Your approach appears to be reasonable. You should include in the BLA all the nonclinical data and published literature used to support the waiver for not conducting the assessment of reproductive and developmental toxicity of moxetumomab for patients with hairy cell leukemia.”

Pharmacology/Toxicology Comments In the application for BLA 761104, AstraZeneca requested a waiver for conducting an EFD or ePPND toxicity study based on the following six considerations: 1) the patient population; 2) the absence of findings in reproductive organs and tissues of sexually mature cynomolgus monkeys treated with moxetumomab pasudotox for 13 weeks; 3) the results of a tissue cross reactivity study with moxetumomab pasudotox using panels of human and cynomolgus monkey tissue; 4) the biophysical properties of moxetumomab pasudotox and impact on placental transfer; 5) CD22 expression during B cell maturation in the embryo/fetus; and 2

Reference ID: 4256518 BLA # 761104 Reviewer: Matthew D Thompson, PhD, MPH

6) salient published non-clinical data related to cluster of differentiation 22 (CD22) knock-out mice. Each consideration is summarized, reviewed, and/or annotated by the nonclinical reviewer.

1) Patient population HCL predominantly affects older men. A monograph published in JNCI notes HCL affects individuals “with a median age of 55 years and sex ratio of 3.7 males to females”.1 Table 1: Demographics from Pivotal CAT-8015-1053 Phase 3 Trial

(Excerpted from Applicant’s AOM Presentation)

[Reviewer Comment: HCL is a rare disease affecting older individuals, tending to be male. Therefore, the patient population treated with moxetumomab pasudotox will be primarily older males and post-menopausal females. The Applicant’s first justification to waive an EFD toxicity study is reasonable.]

2) Reproductive organs and tissues of sexually mature cynomolgus monkeys treated with moxetumomab pasudotox for 13 weeks

Study title: A 13-Week Repeat-Dose (3X weekly) Intravenous Bolus Toxicity, Toxicokinetics, and Pharmacodynamics Study with CAT-8015 in Cynomolgus Monkeys with a 6-Week Recovery Period Study no.: 20009858 Study report location: 4.2.3.2 (b) (4) Conducting laboratory and location:

Date of study initiation: February 15. 2011 GLP compliance: Yes QA statement: Yes Drug, lot #, and % purity: CAT-8015, Lot # G10900B103, 98.3% (SEC for monomer)

1 Monnereau A, et al. Medical history, lifestyle, and occupational risk factors for hairy cell leukemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014 Aug;2014(48):115-24. 3

Reference ID: 4256518 BLA # 761104 Reviewer: Matthew D Thompson, PhD, MPH

Key Study Findings  All animals assigned to the study were reported to be sexually mature  No adverse reproductive histopathological findings were noted

Methods Doses: 0, 0.135, 0.405, or 1.35 mg/kg Frequency of dosing: 3 times per week for 13 weeks Route of administration: Intravenous Dose volume: 5 mL/kg Formulation/Vehicle: 0.65% (w/v) NaCl, 0.62 mM citrate, 6.25 mM sodium phosphate, 1.00% (w/v) sucrose, 2.00% (w/v) glycine, 0.0210% (w/v) polysorbate 80, pH 7.4 Species/Strain: Cynomolgus monkey Number/Sex/Group: 5/sex/group Age: 5.5 to 7.5 years of age (males) 4.3 to 9.2 years of age (females) Weight: 5.3 to 7.0 kg (males) 2.8 to 4.1 kg (females)

Table 2: Design of Monkey Study

(Excerpted from Applicant’s Submission)

Gross Pathology for Reproductive Organs Unremarkable

Histological Findings for Reproductive Organs Moxetumomab pasudotox did not result in adverse findings in reproductive organs in cynomolgus monkeys.

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Reference ID: 4256518 BLA # 761104 Reviewer: Matthew D Thompson, PhD, MPH

Table 3: Reproductive Histopathology in the Monkey

[Reviewer Comment: The Applicant’s second justification to waive an EFD toxicity study is reasonable based on a lack of adverse histopathological findings in monkey reproductive tissues. The monkeys were sexually mature and the evaluated reproductive organs included mammary gland, epididymis, prostate, seminal vesicle, testis, cervix, ovary, oviduct, uterus, and vagina.]

3) Tissue Cross Reactivity

Study title: Study to Assess the Potential Cross Reactivity of GCR-8015 with a Selected Panel of Human and Cynomolgus Tissues Study no.: 2563-001 Study report location: 4.2.3.7.7 (b) (4) Conducting laboratory and location:

Date of study initiation: August 10, 2005 GLP compliance: Yes QA statement: Yes Drug, lot #: GCR-8015, Lot # 05001

5

Reference ID: 4256518 BLA # 761104 Reviewer: Matthew D Thompson, PhD, MPH

The potential for GCR-8015 tissue cross reactivity was assessed in histologically prepared, acetone-fixed cryo-sections from a panel of human and cynomolgus monkey tissues. In human tissues:  There was specific positive staining of B-cells in a number of tissues  Pituitary tissue samples from three donors showed specific diffuse positive staining of individual cells within the pituitary. The specific cell type in the pituitary could not be determined.  Brain (cortex and cerebellum) and spinal cord tissue samples had diffuse non- granular staining present within the white matter (test facility considered the staining to be non-specific).  There was no specific immunohistochemical staining of any other cell types or tissues

Similar findings were reported for B-cell, brain, and spinal cord in cynomolgus monkey tissues. There was no specific immunohistochemical staining of any other cell types or tissue structures in the cynomolgus monkey tissue panel.

[Reviewer Comment: Reproductive organs were not cross reactive with moxetumomab pasudotox. The human tissue panel included breast, fallopian tube, ovary, placenta, prostate, testis, and uterus (cervix and endometrium). The cynomolgus monkey tissue panel included breast, fallopian tube, ovary, prostate, testis, and uterus (cervix and endometrium). The Applicant’s third justification to waive an EFD toxicity study is reasonable based on a lack cross reactivity in human and monkey reproductive tissues.]

4) Biophysical properties of moxetumomab pasudotox and impact on placental transfer  Drugs > 500 Da, as well as acidic drugs at physiologic pH, tend to show incomplete placental transfer.2 Moxetumomab pasudotox is approximately 63 kDa and has an isoelectric point of approximately 5.0 (i.e., acidic protein with negative charge at physiologic pH).  Moxetumomab pasudotox is a disulfide-stabilized Fv, lacking an Fc region. The Fc portion of IgG antibodies is required for placental transfer by the neonatal Fc receptor (FcRN).  Moxetumomab pasudotox has a short half-life (1-2 hours) limiting maternal-fetal exposure, and it is internalized upon binding to CD22.  The toxin domain is genetically fused to the Fv and is released inside the cell following intracellular protease processing.  The toxin domain has a molecular weight >500 Da.

[Reviewer Comment: The Applicant’s fourth justification to waive an EFD toxicity study is reasonable based on the biophysical properties of moxetumomab pasudotox that reduce the likelihood of meaningful fetal exposure.]

2 Pacifici GM, Nottoli R. Placental transfer of drugs administered to the mother. Clin Pharmacokinet. 1995 Mar;28(3):235-69. 6

Reference ID: 4256518 BLA # 761104 Reviewer: Matthew D Thompson, PhD, MPH

5) CD22 expression during B cell maturation in the embryo/fetus The Applicant’s analysis of the literature (primarily Boffil et al.3 and Janossy et al.4) highlights the relative lack of CD22 expression prior to 14 weeks of gestation.

[Reviewer Comment: The lack of CD22 expression would decrease the likelihood of on- target developmental toxicity with moxetumomab pasudotox.]

6) Cluster of differentiation 22 (CD22) knock-out mice CD22 is a B-lymphocyte restricted transmembrane protein. CD22 knock-out (KO) mice are fertile and grossly normal.5 The Applicant’s discussion of the phenotype of mice deficient in CD22 highlights changes to B-cell receptor signaling leading to hypersensitivity, changes in B-cell lifespan, and enhanced rates of apoptosis in B-cells.

[Reviewer Comment: The applicability of the KO phenotype to assessing the potential for developmental toxicity with moxetumomab pasudotox is limited. The KO animals are permanently deficient in CD22 whereas moxetumomab pasudotox treatment will result in transient effects on CD22+ B-cells. In the repeat dose toxicology study in the cynomolgus monkey, moxetumomab pasudotox depleted B-cells. During the recovery phase, B-cell depletion was noted to be reversible.]

3 Bofill M, Janossy G, Janossa M, Burford GD, Seymour GJ, Wernet P, Kelemen E. Human B cell development. II. Subpopulations in the human fetus. J Immunol. 1985 Mar;134(3):1531-8. 4 Janossy G, Caligaris-Cappio F, Bofill M, Campana D, Janossa M. Development of B cell subpopulations in humans and its relevance to malignancy. Haematol Blood Transfus. 1985; 29:461-70. 5 Otipoby KL, Andersson KB, Draves KE, Klaus SJ, Farr AG, Kerner JD, Perlmutter RM, Law CL, Clark EA. CD22 regulates thymus- independent responses and the lifespan of B cells. Nature. 1996 Dec 19-26;384(6610):634-7. 7

Reference ID: 4256518 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------

MATTHEW D THOMPSON 05/01/2018

CHRISTOPHER M SHETH 05/01/2018

Reference ID: 4256518