CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211801Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA/BLA Multidisciplinary Review and Evaluation NDA 211801 IBSRELA (tenapanor) NDA/BLA Multidisciplinary Review and Evaluation Application Type New Drug Application (NDA) Application Number(s) 211801 (IND #108,732) Priority or Standard Standard Submit Date(s) 09/12/2018 Received Date(s) 09/12/2018 PDUFA Goal Date 09/12/2019 Division/Office Division of Gastroenterology and Inborn Errors Products (DGIEP)/ Office of Drug Evaluation III (ODE III) Review Completion Date 09/10/2019 Established/Proper Name Tenapanor (RDX5791; AZD1722) (Proposed) Trade Name Ibsrela Pharmacologic Class Sodium/hydrogen exchanger 3 (NHE3) inhibitor Code name Applicant Ardelyx, Inc. Dosage form Oral tablets Applicant proposed Dosing 50 mg orally twice daily Regimen Applicant Proposed Treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in Indication(s)/Population(s) Adults Applicant Proposed 440630006 SNOMED CT Indication Disease Term for each Proposed Indication Recommendation on Approval Regulatory Action Recommended Treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in Indication(s)/Population(s) Adults (if applicable) Recommended Dosing 50 mg orally twice daily Regimen i Version date: September 12, 2018 Reference ID: 4490899 NDA/BLA Multidisciplinary Review and Evaluation NDA 211801 IBSRELA (tenapanor) Table of Contents Table of Tables ..................................................................................................................... v Table of Figures .................................................................................................................... x Reviewers of Multidisciplinary Review and Evaluation ...................................................... 1 Glossary ............................................................................................................................... 3 1. Executive Summary ......................................................................................................... 5 1.1. Product Introduction ................................................................................................ 5 1.2. Conclusions on the Substantial Evidence of Effectiveness ...................................... 5 1.3. Benefit-Risk Assessment .......................................................................................... 7 1.4. Patient Experience Data ......................................................................................... 10 2. Therapeutic Context ..................................................................................................... 11 2.1. Analysis of Condition .............................................................................................. 11 2.2. Analysis of Current Treatment Options ................................................................. 12 3. Regulatory Background ................................................................................................. 15 3.1. U.S. Regulatory Actions and Marketing History ..................................................... 15 3.2. Summary of Presubmission/Submission Regulatory Activity ................................ 15 4. Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................. 19 4.1. Office of Scientific Investigations ........................................................................... 19 4.2. Product Quality....................................................................................................... 19 4.3. Clinical Outcomes Assessment ............................................................................... 20 5. Nonclinical Pharmacology/Toxicology .......................................................................... 21 5.1. Executive Summary ................................................................................................ 21 5.2. Referenced NDAs, BLAs, DMFs ............................................................................... 24 5.3. Pharmacology ......................................................................................................... 24 5.3.1. Secondary Pharmacology ................................................................................ 26 5.3.2. Safety Pharmacology ....................................................................................... 26 5.4. ADME/PK ................................................................................................................ 27 5.5. Toxicology ............................................................................................................... 27 5.5.1. General Toxicology .......................................................................................... 27 5.5.2. Genetic Toxicology ........................................................................................... 31 5.5.3. Carcinogenicity ................................................................................................ 31 5.5.4. Reproductive and Developmental Toxicology ................................................. 31 5.5.5. Juvenile Toxicology Studies ............................................................................. 39 6. Clinical Pharmacology ................................................................................................... 41 6.1. Executive Summary ................................................................................................ 41 6.1.1. Recommendations ........................................................................................... 41 ii Version date: September 12, 2018 Reference ID: 4490899 NDA/BLA Multidisciplinary Review and Evaluation NDA 211801 IBSRELA (tenapanor) 6.2. Summary of Clinical Pharmacology Assessment .................................................... 41 6.2.1. Pharmacology and Clinical Pharmacokinetics ................................................. 41 6.2.2. General Dosing and Therapeutic Individualization ......................................... 42 6.3. Comprehensive Clinical Pharmacology Review ..................................................... 43 6.3.1. General Pharmacology and Pharmacokinetic Characteristics ......................... 43 6.3.2. Clinical Pharmacology Questions .................................................................... 44 7. Sources of Clinical Data and Review Strategy ............................................................... 48 7.1. Table of Clinical Studies .......................................................................................... 48 7.2. Review Approach .................................................................................................... 50 7.3. Data Integrity .......................................................................................................... 50 8. Review of Relevant Individual Trials Used to Support Efficacy and Safety .................. 51 8.1. Study Design of Key Studies That Support Approval ............................................. 51 8.1.1. Phase 3 Studies: TEN-01-301 (Study 301) and TEN-01-302 (Study 302) ......... 51 8.1.2. Safety Extension: TEN-01-303 (Study 303) ...................................................... 56 9. Review of Efficacy ......................................................................................................... 56 9.1.1. TEN-01-301 (Study 301) Results ...................................................................... 57 9.1.2. TEN-01-302 (Study 302) Results ...................................................................... 66 10. Review of Safety .......................................................................................................... 75 10.1. Safety Review Approach....................................................................................... 75 10.1.1. Overall Exposure ............................................................................................ 78 10.1.2. Demographics / Adequacy of the Safety Population .................................... 79 10.1.3. Categorization of Adverse Events .................................................................. 80 10.2. Safety Result ......................................................................................................... 82 10.2.1. Overall Rates of Adverse Events .................................................................... 82 10.2.2. Dropouts and/or Discontinuations Due to Adverse Effects .......................... 82 10.2.3. Deaths ............................................................................................................ 83 10.2.4. Serious Adverse Events .................................................................................. 83 10.2.5. Common Adverse Events ............................................................................... 83 10.2.6. Adverse Events of “Severe” Intensity ............................................................ 85 10.2.7. Laboratory Findings ....................................................................................... 85 10.2.8. Adverse Events of Special Interest ................................................................ 95 10.2.9. Other Safety Evaluation (Vital Signs, Cardiovascular safety) ...................... 100 10.2.10.