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214622Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 214622Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA214622 Multi‐disciplinary Review and Evaluation Infigratinib (Truseltiq) NDA/BLA Multi‐disciplinary Review and Evaluation FDA review was conducted in conjunction with other regulatory authorities under a regular ORBIS. While the application review is completed by the FDA, the application is still under review at the other regulatory agencies (Health Canada and Therapeutic Goods Administration). Disclaimer: In this document, the sections labeled as “Data” and “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) 214622 Priority or Standard Priority Submit Date(s) September 29, 2020 Received Date(s) September 29, 2020 PDUFA Goal Date May 29, 2021 Division/Office OOD/DO3 Review Completion Date Please check electronic date stamp Established Name Infigratinib Trade Name Truseltiq Pharmacologic Class FGFR Inhibitor Code name BGJ398 Applicant QED Therapeutics, Inc. Formulation(s) Oral capsule Dosing Regimen 125 mg orally once daily for 21 consecutive days followed by 7 days off therapy, in 28‐day cycles Applicant Proposed The treatment of adult patients with previously treated, Indication(s)/Population(s) unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or other rearrangement as detected by an FDA approved test. Recommendation on Approval Regulatory Action Recommended For the treatment of adults with previously treated, Indication(s)/Population(s) unresectable locally advanced or metastatic (if applicable) cholangiocarcinoma with an FGFR2 fusion or other rearrangement as detected by an FDA‐approved test. 1 Version date: January 2020 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4802513 NDA214622 Multi‐disciplinary Review and Evaluation Infigratinib (Truseltiq) Table of Contents Reviewers of Multi‐Disciplinary Review and Evaluation .............................................................. 11 Additional Reviewers of Application ........................................................................................... 11 Glossary ...................................................................................................................................... 13 1 Executive Summary .............................................................................................................. 16 Product Introduction .................................................................................................... 16 Conclusions on the Substantial Evidence of Effectiveness ............................................ 16 Benefit‐Risk Assessment (BRA) ..................................................................................... 18 Patient Experience Data ............................................................................................... 26 2 Therapeutic Context ............................................................................................................ 27 Analysis of Condition .................................................................................................... 27 Analysis of Current Treatment Options ........................................................................ 30 3 Regulatory Background ........................................................................................................ 3 7 U.S. Regulatory Actions and Marketing History ............................................................ 37 Summary of Presubmission/Submission Regulatory Activity ........................................ 37 4 Significant Issues from Other Review Disciplines Pertinent to Clinical Conclusions on Efficacy and Safety ............................................................................................................... 39 Office of Scientific Investigations (OSI) ......................................................................... 39 Product Quality ............................................................................................................. 39 Clinical Microbiology .................................................................................................... 40 Devices and Companion Diagnostic Issues ................................................................... 40 5 Nonclinical Pharmacology/Toxicology ................................................................................. 41 Executive Summary ...................................................................................................... 41 Referenced NDAs, BLAs, DMFs ..................................................................................... 43 Pharmacology ............................................................................................................... 43 ADME/PK ...................................................................................................................... 4 7 Toxicology ..................................................................................................................... 49 General Toxicology ................................................................................................ 49 2 Version date: January 2020 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4802513 NDA214622 Multi‐disciplinary Review and Evaluation Infigratinib (Truseltiq) Genetic Toxicology ................................................................................................ 65 Carcinogenicity ...................................................................................................... 66 Reproductive and Developmental Toxicology ....................................................... 66 Other Toxicology Studies ....................................................................................... 74 6 Clinical Pharmacology .......................................................................................................... 76 Executive Summary ...................................................................................................... 76 Recommendations................................................................................................. 76 Post‐Marketing Requirements and Commitments ................................................ 78 Summary of Clinical Pharmacology Assessment ........................................................... 82 Pharmacology and Clinical Pharmacokinetics ........................................................ 82 General Dosing and Therapeutic Individualization ................................................ 85 6.2.2.1. General Dosing ............................................................................................... 85 6.2.2.2. Therapeutic Individualization ......................................................................... 91 6.2.2.3. Outstanding Issues ......................................................................................... 97 Comprehensive Clinical Pharmacology Review ............................................................. 97 General Pharmacology and Pharmacokinetic Characteristics ................................ 97 Clinical Pharmacology Questions ......................................................................... 105 7 Sources of Clinical Data ...................................................................................................... 114 Table of Clinical Studies .............................................................................................. 114 8 Statistical and Clinical Evaluation ....................................................................................... 125 Review of Relevant Individual Trials Used to Support Efficacy ................................... 125 Study CBGJ398X2204 ........................................................................................... 125 Study Results ....................................................................................................... 134 Integrated Review of Effectiveness ..................................................................... 156 Assessment of Efficacy Across Trials .................................................................... 156 Integrated Assessment of Effectiveness .............................................................. 157 Review of Safety ......................................................................................................... 158 Safety Review Approach ...................................................................................... 159 Review of the Safety Database ............................................................................ 160 Adequacy of Applicant’s Clinical Safety Assessments .......................................... 168 3 Version date: January 2020 (ALL NDA/ BLA reviews) Disclaimer: In this document, the sections labeled as “Data” and “The Applicant’s Position” are completed by the Applicant and do not necessarily reflect the positions of the FDA. Reference ID: 4802513 NDA214622 Multi‐disciplinary Review
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