Report on the Deliberation Results December 6, 2010 Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare [Brand name] Stelara Subcutaneous Injection 45 mg Syringe [Non-proprietary name] Ustekinumab (Genetical Recombination) (JAN*) [Applicant] Janssen Pharmaceutical K.K. [Date of application] January 21, 2010 [Results of deliberation] In the meeting held on November 29, 2010, 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 classified as a biological product, the re-examination period is 8 years, and the drug substance and the drug product are both classified as powerful drugs. The conditions for approval should be modified as follows. After modification [Conditions for approval] The applicant is required to: 1. Conduct a post-marketing drug use-results survey, which covers all the patients treated with the product, until data from a certain number of patients will be accumulated, in order to collect data on the safety and efficacy of the product as soon as possible and to take necessary measures to ensure proper use of the product. 2. Conduct a large-scale post-marketing surveillance study to fully evaluate the safety of the product and to investigate the efficacy and long-term safety of the product, including the occurrence of infections, etc. Before modification [Conditions for approval] The applicant is required to: 1. Conduct a post-marketing drug use-results survey, which covers all the patients treated with the product, until data from a certain number of patients will be accumulated, in order to collect data on the safety and efficacy of the product as soon as possible and to take necessary measures to ensure proper use of the product. 2. Conduct a large-scale post-marketing surveillance study to fully evaluate the safety of the product and to investigate the efficacy and long-term safety of the product and the occurrence of infections etc. (The underlined parts are the changes.) This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version *Japanese Accepted Name (modified INN) This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version Review Report November 10, 2010 Pharmaceuticals and Medical Devices Agency The results of a regulatory review conducted by the Pharmaceuticals and Medical Devices Agency on the following pharmaceutical product submitted for registration are as follows. [Brand name] Stelara Subcutaneous Injection 45 mg Syringe [Non-proprietary name] Ustekinumab (Genetical Recombination) [Name of applicant] Janssen Pharmaceutical K.K. [Date of application] January 21, 2010 [Dosage form/Strength] A solution for injection in a prefilled syringe. Each prefilled syringe (0.5 mL) contains 45 mg of Ustekinumab (Genetical Recombination). [Application classification] Prescription drug (1) Drug with a new active ingredient [Chemical structure] See Figure 1 and Figure 2 below. Molecular formula: H-chain C2207H3410N582O671S17 L-chain C1034H1596N274O337S6 Molecular weight: 148,079 to 149,690 Chemical name: Ustekinumab is a recombinant human IgG1 monoclonal antibody against the p40 subunit of human interleukin-12 and interleukin-23. Ustekinumab is produced in mouse myeloma (Sp2/0) cells. Ustekinumab is a glycoprotein (molecular weight, 148,079-149,690) composed of 2 H-chain (1-chain) molecules consisting of 449 amino acid residues each and 2 L-chain (-chain) molecules consisting of 214 amino acid residues each. [Items warranting special mention] None [Reviewing office] Office of New Drug IV This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA will not be responsible for any consequence resulting from the use of this English version Heavy Chain EVQLVQSGAE VKKPGESLKI SCKGSGYSFT TYWLGWVRQM PGKGLDWIGI MSPVDSDIRY 60 22-96 SPSFQGQVTM SVDKSITTAY LQWNSLKASD TAMYYCARRR PGQGYFDFWG QGTLVTVSSS 120 STKGPSVFPL APSSKSTSGG TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG 180 146-202 222 228 231 LYSLSSVVTV PSSSLGTQTY ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP 240 LC HC HC N-Glycan SVFLFPPKPK DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS300 263-323 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV YTLPPSRDEL 360 TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS KLTVDKSRWQ 420 369-427 QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449 Light Chain DIQMTQSPSS LSASVGDRVT ITCRASQGIS SWLAWYQQKP EKAPKSLIYA ASSLQSGVPS 60 23-88 RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YNIYPYTFGQ GTKLEIKRTV AAPSVFIFPP 120 SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT 180 134-194 LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC 214 HC Figure 1. Heavy and light chains of ustekinumab Amino acid sequences of the heavy and light chains of ustekinumab are indicated in the single-letter code. Complementarity-determining regions are underlined. H-chain K449: partial processing Figure 2. Carbohydrate structure 4 Review Results November 10, 2010 [Brand name] Stelara Subcutaneous Injection 45 mg Syringe [Non-proprietary name] Ustekinumab (Genetical Recombination) [Name of applicant] Janssen Pharmaceutical K.K. [Date of application] January 21, 2010 [Results of review] Based on the submitted data, the efficacy of the product in the treatment of psoriasis vulgaris and psoriatic arthritis in patients who have had an inadequate response to conventional therapy has been demonstrated and its safety is acceptable in view of its observed benefits. Serious adverse drug reactions such as infections may occur following administration of the product. Therefore, prior to the use of the product, the patient’s symptoms etc. should be monitored closely and the risks and benefits of the product should be weighed carefully. The risks of the product should be fully explained to the patient as well. It is necessary to closely monitor the course of the disease also after the initiation of treatment. After the market launch, a post-marketing surveillance study focusing on the occurrence of serious infections etc., covering all the patients treated with the product, and a long-term survey to follow the patients for the development of infections and malignancy etc. need to be conducted. As a result of its review, the Pharmaceuticals and Medical Devices Agency has concluded that the product may be approved for the indication and the dosage and administration as shown below, with the following conditions. [Indication] Treatment of the following diseases in patients who have had an inadequate response to conventional therapy: Psoriasis vulgaris and psoriatic arthritis [Dosage and administration] The usual initial adult dosage is 45 mg of Ustekinumab (Genetical Recombination) administered subcutaneously, followed 4 weeks later by a 45 mg dose, and then every 12 weeks thereafter. If the effect is insufficient, a dose of 90 mg may be used. [Conditions for approval] The applicant is required to: (1) Conduct a post-marketing drug use-results survey, which covers all the patients treated with the 5 product, until data from a certain number of patients will be accumulated, in order to collect data on the safety and efficacy of the product as soon as possible and to take necessary measures to ensure proper use of the product. (2) Conduct a large-scale post-marketing surveillance study to fully evaluate the safety of the product and to investigate the long-term safety of the product and the occurrence of infections etc. 6 Review Report (1) October 12, 2010 I. Product Submitted for Registration [Brand name] Stelara Subcutaneous Injection 45 mg Syringe [Non-proprietary name] Ustekinumab (Genetical Recombination) [Name of applicant] Janssen Pharmaceutical K.K. [Date of application] January 21, 2010 [Dosage form/Strength] A solution for injection in a prefilled syringe. Each prefilled syringe (0.5 mL) contains 45 mg of Ustekinumab (Genetical Recombination). [Proposed indication] Moderate to severe psoriasis vulgaris Psoriatic arthritis with moderate to severe plaque psoriasis [Proposed dosage and administration] The usual initial adult dosage is 45 mg of Ustekinumab (Genetical Recombination) administered subcutaneously, followed 4 weeks later by a 45 mg dose, and then every 12 weeks thereafter. A dose of 90 mg may be administered in patients weighing >100 kg. II. Summary of the Submitted Data and Outline of Review by the Pharmaceuticals and Medical Devices Agency A summary of the submitted data and the outline of a review by the Pharmaceuticals and Medical Devices Agency (PMDA) are as shown below. 1. Origin or history of discovery and usage conditions in foreign countries etc. The active substance Ustekinumab (Genetical Recombination) (ustekinumab) is a human immunoglobulin G (IgG) 1κ monoclonal antibody (mAb) against human