Therapeutic Goods Administration
April 2014Australian Public Assessment Report for catridecacog (rys)
Proprietary Product Name: NovoThirteen
Sponsor: Novo Nordisk Pharmaceuticals Pty Ltd
About the Therapeutic Goods Administration (TGA)
· The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health, and is responsible for regulating medicines and medical devices.
· The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary.
· The work of the TGA is based on applying scientific and clinical expertise to decision-making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices.
· The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action.
· To report a problem with a medicine or medical device, please see the information on the TGA website <http://www.tga.gov.au.
About AusPARs
· An Australian Public Assessment Record (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission.
· AusPARs are prepared and published by the TGA.
· An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations, and extensions of indications.
· An AusPAR is a static document, in that it will provide information that relates to a submission at a particular point in time.
· A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA.
Copyright
© Commonwealth of Australia 2014
This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <>.
Final 10 April 2014 / Page 2 of 55
Therapeutic Goods Administration
Contents
I. Introduction to product submission 4
Submission details 4
Product background 4
Regulatory status 5
Product Information 6
II. Quality findings 6
Drug substance (active ingredient) 6
Drug product 7
Biopharmaceutics 7
Quality summary and conclusions 7
III. Nonclinical findings 8
Introduction 8
Pharmacology 9
Pharmacokinetics 11
Toxicology 12
Nonclinical summary and conclusions 15
IV. Clinical findings 17
Introduction 17
Pharmacokinetics 18
Pharmacodynamics 21
Efficacy 22
Safety 25
Clinical summary and conclusions 26
List of questions 29
V. Pharmacovigilance findings 55
Risk management plan 55
VI. Overall conclusion and risk/benefit assessment 69
Quality 69
Nonclinical 69
Clinical 70
Risk management plan 72
Risk-benefit analysis 73
Outcome 79
Attachment 1. Product Information 80
Attachment 2. Extract from the Clinical Evaluation Report 80
I. Introduction to product submission
Submission details
Type of submission / New Chemical (Biological) EntityDecision: / Approved
Date of decision: / 4 November 2013
Active ingredient: / Catridecacog (rys)
Product name: / NovoThirteen
Sponsor’s name and address: / Novo Nordisk Pharmaceuticals Pty Ltd
PO Box 7586
Baulkham Hills Business Centre NSW 2153
Dose form: / Powder for injection with solvent
Strength: / 2,500 IU
Container: / Vials, Glass Type I Clear
Pack size: / Each pack contains one vial with the 2500 IU drug product and a vial with the water for solution with a vial adaptor for reconstitution.
Approved therapeutic use: / NovoThirteen is indicated for routine prophylaxis of bleeding in patients with congenital, Factor XIII A-subunit deficiency.
Route of administration: / Intravenous
Dosage: / The recommended dose is 35 IU/kg body weight (BW) once monthly (every 28 days +/- 2 days) administered as an intravenous (IV) bolus injection.
ARTG number: / 201776
Product background
This AusPAR describes a submission by the sponsor, Novo Nordisk Pharmaceuticals Pty Ltd, to register a new chemical (biological) entity, catridecacog (rys), with the trade name NovoThirteen. This is a recombinant form of the human coagulation factor XIII A-subunit.
The proposed indication is:
routine prophylaxis of bleeding in patients with congenital Factor XIII A-subunit deficiency.
Congenital factor XIII (FXIII) is a rare autosomal recessive bleeding disorder with an estimated prevalence of 1 patient per 2 to 5 million people.[1] The Australian Bleeding Disorders Registry (ABDR) Annual Report 2010-2011 indicates that there were 17 people in Australia with FXIII deficiency at 30 June 2011, and 7 of these individuals had received FXIII containing product in the 2010-2011 financial year.[2]
FXIII is a pro enzyme (pro transglutaminase) and is the terminal enzyme in the coagulation cascade. In plasma, FXIII circulates as an inactive zymogen heterotetramer (A2B2) held together by strong non covalent interactions. Intracellular FXIII is a homodimer of two A subunits (A2) and is found in circulating platelets and monocytes. The A subunits are synthesised in megakaryocytes and monocyte precursors in bone marrow and placenta, and the B subunits are synthesised in hepatocytes. The FXIII A subunits are composed of 731 amino acids and possess the catalytic site of the FXIII enzyme.
NovoThirteen will be supplied as a lyophilised powder in a glass vial containing 2500 IU (15 mg). For reconstitution purposes, NovoThirteen will be supplied with a glass vial containing 3.2 mL of water for injection (as solvent) and a sterile vial adapter. After reconstitution, one vial of NovoThirteen nominally contains 2500 IU catridecacog per 3 mL corresponding to a concentration of 833 IU/mL. The specific activity of recombinant Factor XIII (rFXIII) is approximately 165 IU/mg protein.
Regulatory status
The international regulatory status for NovoThirteen at the time of the Australian submission to the TGA is shown in Table 1.
Table 1: International regulatory status for NovoThirteen.
The approved indication in other jurisdictions is as follows:
European Union (EU): Long term prophylactic treatment of bleeding in patients 6 years and above with congenital factor XIII A-subunit deficiency.
Canada: Tretten (catridecacog) is indicated for routine prophylaxis for bleeding in patients with congenital Factor XIII A-subunit deficiency
Switzerland: Bleeding prophylaxis in patients over the age of 6 with a congenital factor XIII deficiency of A-subunit and a relevant risk of bleeding (family medical history of congenital factor XIII deficiency and/or bleedings requiring treatment in the case history).
The registration for NovoThirteen (catridecacog) has been deferred by the US Food and Drug Administration (FDA).
No application for registration of NovoThirteen (catridecacog) has been withdrawn or rejected in any country.
Pending application
Novo Nordisk has submitted a variation to the European Medicines Agency (EMA) and SwissMedic including a request for expansion of the indication for NovoThirteen to also include the possibility for treatment of children below the age of 6 years with congenital factor XIII A-subunit deficiency. Final approval from the EMA is expected Q1 2014.
Product Information
The approved Product Information (PI) current at the time this AusPAR was prepared can be found as Attachment 1.
II. Quality findings
Drug substance (active ingredient)
Catridecacog (rys) is a FXIII-A2 homodimer expressed intracellularly in Saccharomyces cerevisiae and is identical is structure and function to cellular FXIII. The rFXIII monomer is a 731 amino acid chain with an acetylated N-terminal serine. There are no glycosylations or disulfide bonds present in rFXIII.
The relative molecular mass is 83,179 Da.
The primary structure of the r FXIII A-subunit is:
SETSRTAFGGRRAVPPNNSNAAEDDLPTVELQGVVPRGVNLQEFLNVTSVHLFKERWDTNKVDHHTDKYENNKLIVRRGQSFYVQIDFSRPYDPRRDLFRVEYVIGRYPQENKGTYIPVPIVSELQSGKWGAKIVMREDRSVRLSIQSSPKCIVGKFRMYVAVWTPYGVLRTSRNPETDTYILFNPWCEDDAVYLDNEKEREEYVLNDIGVIFYGEVNDIKTRSWSYGQFEDGILDTCLYVMDRAQMDLSGRGNPIKVSRVGSAMVNAKDDEGVLVGSWDNIYAYGVPPSAWTGSVDILLEYRSSENPVRYGQCWVFAGVFNTFLRCLGIPARIVTNYFSAHDNDANLQMDIFLEEDGNSKLTKDSVWNYHCWNEAWMTRPDLPVGFGGWQAVDSTPQENSDGMYRCGPASVQAIKHGHVCFQFDAPFVFAEVNSDLIYITAKKDGTHVVENVDATHIGKLIVTKQIGGDGMMDITDTYKFQEGQEEERLALETALMYGAKKPLNTEGVMKSRSNVDMDFEVENAVLGKDFKLSITFRNNSHNRYTITAYLSANITFYTGVPKAEFKKETFDVTLEPLSFKKEAVLIQAGEYMGQLLEQASLHFFVTARINETRDVLAKQKSTVLTIPEIIIKVRGTQVVGSDMTVTVEFTNPLKETLRNVWVHLDGPGVTRPMKKMFREIRPNSTVQWEEVCRPWVSGHRKLIASMSSDSLRHVYGELDVQIQRRPSM (731).
The higher order structure of rFXIII (A2 homodimer) is shown in Figure 1.
Figure 1. Higher order structure of rFXIII (A2 homodimer).
Cylinder: alpha helix; Arrow: beta strand; Grey sphere: active site. N- and C-termini subunits are labelled.
Based on the long term, real time, and accelerated stability data submitted, the proposed shelf life and storage conditions for the drug substance are supported and considered satisfactory.
Drug product
The product is supplied in one strength of lyophilised powder for reconstitution with a diluent vial containing 3.2 mL Water for Injection (WFI). The pack also includes an adaptor with filter for the reconstitution.
The product is to be reconstituted with the water prior to use and may be further diluted if necessary. The in use storage conditions are 3 h at ≤ 25°C or 24 h at 2-8°C. The product contains no preservative and is for use in one patient on one occasion only.
Stability studies have been performed in accordance with the current International Conference on Harmonisation (ICH) stability guidelines. Based on the real-time, long term and accelerated stability data submitted, the proposed shelf life and storage conditions for rFXIII 2500 IU are 36 months when stored at 2-8°C protected from light are considered acceptable.
The proposed in use period is 24 h at 5°C ± 3°C or 3 h at a maximum 25°C for reconstituted rFXIII 2500 IU and for diluted rFXIII 2500 IU. This is acceptable.
Biopharmaceutics
Biopharmaceutic data are not required for this product because the route of administration is intravenous (IV).
Quality summary and conclusions
The administrative, product usage, chemical, pharmaceutical, microbiological and biopharmaceutic data (as applicable) submitted in support of this application have been evaluated in accordance with the Australian legislation, pharmacopeial standards and relevant technical guidelines adopted by the TGA.
There are no objections from a quality and safety perspective to the registration of NovoThirteen catridecacog (rys).
III. Nonclinical findings
Introduction
Novo Nordisk Pharmaceuticals Pty Ltd has applied to register a new chemical (biological) entity, catridecacog (rys) (NovoThirteen) for routine prophylaxis in patients with congenital Factor XIIIA subunit deficiency to prevent bleeding. Catridecacog (rys) is recombinant human Factor XIII (rFXIII) produced in the yeast S. cerevisiae. The product will be supplied as a lyophilised powder in a glass vial containing a nominal dose of 2500 IU (15 mg). The proposed dosing regimen involves injection of 35 IU/kg (0.21 mg/kg) once monthly.
During the period of pre clinical investigation, the production site for manufacture of the rFXIII was changed from Avecia to Novo Nordisk. The sponsor indicated that no new impurities were seen in the Novo Nordisk material, and performed a local tolerance study in rabbits and a repeat dose comparability toxicity study in rats comparing the safety profiles of the materials manufactured at the two sites. No differences between rFXIII from the two sources were observed in either the repeat dose toxicity study (NN209502) or local tolerance study (NN209504). The pharmacodynamic (PD) activity of the product from each site was not compared in PD studies. In rats there did not appear to be any differences in systemic exposure between the Novo Nordisk and the Avecia drug products in the repeat dose toxicity study.
The submitted nonclinical data were in general accordance with the International Conference on Harmonisation (ICH) guideline on the nonclinical evaluation of biotechnology derived pharmaceuticals.[3] All pivotal repeat dose toxicity studies were Good Laboratory Practice (GLP) compliant. The sponsor used two animal models to investigate the kinetics and toxicity of catridecacog: cynomolgus monkey and rat.
The sponsor included a number of reports not directly relevant to the present application. These were combination studies of catridecacog with rFVIIa in monkeys (NN205070, NN205148 and NN206100) and combination studies in vitro of catridecacog with protamine and heparin. The relevant results of these studies are discussed under the section ‘Secondary pharmacodynamics and safety pharmacology’.
The sponsor also included repeat dose toxicity studies conducted in rats and beagle dogs using rFXIII produced in a different strain (ZM146) of S. cerevisiae (SNBL.002.02, HWA 2642-100, HWA 2642-101, HWA 2642-102). rFXIII produced by a different strain of yeast is, by definition, a different product and so results of these studies are not directly relevant to the present submission. The sponsor indicated that they were included as the studies are referred to in several minutes from regulatory interactions, and because the data provide information on the role of activated rFXIII (rFXIIIa) in relation to the observed toxicity. The greater toxicity seen with the rFXIII produced by ZM146 was thought to be related to the presence of greater amounts (up to ~13%) of spontaneously activated rFXIII (rFXIIIa°). The amount of rFXIIIa° in the material produced using strain BJ2n-5-La for clinical use is stated to be 0.80% with a potential increase of 0.1% over 6 hours of use reaching a maximum of 0.9%.
It was necessary in many places to distinguish between the unactivated form of rFXIII (catridecacog) and the two activated forms of rFXIII (rFXIIIa* and rFXIIIa°, thrombin activated and non proteolytically activated, respectively). rFXIII is in reference to catridecacog where this avoids confusion.
Pharmacology
Primary pharmacology
Catridecacog (rys) has been developed for the treatment of congenital deficiency of Factor XIII (FXIII). The life threatening consequences of FXIII deficiency require prophylactic administration of FXIII as soon as the diagnosis is established, usually in infancy or early childhood. In plasma, FXIII circulates as an inactive zymogen heterotetramer (A2B2) composed of two FXIII A subunits (A2) and two carrier FXIII B subunits (B2). Following injury, FXIII is converted by calcium and thrombin into the active enzyme (FXIIIa): the FXIII A subunits are released from the FXIII B subunits, and the active site of the FXIII enzyme is exposed (Figure 2). Factor XIII is the terminal enzyme in the coagulation cascade. Thrombin converts fibrinogen to fibrin monomers, which polymerise and form a fibrin clot at the site of injury. Factor XIII then stabilises the fibrin clot and increases clot strength.