Report on the Deliberation Results November 14, 2016 Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau Ministry of Health, Labour and Welfare Brand Name Parsabiv Intravenous Injection for Dialysis 2.5 mg Parsabiv Intravenous Injection for Dialysis 5 mg Parsabiv Intravenous Injection for Dialysis 10 mg Non-proprietary Name Etelcalcetide Hydrochloride (JAN*) Applicant Ono Pharmaceutical Co., Ltd. Date of Application January 14, 2016 Results of Deliberation In its meeting held on October 31, 2016, the First Committee on New Drugs concluded that the product may be approved and that this result should be reported 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. The drug product is classified as a powerful drug and its drug substance is classified as a poisonous 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 October 17, 2016 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. Brand Name Parsabiv Intravenous Injection for Dialysis 2.5 mg Parsabiv Intravenous Injection for Dialysis 5 mg Parsabiv Intravenous Injection for Dialysis 10 mg Non-proprietary Name Etelcalcetide Hydrochloride Applicant Ono Pharmaceutical Co., Ltd. Date of Application January 14, 2016 Dosage Form/Strength Solution for injection: Each vial contains 2.5 mg, 5 mg, or 10 mg of etelcalcetide (as the hydrochloride salt). Application Classification Prescription drug, (1) Drug with a new active ingredient Chemical Structure Molecular formula: C38H73N21O10S2·xHCl (4 ≤ x ≤ 5) Molecular weight: 1048.25 (free base) Chemical name: N-Acetyl-S-[(2R)-2-amino-2-carboxyethylsulfanyl]-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl- D-alanyl-D-argininamide hydrochloride Items Warranting Special Mention None Reviewing Office Office of New Drug I Results of Review On the basis of data submitted, the Pharmaceuticals and Medical Devices Agency (PMDA) has concluded that the product has efficacy in the treatment of secondary hyperparathyroidism in patients on hemodialysis and that the product has acceptable safety in view of its benefits (see Attachment). 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. 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 Secondary hyperparathyroidism in patients on hemodialysis Dosage and Administration The usual adult starting dose is 5 mg of etelcalcetide administered 3 times per week. Administer by intravenous injection into the venous line of the dialysis circuit at the end of dialysis during rinse back. Thereafter, while parathyroid hormone (PTH) and serum calcium levels should be monitored closely, the dose should be titrated based on the PTH and serum calcium levels. The dose range is 2.5 to 15 mg 3 times per week at the end of dialysis during rinse back. Condition of Approval The applicant is required to develop and appropriately implement a risk management plan. Attachment Review Report (1) September 2, 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 Parsabiv Intravenous Injection for Dialysis 2.5 mg Parsabiv Intravenous Injection for Dialysis 5 mg Parsabiv Intravenous Injection for Dialysis 10 mg Non-proprietary Name Etelcalcetide Hydrochloride Applicant Ono Pharmaceutical Co., Ltd. Date of Application January 14, 2016 Dosage Form/Strength Solution for injection: Each vial contains 2.5 mg, 5 mg, or 10 mg of etelcalcetide (as the hydrochloride salt). Proposed Indication Secondary hyperparathyroidism in patients on hemodialysis Proposed Dosage and Administration The usual adult starting dose is 5 mg of etelcalcetide administered 3 times per week. Administer by intravenous injection into the venous line of the dialysis circuit at the end of dialysis during rinse back. Thereafter, while parathyroid hormone (PTH) and serum calcium levels should be monitored closely, the dose should be titrated based on the PTH and serum calcium levels. The dose range is 2.5 to 15 mg 3 times per week at the end of dialysis during rinse back. Table of Contents 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 .................................... 14 5. Toxicity and Outline of the Review Conducted by PMDA ......................................................................... 17 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......................................... 28 8. Results of Compliance Assessment Concerning the New Drug Application Data and Conclusion Reached by PMDA ......................................................................................................................................................... 51 9. Overall Evaluation during Preparation of the Review Report (1)................................................................ 51 List of Abbreviations A/G ratio Ratio of albumin to globulins AUC Area Under the Curve BAP Bone (specific) alkaline phosphatase BDC Bile-duct cannulated Ca Calcium CaSR Calcium-sensing receptor CKD Chronic kidney disease CKD-MBD Chronic kidney disease-mineral and bone disorder Clinical Practice Guideline for Management of Chronic Kidney Disease- Clinical Practice Guideline Mineral and Bone Disorder. Japanese Society for Dialysis Therapy, ed. (J. for CKD-MBD Jpn. Soc. Dial. Ther. 2012; 45: 301-356) Cmax Maximum plasma concentration CQA Critical quality attribute CYP Cytochrome P450 Cys Cysteine EC50 50% effective concentration Etelcalcetide Etelcalcetide hydrochloride fe Urinary excretion rate FAS Full Analysis Set GC Gas chromatography GLP Good Laboratory Practice HEK293 Human Embryonic Kidney 293 hERG human Ether-a-go-go Related Gene HPLC High performance liquid chromatography International conference on harmonization of technical requirements for ICH registration of pharmaceuticals for human use ICP-MS Inductively coupled plasma-mass spectrometry in silico via computer simulation IP-1 Inositol-1-phosphate iPTH Intact parathyroid hormone IV intravenous KP-2140 A peptide without D-Cys (removal of D-Cys from M11) LC/MS/MS Liquid Chromatography-Tandem Mass Spectrometry LLC-PK1 cells Lilly Laboratories Cell - Porcine Kidney 1 cells M10 Glutathione disulfide M11 Etelcalcetide D-amino acid peptide without L-Cys M13 L-cysteinyl-L-glycine disulfide MDCKII cells Madin Darby canine kidney cells MedDRA/J Medical Dictionary for Regulatory Activities Japanese version MS Mass spectrometry NMR Nuclear magnetic resonance OAT Organic anion transporter OATP Organic anion transporting polypeptide OCT Organic cation transporter P Phosphorus PEPT Peptide transporter PMDA Pharmaceuticals and Medical Devices Agency PT Preferred Terms PTH Parathyroid hormone QbD Quality by design QTc Corrected QT interval QT interval corrected using the following formula QTca QTca = QT interval [ms]/(RR interval [ms]/750)0.273 2 QTcF QT intervals from Fridericia’s formula RH Relative humidity S9 fraction 9000 × g supernatant fraction of cell homogenate SAPC Serum albumin peptide conjugate SHPT Secondary hyperparathyroidism SH group Thiol group SMQ Standardised MedDRA Queries t1/2 Elimination half life CByB6F1-Tg(HRAS)2Jic (+/- hemizygous c-Ha-ras) Tg.rasH2 mouse [a hemizygous transgenic mouse carrying the human c-Ha-ras gene] TRACP-5b Tartrate resistant acid phosphatase-5b 3 1. Origin or History of Discovery, Use in Foreign Countries, and Other Information Secondary hyperparathyroidism (SHPT) is a common condition in patients with worsening chronic kidney disease (CKD) and is characterized by excessive secretion of parathyroid hormone (PTH) in response to decreased excretion of phosphorus