Report on the Deliberation Results May 16, 2016 Pharmaceutical
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Report on the Deliberation Results May 16, 2016 Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau Ministry of Health, Labour, and Welfare Brand Name Kyprolis for Intravenous Injection 10 mg Kyprolis for Intravenous Injection 40 mg Non-proprietary Name Carfilzomib (JAN*) Applicant Ono Pharmaceutical Co., Ltd. Date of Application August 26, 2015 Results of Deliberation In its meeting held on April 25, 2016, the Second Committee on New Drugs concluded that the product may be approved and that this result should be presented to the Pharmaceutical Affairs Department of the Pharmaceutical Affairs and Food Sanitation Council. The re-examination period is 10 years. The product is not classified as a biological product or a specified biological product. The drug product and its drug substance are both classified as poisonous drugs. Conditions of approval 1. The applicant is required to develop and appropriately implement a risk management plan. 2. Because of limited number of subjects in Japanese clinical studies, the applicant is required to conduct a post-marketing drug use results survey covering all patients treated with the product until data from a specified number of patients are collected, in order to understand the characteristics of patients and to promptly collect safety and efficacy data of the product. Based on the collected data, necessary measures should be taken to ensure correct use of the product. *Japanese Accepted Name (modified INN) This English translation of this Japanese review report is intended to serve as reference material made available for the convenience of users. In the event of any inconsistency between the Japanese original and this English translation, the Japanese original shall take precedence. PMDA will not be responsible for any consequence resulting from the use of this reference English translation. Review Report April 13, 2016 Pharmaceuticals and Medical Devices Agency The following are results of the review of the following pharmaceutical product submitted for marketing approval conducted by the Pharmaceuticals and Medical Devices Agency (PMDA). Brand Name Kyprolis for Intravenous Injection 10 mg Kyprolis for Intravenous Injection 40 mg Non-proprietary Name Carfilzomib Applicant Ono Pharmaceutical Co., Ltd. Date of Application August 26, 2015 Dosage Form/Strength Powder for reconstitution for injection, each vial contains 10.7 mg or 42.6 mg of carfilzomib Application Classification Prescription drug, (1) Drug with a new active ingredient Chemical Structure Molecular formula: C40H57N5O7 Molecular weight: 719.91 Chemical name: N-{(2S)-2-[(Morpholin-4-ylacetyl)amino]-4-phenylbutanoyl}-L-leucyl-L-phenylalanin-N-{(2S)-4- methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl}amide Items Warranting Special Mention Orphan drug (Designation No.: [27 yaku] No. 363, dated August 20, 2015, issued by the Evaluation and Licensing Division, PFSB/ELD Notification No. 0820-1) Reviewing Office Office of New Drug V Results of Review On the basis of the data submitted, PMDA has concluded that the product has efficacy in the treatment of relapsed or refractory multiple myeloma, and that the product has acceptable safety in view of its benefits (see Attachment). As a result of its review, PMDA has concluded that the product may be approved for the indication and dosage and administration shown below, with the following conditions. Further investigation is necessary through post-marketing surveillance for the following events: cardiac disorder, interstitial lung disease, pulmonary hypertension, haematotoxicity, infection, liver disorder, renal disorder, haemorrhage, infusion-related reaction, tumour lysis syndrome, hypertension including hypertensive crisis, venous thromboembolism, reversible posterior leukoencephalopathy syndrome and leukoencephalopathy, thrombotic microangiopathy, gastrointestinal perforation, pericarditis, and pericardial effusion. This English translation of this Japanese review report is intended to serve as reference material made available for the convenience of users. In the event of any inconsistency between the Japanese original and this English translation, the Japanese original shall take precedence. PMDA will not be responsible for any consequence resulting from the use of this reference English translation. Indication Relapsed or refractory multiple myeloma Dosage and Administration In combination with lenalidomide plus dexamethasone, carfilzomib is usually administered to adult patients once daily by intravenous infusion on Days 1, 2, 8, 9, 15, and 16 followed by a 12-day rest period. This 28- day cycle is repeated until Cycle 12. From Cycle 13 onward, carfilzomib is administered once daily by intravenous infusion on Days 1, 2, 15, and 16 followed by a 12-day rest period. The dose of carfilzomib is 20 mg/m2 (body surface area) only on Days 1 and 2 of Cycle 1 and 27 mg/m2 (body surface area) thereafter, and is administered as an intravenous infusion over 10 minutes. The dose may be reduced according to the patient's condition. Conditions of Approval 1. The applicant is required to develop and appropriately implement a risk management plan. 2. Because of limited number of subjects in the Japanese clinical studies, the applicant is required to conduct a post-marketing drug use results survey covering all patients treated with the product until data from a specified number of patients are collected, in order to understand the characteristics of patients and to promptly collect safety and efficacy data of the product. Based on the collected data, necessary measures should be taken to ensure correct use of the product. 1 Attachment Review Report (1) February 23, 2016 The following is an outline of the data submitted by the applicant and content of the review conducted by the Pharmaceuticals and Medical Devices Agency. Product Submitted for Approval Brand Name Kyprolis for Intravenous Injection 10 mg Kyprolis for Intravenous Injection 40 mg Non-proprietary Name Carfilzomib Applicant Ono Pharmaceutical Co., Ltd. Date of Application August 26, 2015 Dosage Form/Strength Powder for reconstitution for injection, each vial containing 10.7 mg or 42.6 mg of carfilzomib Proposed indication Relapsed or refractory multiple myeloma Proposed Dosage and Administration Carfilzomib is usually administered to adult patients once daily on Days 1, 2, 8, 9, 15, and 16, followed by a 12-day rest period. This 28-day cycle is repeated. The dose of carfilzomib is 20 mg/m2 (body surface area) only on Days 1 and 2 of Cycle 1, and 27 mg/m2 (body surface area) thereafter, and is administered intravenously over 10 minutes. Table of Contents 1. Origin or History of Discovery, Use in Foreign Countries, and Other Information .......................... 6 2. Data Relating to Quality and Outline of the Review Conducted by PMDA ..................................... 7 3. Non-clinical Pharmacology and Outline of the Review Conducted by PMDA ................................ 9 4. Non-clinical Pharmacokinetics and Outline of the Review Conducted by PMDA ......................... 14 5. Toxicity and Outline of the Review Conducted by PMDA ............................................................. 20 6. Summary of Biopharmaceutic Studies and Associated Analytical Methods, Data on Clinical Pharmacology Studies, and Outline of the Review Conducted by PMDA...................................... 28 7. Summary of Submitted Data on Clinical Efficacy and Safety, and Outline of the Review Conducted by PMDA ......................................................................................................................................... 37 8. Results of Compliance Assessment Concerning the New Drug Application Data and Conclusion Reached by PMDA ........................................................................................................................ 102 9. Overall Evaluation during Preparation of the Review Report (1) ................................................. 103 List of Abbreviations ALP Alkaline phosphatase ALT Alanine aminotransferase Application marketing Application for marketing approval approval AST Aspartate aminotransferase ATP Adenosine triphosphate BAX Bcl-2-associated X protein BCRP Breast cancer resistance protein Boc-group tert-Butoxycarbonyl group BSC Best supportive care Carfilzomib Carfilzomib 2 Carfilzomib/DEX Co-administration of carfilzomib and dexamethasone CI Confidence interval CLd regimen A combined regimen of carfilzomib with lenalidomide hydrate plus dexamethasone CLint Intrinsic clearance CrCL Creatinine clearance CR Complete response CYP Cytochrome P450 DEX Dexamethasone DLT Dose limiting toxicity EBMT criteria Evaluation criteria created by European Group for Blood and Marrow Transplantation (EBMT) FDA Food and Drug Administration FOB Functional observation battery GC Gas chromatography GGT Gamma-glutamyltransferase GLP Good Laboratory Practice Hb Hemoglobin HCT Hematocrit hERG Human ether-a-go-go-related gene HLT High level term HPLC High performance liquid chromatography HPBCD Hydroxypropyl-beta-cyclodextrin IDMC Independent data monitoring committee ILD Interstitial lung disease Immunodeficient mouse Nude mouse NIH-Lystbg Foxn1nu Btkxid IMWG International Myeloma Working Group IMWG criteria Evaluation criteria created by the International Myeloma Working Group (IMWG) IR Infrared spectroscopy IRC Independent review committee IRR Infusion-related reaction ITT intent-to-treat LD regimen A combined regimen of lenalidomide hydrate and high-dose