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210867Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210867Orig1s000 CLINICAL REVIEW(S) Clinical Review Hiwot Hiruy, MD, PhD NDA 210867 Moxidectin CLINICAL REVIEW Application Type NDA Application Number 210867 Priority or Standard Priority Submit Date 10/13/17 Received Date 10/13/17 PDUFA Goal Date 06/13/18 Division/Office Division of Anti-Infective Products/Office of Antimicrobial Products Reviewer Name Hiwot Hiruy, MD, PhD Review Completion Date 04/06/2018 Established/Proper Name Moxidectin (Proposed) Trade Name Not proposed Applicant Medicines Development for Global Health Dosage Form 2mg Tablet Applicant Proposed Dosing 8mg (Four 2mg Tablets) Single Oral Dose Regimen Applicant Proposed Treatment of onchocerciasis due to Onchocerca volvulus in Indication(s)/Population(s) patients aged 12 years and older Recommendation on Approval Regulatory Action Recommended Treatment of onchocerciasis due to Onchocerca volvulus in Indication/Population patients aged 12 years and older CDER Clinical Review Template 1 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4259603 Clinical Review Hiwot Hiruy, MD, PhD NDA 210867 Moxidectin Table of Contents Glossary ......................................................................................................................................... 10 1. Executive Summary ............................................................................................................... 12 Product Introduction ...................................................................................................... 12 Conclusions on the Substantial Evidence of Effectiveness ............................................ 12 Benefit-Risk Assessment ................................................................................................ 13 Patient Experience Data ................................................................................................. 16 2. Therapeutic Context .............................................................................................................. 16 Analysis of Condition ...................................................................................................... 16 Analysis of Current Treatment Options ......................................................................... 19 3. Regulatory Background ......................................................................................................... 21 U.S. Regulatory Actions and Marketing History ............................................................. 21 Summary of Presubmission/Submission Regulatory Activity ........................................ 22 Foreign Regulatory Actions and Marketing History ....................................................... 22 4. There have not been foreign submissions for marketing status. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............. 22 Office of Scientific Investigations (OSI) .......................................................................... 23 Product Quality .............................................................................................................. 23 Clinical Microbiology ...................................................................................................... 23 Nonclinical Pharmacology/Toxicology ........................................................................... 24 Clinical Pharmacology .................................................................................................... 25 Devices and Companion Diagnostic Issues .................................................................... 27 Consumer Study Reviews ............................................................................................... 27 5. Sources of Clinical Data and Review Strategy ....................................................................... 27 Table of Clinical Studies .................................................................................................. 27 Review Strategy .............................................................................................................. 30 6. Review of Relevant Individual Trials Used to Support Efficacy ............................................. 30 Primary Endpoint for Phase 2 and 3 Trials ..................................................................... 30 Phase 2 Study (NCT00300768) ....................................................................................... 31 CDER Clinical Review Template 2 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4259603 Clinical Review Hiwot Hiruy, MD, PhD NDA 210867 Moxidectin Study Design............................................................................................................ 31 Study Results ........................................................................................................... 34 Phase 3 Trial (NCT00790998) ......................................................................................... 40 Study Design............................................................................................................ 40 Study Results ........................................................................................................... 45 7. Integrated Review Effectiveness ........................................................................................... 57 Assessment of Efficacy Across Trials .............................................................................. 58 Primary Endpoints ................................................................................................... 58 Secondary and Other Endpoints ............................................................................. 58 Subpopulations ....................................................................................................... 59 Dose and Dose-Response........................................................................................ 59 Onset, Duration, and Durability of Efficacy Effects ................................................ 59 Additional Efficacy Considerations ................................................................................. 59 Considerations on Benefit in the Postmarket Setting ............................................ 60 Integrated Assessment of Effectiveness ........................................................................ 60 8. Review of Safety .................................................................................................................... 60 Safety Review Approach ................................................................................................ 60 Review of the Safety Database ...................................................................................... 61 Overall Exposure ..................................................................................................... 61 Relevant characteristics of the safety population: ................................................. 62 Adequacy of the safety database: .......................................................................... 62 Adequacy of Applicant’s Clinical Safety Assessments .................................................... 63 Issues Regarding Data Integrity and Submission Quality ....................................... 63 Categorization of Adverse Events ........................................................................... 63 Routine Clinical Tests .............................................................................................. 64 Safety Results ................................................................................................................. 64 Deaths ..................................................................................................................... 64 Serious Adverse Events ........................................................................................... 66 Dropouts and/or Discontinuations Due to Adverse Effects ................................... 69 Significant Adverse Events ...................................................................................... 70 CDER Clinical Review Template 3 Version date: September 6, 2017 for all NDAs and BLAs Reference ID: 4259603 Clinical Review Hiwot Hiruy, MD, PhD NDA 210867 Moxidectin Treatment Emergent Adverse Events and Adverse Reactions ............................... 70 Laboratory Findings ................................................................................................ 77 Vital Signs ................................................................................................................ 95 QT Study ................................................................................................................ 101 Immunogenicity .................................................................................................... 103 Analysis of Submission-Specific Safety Issues .............................................................. 104 Mazzotti Reaction ................................................................................................. 104 Subgroup Analysis by Body Mass Index (BMI) ...................................................... 107 Subgroup Analysis by Baseline Mean O. volvulus Microfilariae Density .............. 107 Subgroup Analysis for Nervous System Adverse Events ...................................... 108 Phase 3 Subgroup Analysis by baseline hepatobiliary disease ............................
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