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Report on the Deliberation Results June 7, 2017 Pharmaceutical Report on the Deliberation Results June 7, 2017 Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau Ministry of Health, Labour and Welfare Brand Name Amenalief Tab. 200 mg Non-proprietary Name Amenamevir (JAN*) Applicant Maruho Co., Ltd. Date of Application April 27, 2016 Results of Deliberation In its meeting held on May 30, 2017, 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 product is not classified as a biological product or a specified biological product. The re- examination period is 8 years. Neither the drug product nor its drug substance is classified as a poisonous drug or a powerful drug. Condition of Approval The applicant is required to develop and appropriately implement a risk management plan. *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 May 8, 2017 Pharmaceuticals and Medical Devices Agency The following are the results of the review of the following pharmaceutical product submitted for marketing approval conducted by the Pharmaceuticals and Medical Devices Agency (PMDA). Brand Name Amenalief Tab. 200 mg Non-proprietary Name Amenamevir Applicant Maruho Co., Ltd. Date of Application April 27, 2016 Dosage Form/Strength Tablets: Each tablet contains 200 mg of Amenamevir. Application Classification Prescription drug (1), Drug with a new active ingredient Chemical Structure Molecular formula: C24H26N4O5S Molecular weight: 482.55 Chemical name: N-(2,6-Dimethylphenyl)-N-(2-{[4-(1,2,4-oxadiazol-3-yl)phenyl]amino}- 2- oxoethyl)-1,1-dioxothiane-4-carboxamide Items Warranting Special Mention None Reviewing Office Office of New Drug IV Results of Review On the basis of he data submitted, PMDA has concluded that the product has efficacy in the treatment of herpes zoster, 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 condition. Indication Herpes zoster Dosage and Administration The usual adult dosage is 400 mg of amenamevir administered orally once daily after a meal. Condition of Approval The applicant is required to develop and appropriately implement a risk management plan. 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. Attachment Review Report (1) March 1, 2017 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 Amenalief Tab. 200 mg Non-proprietary Name Amenamevir Applicant Maruho Co., Ltd. Date of Application April 27, 2016 Dosage Form/Strength Tablets: Each tablet contains 200 mg of Amenamevir. Proposed Indication Herpes zoster Proposed Dosage and Administration The usual adult dosage is 400 mg of amenamevir administered orally once daily after a meal. Table of Contents Product Submitted for Approval .............................................................................................................. 1 1. Origin or History of Discovery, Use in Foreign Countries, and Other Information......................... 4 2. Data Relating to Quality and Outline of the Review Conducted by PMDA .................................... 4 3. Non-clinical Pharmacology and Outline of the Review Conducted by PMDA ............................... 6 4. Non-clinical Pharmacokinetics and Outline of the Review Conducted by PMDA ........................ 12 5. Toxicity and Outline of the Review Conducted by PMDA ............................................................ 18 6. Summary of Biopharmaceutic Studies and Associated Analytical Methods, Clinical Pharmacology, and Outline of the Review Conducted by PMDA ................................................. 22 7. Clinical Efficacy and Safety and Outline of the Review Conducted by PMDA ............................ 27 8. Results of Compliance Assessment Concerning the New Drug Application Data and Conclusion Reached by PMDA ..................................................................................................... 39 9. Overall Evaluation during Preparation of the Review Report (1) .................................................. 39 1 List of Abbreviations ACV Aciclovir ALP Alkaline phosphatase ALT Alanine aminotransferase Amenalief Amenalief Tab. 200 mg Amenamevir Amenamevir AST Aspartate aminotransferase AUC Area under the plasma concentration versus time curve Area under the plasma concentration versus time curve AUC inf extrapolated to infinite time Area under the plasma concentration versus time curve over the AUC tau dosing interval BA Bioavailability BCRP Breast cancer resistance protein BID bis in die BSEP Bile salt export pump CL Clearance CL/F Apparent oral clearance CLcr Creatinine clearance Cmax Maximum plasma concentration CV Coefficient of variation E217βG Estradiol 17-β-D-glucuronide EC50 50% effective concentration FAS Full analysis set FCV Famciclovir HCMV Human cytomegalovirus HEF Human embryonic fibroblast HEK Human embryonic kidney HIV-1 Human immunodeficiency virus type 1 HPLC High performance liquid chromatography HSV Herpes simplex virus HSV-1 Herpes simplex virus type 1 HSV-2 Herpes simplex virus type 2 IC50 50% inhibitory concentration MATE Multidrug and toxin extrusion MDCK Madin-Darby canine kidney mRNA Messenger ribonucleic acid MRP Multidrug resistance-associated protein NAG N-Acetyl-β-D-glucosaminidase Ratio of permeability coefficient in transporter-expressing cells to net flux ratio that in the control cells NTCP Sodium-taurocholate cotransporting polypeptide OAT Organic anion transporter OATP Organic anion transporting polypeptide OCT Organic cation transporter PCR Polymerase chain reaction PD Pharmacodynamics PEPT Peptide transporter P-gp P-glycoprotein PHN Post herpetic neuralgia PK Pharmacokinetics PMDA Pharmaceuticals and Medical Devices Agency PPK Population pharmacokinetics QD quaque die QTc Corrected QT interval 2 QTcF Fridericia-corrected QT interval t1/2 Elimination half-life TID ter in die Time above Duration of the day in which plasma amenamevir concentration is 50/100/200/400 maintained at ≥50, 100, 200, or 400 ng/mL tmax Time to maximum plasma concentration URAT Urate transporter VACV Valaciclovir Vero African green monkey kidney cells VZV Varicella zoster virus α1-MG α1-Microglobulin 3 1. Origin or History of Discovery, Use in Foreign Countries, and Other Information Once infected through respiratory or ocular mucosa, varicella zoster virus (VZV) proliferates in the lymph nodes, liver, spleen, etc., and approximately 2 weeks after infection, varicella lesion develops. Although varicella spontaneously heals in several weeks, VZV is latently-infected in the ganglia. Latently-infected VZV is reactivated as a consequence of decreased immune function due to overwork, aging, malignant tumor, autoimmune disease, immunosuppressive agent, etc., leading to onset of herpes zoster, of which major symptoms include skin lesion and pain. The skin lesion heals in 2 to 3 weeks after onset, but the pain may persist as post herpetic neuralgia (PHN). PHN is a peripheral neuropathic pain caused by neurodegeneration due to virus infection and may become refractory (Comprehensive Handbook of Clinical Dermatology 15. First edition. 2003;33-41, Handbook of Viral Skin Diseases. 2011;67-76). Amenamevir is an antiviral agent discovered by Astellas Pharma Inc. and is considered to exert an antiviral effect by inhibiting the activity of the helicase-primase complex, which is involved in DNA replication of herpes virus. Outside of Japan, development of amenamevir was implemented by Astellas Pharma Global Development, Inc. and Astellas Pharma Europe B.V. However, ***************************** ******************************** because serious thrombocytopenia, etc. for which a causal relationship to amenamevir could not be ruled out were observed in a phase I study in the US (Study 15L-CL-019), and the development was suspended in February 2011. Later, Maruho Co., Ltd, the applicant, acquired a license for the development in and outside of Japan, and then conducted a phase III study in patients with herpes zoster (Study M522101-J01), based on the safety data from non-clinical studies and Japanese clinical studies conducted by Astellas Pharma Inc. The applicant has submitted a marketing application for Amenalief, claiming that the efficacy and safety of amenamevir have been confirmed in patients with herpes zoster. After the development was suspended outside of Japan in February 2011, a clinical pharmacology study in healthy adult subjects was conducted in Europe, but the development
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