CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 214621Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multi-disciplinary Review and Evaluation: NDA 214, 621 Relugolix NDA/BLA Multi-disciplinary Review and Evaluation Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant, which do not necessarily reflect the positions of the FDA. Application Type NDA Application Number(s) NDA 214621 Priority or Standard Priority Submit Date(s) April 20, 2020 Received Date(s) April 20, 2020 PDUFA Goal Date December 20, 2020 Division/Office OND/CDER/OOD/DO1 Review Completion Date Established Name Relugolix (b) (4) (Proposed) Trade Name Pharmacologic Class Gonadotropin-releasing hormone (GnRH) receptor antagonist Code name TAK-385 Applicant Myovant Sciences, Inc. Formulation(s) oral tablet Dosing Regimen One time loading dose of 360 mg followed by 120 mg daily Applicant Proposed RELUGOLIX is a gonadotropin-releasing hormone Indication(s)/Population(s) (GnRH) antagonist indicated for the treatment of patients with advanced prostate cancer. Recommendation on Regular approval Regulatory Action Recommended RELUGOLIX is a gonadotropin-releasing hormone Indication(s)/Population(s) (GnRH) antagonist indicated for the treatment of (if applicable) patients with advanced prostate cancer. 1 Version date: January 2020 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4719259 NDA/BLA Multi-disciplinary Review and Evaluation: NDA 214, 621 Relugolix Table of Contents Reviewers of Multi-Disciplinary Review and Evaluation ................................................... 8 Additional Reviewers of Application ................................................................................. 8 Glossary ...................................................................................................................... 9 1 Executive Summary .................................................................................... 12 1.1. Product Information ................................................................................... 12 1.2. Conclusions on the Substantial Evidence of Effectiveness ......................... 12 1.3. Benefit-Risk Assessment (BRA) ................................................................... 15 1.4. Patient Experience Data ............................................................................. 19 2 Therapeutic Context ................................................................................... 21 2.1. Analysis of Condition .................................................................................. 21 2.2. Analysis of Current Treatment Options ...................................................... 22 3 Regulatory Background .............................................................................. 27 3.1. U.S. Regulatory Actions and Marketing History ......................................... 27 3.2. Summary of Presubmission/Submission Regulatory Activity ..................... 27 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................ 30 4.1. Office of Scientific Investigations ............................................................... 30 4.2. Product Quality ........................................................................................... 30 4.3. Clinical Microbiology .................................................................................. 30 4.4. Devices and Companion Diagnostic Issues ................................................. 30 5 Nonclinical Pharmacology/Toxicology ........................................................ 31 5.1. Executive Summary .................................................................................... 31 5.2. Referenced NDAs, BLAs, DMFs ................................................................... 34 5.3. Pharmacology ............................................................................................. 35 5.3.1. Primary Pharmacology ............................................................................... 35 5.3.2. Secondary Pharmacology ........................................................................... 36 5.3.3. Safety Pharmacology .................................................................................. 37 5.4. ADME/PK .................................................................................................... 38 5.5. Toxicology ................................................................................................... 45 5.5.1. General Toxicology ..................................................................................... 45 5.5.2. Genetic Toxicology ..................................................................................... 54 2 Version date: January 2020 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4719259 NDA/BLA Multi-disciplinary Review and Evaluation: NDA 214, 621 Relugolix 5.5.3. Carcinogenicity ........................................................................................... 55 5.5.4. Reproductive and Developmental Toxicology ............................................ 56 5.5.5. Other Toxicology Studies ............................................................................ 63 6 Clinical Pharmacology ................................................................................. 67 6.1. Executive Summary .................................................................................... 67 6.2. Summary of Clinical Pharmacology Assessment ........................................ 70 6.2.1. Pharmacology and Clinical Pharmacokinetics ............................................ 70 6.2.2. General Dosing and Therapeutic Individualization .................................... 75 6.2.2.1. General Dosing ........................................................................................... 75 6.2.2.2. Therapeutic Individualization ..................................................................... 79 6.2.2.3. Outstanding Issues ..................................................................................... 87 6.3. Comprehensive Clinical Pharmacology Review .......................................... 88 6.3.1. General Pharmacology and Pharmacokinetic Characteristics .................... 88 6.3.2. Clinical Pharmacology Questions ............................................................... 93 7 Sources of Clinical Data ............................................................................ 100 7.1. Table of Clinical Studies ............................................................................ 100 8 Statistical and Clinical Evaluation ............................................................. 105 8.1. Review of Relevant Individual Trials Used to Support Efficacy ................ 105 8.1.1. MVT-601-3201 .......................................................................................... 105 8.1.2. Study Results ............................................................................................ 113 8.1.3. C27003 ...................................................................................................... 138 8.1.4. Study Results ............................................................................................ 138 8.1.5. Integrated Review of Effectiveness (supplements only) .......................... 145 8.1.6. Assessment of Efficacy Across Trials ........................................................ 145 8.1.7. Integrated Assessment of Effectiveness ................................................... 148 8.2. Review of Safety ....................................................................................... 152 8.2.1. Safety Review Approach ........................................................................... 152 8.2.2. Review of Safety Database ....................................................................... 154 8.2.3. Adequacy of the Applicant’s Clinical Safety Assessments ........................ 159 8.2.4. Safety Results ........................................................................................... 163 8.2.5. Analysis of Submission-Specific Safety Issues .......................................... 188 8.2.6. Clinical Outcome Assessment (COA) Analyses Informing Safety/Tolerability .................................................................................................................. 188 3 Version date: January 2020 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4719259 NDA/BLA Multi-disciplinary Review and Evaluation: NDA 214, 621 Relugolix 8.2.7. Safety Analyses by Demographic Subgroups............................................ 188 8.2.8. Specific Safety Studies/Clinical Trials ....................................................... 190 8.2.9. Additional Safety Explorations ................................................................. 192 8.2.10.