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Report on the Deliberation Results March 6, 2020 Pharmaceutical Report on the Deliberation Results March 6, 2020 Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau Ministry of Health, Labour and Welfare Brand Name Viltepso Intravenous Infusion 250 mg Non-proprietary Name Viltolarsen (JAN*) Applicant Nippon Shinyaku Co., Ltd. Date of Application September 26, 2019 Results of Deliberation In its meeting held on February 28, 2020, the First 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 10 years. Neither the drug product nor its drug substance is classified as a poisonous drug or a powerful drug. Approval Conditions 1. The applicant is required to develop and appropriately implement a risk management plan. 2. Because of a limited number of Japanese patients participated in clinical studies of the product, the applicant is required to conduct a drug use-results survey involving all Japanese patients treated with the product over the re-examination period to identify the characteristics of patients using the product, and to promptly collect safety and efficacy data so that necessary measures are taken to ensure the proper use of the product. 3. The applicant is required to conduct clinical studies and a Japanese registry-based survey aiming to evaluate the efficacy and safety of the product, and to submit the study data and analysis results promptly upon their completion. *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 February 19, 2020 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 Viltepso Intravenous Infusion 250 mg Non-proprietary Name Viltolarsen Applicant Nippon Shinyaku Co., Ltd. Date of Application September 26, 2019 Dosage Form/Strength Solution for injection in vials, each (5 mL) containing 250 mg of viltolarsen Application Classification Prescription drug, (1) Drug(s) with a new active ingredient Chemical Structure B(n): The position of the nth base from the 5'-terminal end (B(21) indicates the 21st base from the 5'-terminal end). Base sequence: CCTCCGGTTC TGAAGGTGTT C C, Cytosine; T, Thymine; G, Guanine; A, Adenine Molecular formula: C244H381N113O88P20 Molecular weight: 6924.82 Chemical name: all-P-ambo-[2',3'-Azanediyl-P,2',3'-trideoxy-P-(dimethylamino)-2',3'-seco] (2'-N→5')(CCTCCGGTTC TGAAGGTGTT C) Items Warranting Special Mention Orphan drug (Orphan Drug Designation No. 440 of 2019 [31 yaku], PSEHB/PED Notification No. 0820-3 dated August 20, 2019, by the 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. Viltepso Intravenous Infusion 250 mg_Nippon Shinyaku Co., Ltd._Review Report Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministry of Health, Labour and Welfare) SAKIGAKE designation drug (SAKIGAKE Drug Designation No. 2 of 2015 [27 yaku]; PSEHB/ELD Notification No. 1 dated October 27, 2015, by the Evaluation and Licensing Division, Pharmaceutical Safety and Environmental Health Bureau, Ministry of Health, Labour and Welfare), SAKIGAKE comprehensive assessment consultation conducted The product is subject to Conditional Early Approval System (PSEHB/PED Notification No. 1029-3 dated October 29, 2019). Reviewing Office Office of New Drug III Results of Review On the basis of the data submitted, PMDA has concluded that the product has efficacy in the treatment of Duchenne muscular dystrophy with a deletion in the dystrophin gene amenable to exon 53 skipping therapy 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. Indication Duchenne muscular dystrophy with a deletion in the dystrophin gene amenable to exon 53 skipping therapy Dosage and Administration The usual dosage is 80 mg/kg of viltolarsen injected intravenously once weekly over 1 hour. Approval Conditions 1. The applicant is required to develop and appropriately implement a risk management plan. 2. Because of a limited number of Japanese patients participated in clinical studies of the product, the applicant is required to conduct a drug use-results survey involving all Japanese patients treated with the product over the re-examination period to identify the characteristics of patients using the product, and to promptly collect safety and efficacy data so that necessary measures are taken to ensure the proper use of the product. 3. The applicant is required to conduct clinical studies and a Japanese registry-based survey aiming to evaluate the efficacy and safety of the product, and to submit the study data and analysis results upon their completion. 2 Viltepso Intravenous Infusion 250 mg_Nippon Shinyaku Co., Ltd._Review Report Attachment Review Report (1) January 21, 2020 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 (PMDA). Product Submitted for Approval Brand Name Viltepso Intravenous Infusion 250 mg Non-proprietary Name Viltolarsen Applicant Nippon Shinyaku Co., Ltd. Date of Application September 26, 2019 Dosage Form/Strength Solution for injection in vials, each (5 mL) containing 250 mg of viltolarsen. Proposed Indication Duchenne muscular dystrophy with a deletion in the dystrophin gene amenable to exon 53 skipping therapy Proposed Dosage and Administration The usual dosage is 80 mg/kg of viltolarsen injected intravenously once weekly over 1 hour. Table of Contents 1. Origin or History of Discovery, Use in Foreign Countries, and Other Information......................... 2 2. Data Relating to Quality and Outline of the Review Conducted by PMDA .................................... 3 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 ........................ 17 5. Toxicity and Outline of the Review Conducted by PMDA ............................................................ 21 6. Summary of Biopharmaceutic Studies and Associated Analytical Methods, Clinical Pharmacology, and Outline of the Review Conducted by PMDA ................................................. 28 7. Clinical Efficacy and Safety and Outline of the Review Conducted by PMDA ............................ 35 8. Results of Compliance Assessment Concerning the New Drug Application Data and Conclusion Reached by PMDA ..................................................................................................... 68 9. Overall Evaluation during Preparation of the Review Report (1) .................................................. 69 List of Abbreviations See Appendix. Viltepso Intravenous Infusion 250 mg_Nippon Shinyaku Co., Ltd._Review Report 1. Origin or History of Discovery, Use in Foreign Countries, and Other Information Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disorder. The disease is caused by the deficiency of functional dystrophin protein resulting from deletion or duplication by mutations in the dystrophin gene on the X-chromosome (Cell. 1987;51:919-28). DMD is a type of designated intractable disease of “muscular dystrophy” and is an intractable and progressive muscular disease complicated by respiratory muscle and myocardial weakness as well as serious motor dysfunction, dysphagia, sputum retention, and gastrointestinal dysfunction. Children with DMD lose walking ability by around 10 years of age, with the average life-span of approximately 30 years (Practical Guideline for Duchenne Muscular Dystrophy (DMD) 2014. Nankodo Co., Ltd.; 2014:2-5). DMD occurs in 1 out of every 3500 newborn boys (Neuromuscul Disord. 1991;1:19-29), and approximately 5000 patients are estimated to be affected in Japan (Experimental Medicine. 2016;34:3151-8). Given that approximately 8% of patients with DMD have the genetic mutations eligible for treatment with viltolarsen (Hum Mutat. 2009;30:293-9), and viltolarsen is expected to be indicated for approximately 400 patients in Japan. Viltolarsen was designated as an orphan drug (Orphan Drug Designation No. 440 of 2019 [31 yaku]) on August 20, 2019 for the intended indication of “Duchenne muscular dystrophy with a deletion in the dystrophin gene amenable to exon 53 skipping therapy.” Viltolarsen is a synthesized morpholino oligonucleotide, developed by the applicant and the
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